AU2014201027B2 - FAM26F polypeptides and polynucleotides, and uses thereof as a drug target for producing drugs and biologics - Google Patents

Abstract

This invention relates to a novel target for production of immune and non-immune based therapeutics and for disease diagnosis. More particularly, the invention provides therapeutic antibodies against KRTCAP3, FAM26F, MGC52498, FAM70A or TMEM154 antigens, which are differentially expressed in cancer, and diagnostic and therapeutic usages. This invention further relates to extracellular domains of KRTC AP3, FAM26F, MGC52498, FAM70A and TMEM154 proteins and variants, and therapeutic usages thereof. 1728,8 + + -4 + + +N -4 '~ + + C C CD c (D + + c) C - - .9C?99 6 "(N N (Nj ce (NJ I~ IN IN pN C fl~c)Y) CY~ I CY 0- E -3 a) M CUB () ) a) a -c- , Ed E E E 0 ~ 0 E __ 0 2 n uj ) ~ S~ ~~C -~ - -L U~~ ) a ) cu 0 S_-a

Description

POLYPEPTIDES AND POLYNUCLEOTIDES, AND USES THEREOF AS A DRUG TARGET FOR PRODUCING DRUGS AND BIOLOGICS [0001] This application is a divisional of Australian Patent Application No. 2009325878, which claims priority to U.S. Provisional Application No. 61/120,540, filed 8 December 2008. The contents of both Australian Patent Application No. 2009325878 and U.S. Provisional Application No. 61/120,540 are incorporated herein by reference in their entirety. [0002] FIELD OF THE INVENTION This invention relates to KRTCAP3, FAM26F, MGC52498, FAM70A and TMEM154 related polypeptides and polynucleotides that are differentially expressed in some cancers and specific blood cells, and therefore are suitable targets for development of therapeutics and diagnostics, particularly for cancer therapy and treatment of immune related disorders. [0003] BACKGROUND OF THE INVENTION [0004] Tumor antigens are ideally positioned as biomarkers and drug targets, and they play a critical role in the development of novel strategies for active and passive immunotherapy agents, to be used as stand-alone therapies or in conjunction with conventional therapies for cancer. Tumor antigens can be classified as either tumor-specific antigens (TSAs) where the antigens are expressed only in tumor cells and not in normal tissues, or tumor-associated antigens (TAAs) where the antigens are overexpressed in tumor cells but nonetheless also present at low levels in normal tissues. [0005] TAAs and TSAs are validated as targets for passive (antibody) therapy as well as active immunotherapy using strategies to break immune tolerance and stimulate the immune system. The antigenic epitopes that are targeted by these therapeutic approaches are present at the cell surface, overexpressed in tumor cells compared to non-tumor cells, and are targeted by antibodies that block functional activity, inhibit cell proliferation, or induce cell death. [0006] There are a growing number of tumor-associated antigens against which monoclonal antibodies have been tested or are in use as treatment for cancer. The identification and molecular characterization of novel tumor antigens expressed by human malignancies is an active field in tumor immunology. Several approaches have been used to identify tumor-associated antigens as target candidates for immunotherapy, including high throughput bioinformatic approaches, based on genomics and proteomics. The identification of novel TAAs or TSAs expands the spectrum of tumor antigen targets available for immune recognition and provides new target molecules for the development of therapeutic agents for passive immunotherapy, including monoclonal antibodies, whether unmodified or 1 armed. Sh:v aninsa also ointtheway to ore effective thepeuti SO pcines for actieO a tV munteav W007 Cancer vaccinaon inwhles the adnim tions f tno"angns - si a usae to break imune toleunce and mduce a ac iet -ce i tespoAse to the rum \ Vacie theranv tludes the use of' nked DN\ prpides. secoobinant prote o at whote cell therapy where the pat en own tumoe cells are toe ah th source oa she ICCete, \\ith the sientficatnon of speciti umor awlens vuacmg atu are mor lten eamed out bs dendrittc cell herd% ho & de cels att loaded Wtth the teievtimtt protemn or pCetx 0s 'tu'sfembuclh vector Na \ or RNn [OOUSI The mnajor apiations of anti -TAA atAnbodiesfot rattart of caneer ares heny with an'ea e00ody; thempy with a drgacnjugated antibody and onn therapy tsa rendar Tnunitk~e si nce their discoer. antibodies enetwisionied as "ina2ie bulhes that woukd deliver texic agentts. stich'c~ a s. toxti.s enzyrnes andi uaioisotopea pecalv to te a 'd samanianghe nontaret normal s toss ixe d xndee (1nutibodis 'and in particuar aatsbodv framents. ca n neden as rarriers 01 cyt~ otoic substances such as ltdO$stOpe5 dOgUS and toxinS. lrnracuotherapv wth sucle anpathand cornjaed antibodies (such as Bela ad Zevaln 1 trea ing hetoloaleda ndinar wec l *onh odest success has brs"acsed hthe unimonothemp of slid tumors. One of the major onionss in successful appucatiof ofimnotherapy to soid tImors is the large roitular size of the intact inlunotlbalirn that results in piioniged seum half.l1f bt in poor tumo penetatin and upake. Indeed only a ey small amount of adaninteted antibody ( Ma low as 0d % eaches the tluiot. lk atditon to their i antibodies encounter other impediments before reaching their target antigens exressed on the c suace of soli tunrirs. Some of the barner indlde poor blod How in a tmrs. pertiihmtAy Ot vascular edotheiumelevatd interstaflui pressue of tumor [00101 With the advent of antibody engineering sml molecuar eih antibody -ragmnsents eti ing proved tnor penetration have been generated Such anybody tagets~'l- are oien cionugnated tospctinc cytotoc noleerdes ari are desinedoo -8 s.eietivei deve ehm to cance eW tilt. slid tumors irana oentidablenchahenge for therap even th rtom uoco iated awtibod 'agnints k t jine new wve ptisiita en svntee es ihese of bh:oiattm ;Otodifiers to nSoNdate t "te impediments posed soid tapor.Thus n cobinatioto antoder theiro umin nt ibodstfag~ents S v .ager% ar' bein med to mpr P the tumor bo flow, nuance v fa i pemabuityower tu mo urtat Oid fenre 1 ndulaagny trat cotl, and extracelimar ratr< components up3'gn inte t'poar> of target at gnaad inpoe puematio.n and retention the terapee ageI [10121 !imunotherapy pwih antbocues repxseens n exci ug opportuity foe crimntinhstandard modaliies sih s cheniothen . as well as inationS wit diverse oloeiycal to. a y g -e . n tCo t$tan tle mrAbs ame moretffective when used in combumaton with other terane agen ackiding oter natibodies [0010 Passie tumor itoenoterapy e the eqmuse specificity and tyticapabity ofe ime syemw t target tmr seei eating anir aiua mease wit t4nimuma of damageto nornit isse Sevrlapproachesihae been used to identify tu r scciatepd agntas.targ candidates foe nmamnotlerap The deurTion o novel tumoreefi antns epamds te spetm of tumor antigen targets avaihble for immune recogni on and pro idenew tov w iolneulIs fir the deWoprent Of theapeeNC agetfs toe passiveinmotherapy iflclding m onoctoni antibodies, whetherunmodooied Or amied. Such novel antigens may an goat thePO Me to mom cfW ecwi the rlrapen, ac active or adagtive mmoterapy [0141 Desupe recent press in te cndvstaning ofcaner oay and cancer treament. as wet: a better wd n l the rdotectIts navolvecn immune espo the sces Me fi cancer tenp and fo e atme m e ratd disde remains to Ieroi ee is an mrneed orew tlteraeo which can successfully ra~t both cncer af n ;mune mnsised disorders, [0015,1 kRIEE SUMMARY OF THI INVENTION nuc1e In at leaet sonc whi nrisi f te onpon dae novel aieunO acid and nucei aid ~ertncs. h~h or aiintsof thecortespwtdill aritirt ed sde sad -anc n tvoe for kDWwn or 'WVT' iwild typtr KRTJCAP3. FA VM26FMC52498, PAM70A. or TMEM154. respectively, Accordin io at least some ernboments t the preaem invention, the KRTCAPS FAM26F, MGCS2498, FAM7A. and TMEM 54 protein na are d iff~estial x p sed by omI (O3cers and specific blood cNlws, and trfore are suitabie targets tot etmeert therapy, treatment of .imune related condfittitms, and dirug development, As descenbed in greater detai.1 below, the terms "polypeptide' :and'"protms" are used to dsenbe specific varNants die known protins themselves to deiived amino aci sequences related to KRTCAP, FAM26F, MGC5249, FAM70A, or TMEM 154. or ftragments or portionts of ny of the above. [0017 In at least some embodiments, the subject invetii provides novi therapeutic and dag~ntie compositns containing at least one of the KRTCAP3. FAIM6FMGC52498 EAM20A, or TMEN154 protein. or variants disclosed herein. or rucleic acd sequences [OiiIn t east some embcdnentshe subjeCt Invennon provides discrete portions of KRTCAlPY FAM2E M"414524970 10 and TMEN54 ai variants. and ie' seiac K equ necdtng a.met Or fragmeschereof [0V10I It at least sogme enootinees thae eatetinvention provides a secreted for o TM E:M 154 ooteuiNs, *pee'6tlly the etN ia d<3Zmiri jlssECD) of IMEM 54proteins d nzleic. ae d se nces encodint same or . gments portionsor oor conjagates there mi compsitions Oomprsing Same [O.201 According to at east soine embodiments of the present. veetion the poyptlides ccrespondng. to an etaceular domain of TMEM154 proteins are used a theraoendt agents for cankeIherapy treatnem oenasne reatd conditions ne du deveoprnt {)W21 : In at lenst some embodiment the sutect tntan prendes po1ypeptde corresponing to ani etineeluhir domain of RIAPa3,FAM26P.MOC5249h, PAM7OA proteins and/or newv variants and. nrecle aendlequenc encoding same or ragments or homtologous thereof. [0022I I at least sonie embodiments, the suteet inventon provides therapeutte ani diagnmistic antibodies, antibody fragnts and compositons Comprion sane and thera ies and diagnostic nethods sing said antbodies and annbodf Owlants taspecinezay bind to any one of RTCAtFA 26F M0C5249; A 7 and IMMi p4ooteinsor varant, or a solbleo or extracelliar portion thereof. especiva y the ectodnomai. or a the unque brAdge, edge potion, tii Or head portio thereof. 00231 According to at Meast some emTOdiCmtS of the present nvention, the KRTC AM FAM26Fj MC5249$ FAM70A, TMEM 54 protis o nd/or vaants polypepideS aid miccleic acid sequences are used a novel tarts for developmen t of drugs which specificaly bind to the KRTCAP3. FAM26, MC5S2498, EAM7A. TM EM 154 proteins and/or nmw variatpo and/o drugs which agonize or antagoniz the binding of othei noieties tW the KRTCAP3 FAM26F, MGC52498 FAM7A, TMEM 154 proteins and/os new 0211 us, in a least sortie etadiments. the present invention poades KETLAP3 protet and no''e1 variants of a KRTCAP3 (SEQ U) N O:7) Keaocytes*sided profan 3% discrete portions therot and polynueleotides encoding sameo and URTCMAP pSRpemides and discrete portions tzereot aid polncletde encoding same. heh cun be di 4 I didiginOsti 151NM rki' d/nif Mi futa.5it 101 cian:ti theapy trattiiznt of itOV$On b ed cndonfad dog dem ent and ateapende egets which agonize or ntagve he ending of othrmaoieties to the KRICAP3 proteins and/or which agonies or antagoinite at enz one KRTCAP3 reated bioloacal etisowy 4ii21 Accordng to sorne embodments the present :venion provides an oted polyped selected from W93941 P13 (SEQ 3ID NOAO W9394 _Pl4 tSEQ MD NO"1 'W9394JPl S SEQ HD NO: 13). 0ra fracinet or' a ain hrotta losses es 85, 90, 95- 96 97 98 o 99% eggence deptty therewith. C0026J Accordmg to some em inents of the pwent venuon ther pro vded an Isolated polx epude co.nOn 5 on a un urirge etdgt tal 5had porin of KRTCAP3 no\e'riants, rahmor a lnologue or a fagnt theaof as wyet as nwel eic acid sequences encodig the unione b e ede tIl or head portion. as well as fs thereof and coM'Nga and the use thereof as thesapeutics and/for for diagnoshes 027 \cording to at east some enbodiments, the subject inetion provides an isolated polypeptide conip trng an amnto aiaqenefament of au on of Aeitqebig ede, tail or heAd poron sected Mthe gnsup .tg of ao one 'o'f S D NO; 146, cOnsponding a anmmo ankd residues 72 - 97 of S943*P SEQ ID NO 10 SEQ ID NO: contending to amino arid nsahies 206 221 of W93943 P 1 SIEQ ID) NOu 11) SEQ ID NO: 148 corresinding to amino acid residue 2.06- 231 of W93943 P7 (SQ D NO;) orsa fagment or vai ttthereof that possesses at least 85. q0 5. 96.

9)7, 98 at- 99% cu cient trwthAcctn a eat50Ct nxt as u ject nentin pr &oie an aised poypeptide aing an aun acid et ence as set fort in any one of SEQ 15 Nds:146- 4 [00281 according to at les some efod men anect imeion :wovides polypepides coipixng aequenee o anno acid residues corrsponding t disrrte portions of the KRTCAP3 proteins. nciuding different porthions f he extraceiiunir domain c~onespoiinL to reidue 4 of the KRTCAP3j pin "K quenCe contained in the He)ence N% t4 P SQ N 3943 GS kQ I N WV 43 P i$ "1 NOtW 1 nd ~ 0)4 ~P 9 S Q iNO13 or eid1ue 5 62, i A protela seqjuaneconiated in thesequence oW9*394OI m SEQ D 0): W) M Y 14 (SEQ ID NOI nd W 3943jPI (SEQ OD NO, ! r , endes2 ofthe KR itC AP prote t sequence continued i the sequence of W9943P s ID NO 0 corresponding to amino acd sequence depicted in SEQ ID N0,49. or rous 77d91 of the KRTCAP3 proein sequenc cntined inteseqience of W93 15 SEiD NO cenponcig toanirno acd s ce dpced inSEQ i-r N 0 o4es 14JS of flhr KRTCAPW3 Protein seunecnanda h euneof 'W9.'3945 -- f" I SfI ) .0 NO' 10) corespoding to amino acid seq nence depicted in SEQ ID NC:Q or residues 115 1 of te kRCAP3 pntein sequence contained in te sequence of W93943 _P1 (Si - ID f<, 3 cc onrsponuding to amino aci aquence depicted in SEQ ID N- 5 o fagmento or a r ant thereof possessing ateas 80%,' 5%9% 0.: 95, 96. 998 or 99% ntience 10091Aco'ho O t east Snte etittodinint te snoe itt nr on proides KICA P3 aino e xequces selected rnti any f te solated for rabbit u a ran ce mbodiees ducti.an ar avrto acd sequence as set fh i h any one of SEQ ID NOs% 1 116 or agent or a v'aant thereof possessing at ean 8l)' 85o % a90% 95 , W 7. 98 or 99% ience deit 1 therewitb [O nO] Accodin toat least soe embodiments the subject pentio provides isolated ntclcV'dcwce nodn n of, the toregg oitn K-R.'( 1CASoot3 scxisena domia polypepides orrgonat oroeis themof. [003M] Accorxin to at least sine emodxients the subjecinventon proides an isolated ponynudeotd ncorinj a pal epeptide conpiing any one of dhe anino acid sequence, ai ret forth in IT) Q N:P,. f, 3 47 , 146448 or a fragment or vacant (hemeo that possesses a let80 8 0 9 6 97 98 or 99%sequece tdent therewih [OO321 According. to at iXOt soie tm4ohdIat .. {he sbjet. naenn0argovdeS' an taoiated pOit i &otIk.ctimlprlieina nucleic acihaving a iveciic acdisequence a et fhrh to any Oaor owla' rQ3 3 hVSLEQ ID NOC'3 W 40 SEQyD3N4W (SEQD O f a ragm'nt thereiot r s nef homd l us theaeto that pSeStS atleas ebdiunts, rebe n geaen is SCSCutO 1OT a groupO coinrisn anty one of SEQt It) NC)2 9. 94.9-5 ra maneat rt f o qewe homgos tereto Accord~n to another cioinent he isoimet p eInddCte~ i at t'st 80. 85. 90 95 96 97. 98PM M ortohtns. . a nucleic acdd Seoomne w" "et toritl ima n o E 1 Ns:2 .4 6. 9, .:,4, 19315 In at least n bodime5 th present nventon proadee ad dscete portion of hypothnetical protein 1L&44 1168 dSEQ (SWiss t accession idener NF ~ 0 99 FM6F0or p tone coudes encodte same. bich cat be used zs; tic maers oardor an targets for cancer themrap teatmen onmm ne relaed hab dn i f ote FtAenklit to the AM.26F proteins and or wch artonze ng Accorwding to at leastl somse cndienth suject irn onpo:ds pulopepades comipi on a sequence of auni o acid sides ot cesponding to discrete potiams of the FAM26F proteins. idna different prions of the eureellam at dotan corwespomcing to resides 4Pet8 of sequenceUs o 8290 4 StQ O:S cresponcdng to danino acid sequence depicted i SEQ ID NO: 52, or esidtues 125-175 o fences o' T82906J SE 1D NO::18cospondig to amino acid %equec depicted in SEQ i NO, or esRdt S 2 14 of 0eenes of 82906P3 SEQ ID N0:16 correspondirng to amino acid sequence depicted in SEQ it) NO: 27 or :,ag nts or vaiantsa ereof posses aleas 80% 5% 90 95 9S 97 98sequenceien mem A Accrdngto <a least soni m oe n, (he sujctlnetonpoie MAMA tmnino acid seqoencesi selected aiot c4,, ,the 3sotate polypeptiu used. for rabbt nnoation and specifi antilode pmaon'tton, avn a n amino acid sequence as Set forth in any one SEQ iD Os or atmIt. or a varint thereo pOssessing tleast80% 35% 90% 9596 97, 98 or 99% sequence identityherewith [0033] In at least some embhodhimns the present invention pmavides .MGC52498 proteins and nove viants of a known hypothetica protein MGC52498 (SEQ RD NO: 32) Swi ssProt accessio identier N P_872427: LCMM8378. discrete nportions therof. and polync0tides encoding same, and their use as diagnostic markers and/or as targe for cancer therapy, treatment of immune related condition and drug devel opment and as therapentic agents which ageone or atagonize the binding of other mtoetes th! MOC7S2498 proteins amd/ct which agonize or aitagoalzeat least one MGC52408 ielatedi hirdoi' actii. [00341 Acordhig o some einodments the eent etio providean isoMated polypt i-de teeted from AA2I3820 Q NO 19 or a fragment t or a variant thcseof that possess at least 801 8 90 95, 96, 97, 98 or 99% seg ce ideniy therei& RIO0 ] ccodin to some emrzodtments of the preen ieit them s V vie aok noted polypoetde compsnoga unique airge edge. tailor head potion of MGt25N491S novel variant, or a homoigue or a fragment thereof as wet as mucleic acid sequences enicodinqg the t bidge ue t il or head ario a e as Inignent thereof and Accrding to at least sonia emrbodircn a Me lobect veoItior p~vo an 1.olatec poivpeptide ccmprigan armn acid oeqfence o e ue ad portion AA218 2OY6 (SEQ 099 coson d o amio acid res.dues I 64 AA2 382026 t.l2:Q iD N 9 as set fb rh SEQ NOD N1 ' , 25o: a ftrignent ow variant theremof th"a posse at: lest$0 . 9 5 9 9)7, 953o WM' 99kevec dentityteeih RI3~Accordn to at least sorte eodinrent4 the.sobjectinenet~o pioides ant isolated -- ~ec in~ -e piuvi..x an Cfl l etde ha k -n . g uanao aid sequence a a rorth SEQ iD NO 25, [00W According to at least seme embodinents the subject invenelon provides potipepudes comprisings a sequence of amino acid residues correpnondlt tn discrete portions IGC oth.MO24S1f proweins, inciochn, -diffont norlioos of thJutaeloa bo tn cortespondintg mo des1 5 of te seue AA233820P4 SEQ 1D N:35) coresponeng to aminoacid sequence depicted in SEQ ) NO60 or residues 91. 9 of the sequences AA21 3820{P SEQ ID NO:135) co spending to auno acid sequence depicted S S9Q ID NO:61, or reaes 41 of the sequences AA2 3820P6 (WSEQ TD NO 91corresonding to amiuno acid eqae depited. in S.Q U) N 2, oragment. of arias thereof passing at las 80 %, 90% 95, 9Q 978 91 or 9% sequence identiy hletewihi "Womiit k)93SI According 10 Lt least sornw ens hod eu the enbjec ineton provie potypeptides canpAg a sequence of amino cid eTsdes corresponding to disretc frngmenis o MGCS2A98. seected fron the group co sisting of SEQ Ii)Nbis: I50154. 00 or fagmens or vagrants therof possessing at least 8O 8 0% 95 %V % 98o 99 quence ideaaty thMrew . & [IP9 Acaording to at east so embodnant the subiec invention proi de soAted om ail pa pnles evr fragmenlst o -. .iolo ef X441~ According t at et some inenthe bject inetion poides art i soted pegndeotie coding a poiypeptide cmipoig any one ofh at s adseienea sefi '1 4E 'Q 10 NOt 9, 251 60. 6 1, 62 50- 54 00 Or aa mmat or vacant the21of 0 iat pssesses at least 8, 90: L9) wiO 079 98 or 09% 99 etequeInce identsty therewie., [00411 According to least some ermodiments the subectitiventa prides an solate py totdde comprising a nucleic adwd as set for'di in SEQ ID NO20 or a fragtmen teno a eqn htC.Cjt3 nlome ris there to nt p' gesscs s ast I0 85. 90, 95 96 9 8 or 9% sequence identity therewh. According toa lease emod mets. he subject ineIn t-hci- provides an isolated polynneiotide comprising a uuelete acid oguenceselected furm a group comprixsig any one of SEQID NOs 2. 910 201 or a ftragrent thereof or a sequence homolousrs theret that possesses at east 8 8 90S 95s 96.97. 98 or 99% sequence dent-y I-erewit [00421 -In at leat some enbodimenis ti preent inen rodes FAM7A prot--' and novel variants of a known hypothetical prt in FAM7A\ (SEQ T) N-9 SYissProt accessdon idenitien NP 060408 is crete' jfldOns thseot and polyumdeitidQ:N ncodingr samge, and payvnucleicues encocling same which can be uisedc as dlignlostir macikerc and/or as agetts for cancer therapy. trea ment otmnne csed cnion and drug, developroent. and therapeuic ags wich aosire or antagonize the binding of othwe movetos t1 h 1 AM -0 protein and/ar which gote or amagonis atleast one FAM0A ei ad bio iogicas acticvits polypepwe se1eced imn anyne of .9 SEQ ITNO .5) 06491>2 - ) NO:16 or a agment or a v--tant thereof that pssesesaeast 80 85 90 9 96o 98 or 99%seon ice identy lhherwi th 9i 0441 A in ome em odiment of th gracn viriAn there wde ut .oitd poivtaed3 eoari~ a o ehrdgede.'zi on hea pio o AMT ot ec a nnt haTof ea woN t ntlecic acid eoueacncodi he o h e rNesO fn dt Con h [O4S1 AccordIg t latest soie embteN s h bt Venon provides an coated ysprptie (a ~ psgn n d sequetic of anyoe (I the vunHice AsiaM. or head jipor orepon tn 6 to go [ ) 33 .11oe wss t forth in S E i o N' 1i. or amino lai seqenes set ort4 it) on o0 of $$ 3T)P N& 5 17 158. 60 19 99 or a ragw nt or variant thereof that passed "at least 80. 85 90k 96 9V 98 or 09 segae "e identity therewith. 100401 ccdi:toat least sorne extodionamm vV tc inlven 'tio prnovide An ioae pO spepde hn. an amo acadsequence as set ,t. -m any one of S IQ NO. 15$ ab47 Accoding to pea unbodiak, rodIvl. the ieCat qeventeon Ride pAYpA Aiino acidsia slee of teaxis koted s crete portions of tho FAo M s()A roex a incltdng d ire orons of te ene IWdar doumi Os:,k~o~d I)).s ,86 or, a lmmet or . af varian thkoses SEQ D NQ 3 649JaSEQo ID Nne:35) ofrn Qo am o d equence a-la in SEC) 9 9% or Q 0- of Ftt0649 dtth4 SQ D 101crn to a teu east s ND55 rept arem p desence dnpctedSEQ D NO oesii MA ofh se E Q644 D NO wrrespoNintg to anno MidI sequence depicted in SEQ ID NO:58 o resides II >20 01theseqenc I'I%40 93 SQ.> O36cnopoigt oinat dep ted in SEQ In NO :9 redues 25 o8 he sequence E0649 (SEQ ID NOzSf or residues 80-15 of the seg ance 010649W STEQ ID N . 2 O)trSpoNding amnocdneceepitdinSETrvain s poS \e5s. azat 80%. 25%. 90% 956, 97. 98 o99% equence identt therewh [DU499J Accozrding to teaome embodi ents theu seet ent o provides listed icac add squencegnoodn9g ay of the foregoing RAM7{A proteineeiracedula domain. polypepi des o framet r f homelogou Stbereof, [O05N (cordeo gaeast som e embodiments, the subeci Ins emo provides an iolad poymn cleolde encoding A poiypeptide omping any one f te amiio aKk ! ee et fort SEQf NO 5 5058 121. 155-160, 126. 196. 199 or a Agment or varant thereof that posses ,uat least 80 85 90, 95, 96, 97, 91 or 99% seqtcetdet thereiNhi [1P5311 Accordig to ateassome embodiment the subjectinvention plroides an rated polyvntlendde compising a m Inuclc acid having a nulic ad see c as set fhrud tn one ol.Q6494 (EQ ID N24 E1)49 6 {Q U) NtO o60 ragmnt tereot or a sequence at imi 8 9 8 0 9 9 7793 or 99 homolog s there. We t atest some embodtaents the foretgsing agment ompAses ny of the nuceic acid as set forth in any one of SEQ D Qr103. 197. 192, or a fragment thereof or a sequncelCC at least 85 90 95 9,97 98 or 99% hom lAgok theto, U00521 tn at leats embodiments the present n veation pmvidespo us and discrete portions ol a known hypothetial protein PL C2017) (SEd) 10 NO1.1) (SwissP6r t acsaton tdemlienris paschoide encnr same ich can be Used aN dzgnost esathrs andrr as tamtgt tot cancer therapy treatttet ofIn.uOC relsted ondhtig and drug evelopment, and therapeutic .aget ich agonize or antaganime the iinding of other nietoes t theMEM 4 poteAns andor which agonize or Ci~ttgfn~ t tcaa (}nc T(mw A 5 Tented biological acivity. polypeptides comprisg he soluble Mctodomahi tECO) of the TM4EMl! 54 proteins andi n~tst5 andconates thereof. as vel as nuaclei aci SeueneteCodig said soluble ectodoman and these thereof as theapetc fO4I According to at least some embodimen h ubject irnvion pntvides poypeptides comp nsM a sequence of aino aid resatus corresponding to diseae pOrdens5 of the 'MEM 134 proteins. inchuding different poltions oft the e racedlahr 4omi~ W386 P7(SEQ ID NOA6L conrespondagl5 to amina acid sequence depleted in SEA) I N:63. or residues 20105 of the sentence W38346PA SEQ ND NO:45) corpnoonding to amino acid sequence depicted in SEQ 1 NO:64, or isidues 122 - 44 of the sequee of WY38 36_P7 (SEQ ID NO:4~6A cepodn to amin[o~ acid dpicted iSEQ ID NO:1i62 or fragmuents thereof or variants thereof possessmga at least 80%4 85%, 90% 9> 96, 97, 98 or 99% equnt ideitr the rei di 0)0551 According to at keatson emboctinents, the ombjec nwenn pres T'MEMV24 iia acdd srAences selected trotn of the ooited polvpeptdes Cad tabrit inmnunizrio andspeo z atibodies pxrection.. Avig r anc;ri vuto " actOerlun as st~t for n any one of N 9 orin ant o n vaintthenofposfesin at ,east 80.85%, 90%'. 95,16 70 t0%sqec dniyteeaa WOO6 ' .. t at leas sonw tmndme t th wsbet in vertiot; provides isolaed :a akn( aidsequences erncoding an of the tottgong TMEM 154 protins extracellar don ajrt poaNypeptides o n Uragmments or m udhere [\#7 according to at least somec embaodiments. the soieet itiefltioi provides n moed v'ntk~p ie aon~rsny n Ali ri set forth in SEQ ID NOs: 63, 64s 161 162 o a fagment orant thereof that possesses at eaS 80 5 90,. . 96. 97, 98 or 99% requence dtiefrre\idh [00581 Accoring to a least sote bodimentsthe srbecA invention proviesan ioted cooprising a nucleic acid as set forth in any one of QI1 NO:23,06 or 0 S 9fl . : " 98 99C -a.nbeao a seqene at kait se0 s .,90 se Qo 98 .99vrsni gm tratrtnteroto sern theuro. According to another eiuhodrmcnt theo ted polyrmceotide i~s atlaast 84 85. 90. 91~ i , 18 r 99% homologos to .a nncoc acid oquw:nca ettrenayoe of S~ ID NOs: 23 06 [00591 Ac 'coxdog to at least sine eombodirnentas 'te subject invetion provides anyof the foreging polgpeptlde; correWponding ay one ofhe sw!mbje. T54 proteins snd/or M prote,>4s extnaceillr domai, wherein sad poJypeptkde bloks or inhibits the nircion of IAEM 154 prote swimt a corespo ndine tmetionaL gnd [00601 According to at least some embodinrns he subject vweton provides any Qf the egoing poigfpt~des c~rresponding to any one f the soble: TMEM15 proteins adio TMEM154 protins trace ar dainswerein gnd polypepntid replaces or augments Mchuminertohn oft IMI NI>4protens ih. orsodngtntoa ,n0 9061 Acceording to romte emthoimxents kf the preset .invention them~ iN provlied a insuon protein, or a nucleic acid encoding same, comprising an .isolated or purified TEMEM 15 proteins antd/or ^TMEt 54 poteins exttracelular doman or fotamenhs or variants or homologs thereo. According to some embtodiments of the present ivenion, the fusion protein, or a micleic acid encodi ptionaly may he dimecly or indirectly attched to a nonTMEM 54 protein or nucleic acd sequence. respectively, 00621 According to som embodiments of the present ovention the non-TME154 protein or neteie aci sequence i at east aportiun of soluble ummunoglobuln domain or fragnen t (&I06~ Inanoter ebodient he ms'enindcudes ami ofbte freoohw in fusionprtns wheim a polyalkyl oxine moit chas polythy 'ne gycol ei attached to the polypeptide. (00641 in another embodiment the invenio includes ay of the foregoig nuon poteus wherinn the irmuunoglobutin heavy cnain co(nstant region is to bc fragiment [00651 In antereino ie tbem SnetinichdW any' of the- foregoingfsio protewins Wmb ~bgy h tntei 1 isotype selected P'om the group conastig of an lgG g1. ig.W igNg A aae [0066 I another embodiment tie inan includes any of the foregoing fusion proteins wrT t he povietd is usd ti\A\,dona, [00671 n another eibodinien te sendon inchdues any of the foie in fun protens where nthe tusson protennmoetesilymphocyte actititton. (00681 1nao1e1modmn the- invenAon include, n'oftefrolg oppie. attached ~ ~ ~ O toadtetbe rterape!utic rnoxaetv. [00691 Accorfig to 5On eiembOdin cats of the priest nveit on there is provided vetors such as p3smid and teabinant viral eir cntainin of the tregoing nuclc aci segences. ad host cela cotaign the etrs at press Io One of drscret poritons of KRTCAP FA M26E MdC249 AMOA M 5 o s Qbeeted or fbmntm and/oar the ECD' or aeunecon'sponding ~.Ip o bmige. ed~ge til or ha port of KRTCAP3 EAM.26F, MGC5249& F.ANM(OA. Mf"MN5 protehs Or homologous thereof or corn angates contatnug any the fretiolW (0070] Accordint stil other enbodinets them is fpolded ise of ay of the forgoing ctors n host ce for prorhicing matny Otne of the KRTCAPS A 42E MO(52498, PAM70A, TMIEM 154 polypeptides.

the KRTCAPI FAM6F,M 2, FAM70A, T MEM 154 ectodomain polypetides sequences correspondingf to a unique budge, edge, taid or head po~rtinI of RTCA P3 FAM26F, MGC52)498, FA M70A, TMEM 154 polypeptider. or a t ragmreni or a homiolog or a conlte thereof, coinpsing ctring the forgoing host c.l wherein the ce >resses the poiypeptude en coded by the DNA segment or nucleic acid amd recovering said R10t1 Accorg to anther eAadanert of a vention. th KRTCAP AM26 MGC5:249& FAMYA MEM S polvpepde' o g o o hereOtf ca, e Produced ua zaxj0ccof inccriia arm s'rt sucthods by r stanar so hasee teo hie 'olteud compttshn fn and ry the forgginng pouynncmkkd in! Rurhr crpts (nc00 r1 ii ptrhi g ph enota-"ima.elit fhen er Wo tkn attht ing hfrhome~ emoie rthe prenenun nctdsdhiraett e pmv ~tid mdr ane e nornast i and heroo nOsa a riar accet p rele di cnrn or cam e meth fr anth er ebent heneotand irdunes ae coniti aopig coniwsrin y of the f or ep Phnypeptepidescand/or. o f mpftO gmT71 Acaordinga to oreng of thepresent e thris g rovidd t'oolente ahnd s tnoac o iduhaing aTMaE0% 85% e 90%rni 9o% 96%~tt 97% 98%~t anntt or pentio mf rner acidne rth inc o : r o pdomt cping poeptih ith erenpaarmic oMEos5tion enpni.g any osne OE a MlCueAvi the, ex6tc ,a omlainofM 14rbpnae.o .tiiiernent or" varicanthi'nbm or fi -vf or pt.Yppidc.- eornpritrng a sequenc of amo acid re4ue ivine, at lea st $0% "35% 90%. 9OS i. 96"', 97%. 98%, 99%,tJtsneneidni with amnino aid set forth in SEQ ID NOsti. fi, or w afso According to at Neac "ain flbOcditnn cth a ISe W t 6 there & proIided auif the tO oo mhd for treat in or pre veninI cancer, Wheiur die cancer i seeded om he group con sning of sttomahematolged mAMgna eRe jnctudinoa not known!e to bran!stanter io.. brast cr nmt..aUiBcr ovary cancer ovamy carclnonma. endornetnal Colanrvvetnma tha&e C.oa b. d'ddr oZ2i1'o~tb h. aee c dey. numa and nots sma en cel S Ca n rranceathe. caneOe ps nitpccrinoma ;pch s . iea in"rnat M ranrerrg ceANretacnionaishd coln dencarcioaand en on adenoms p Stdte cancer inclucroig the A dvncted dase ematopoitic tumors f lynaphoid ineage 1 ecg.a lvikeran actet'.i t lph ocytt heinna.i coe lvriphocn ey entila t~elinphoinia ni mpmho an tr tnmp mvona, Eindgkin's Iyrnphoma, Nondodgkin's yphona anti ( t ( 1 , nx "c b) resi Stant .lvhon a tmelo eukendfr example acute myelogenottsekemia (AM~i thonic my etoos iekendag, hyroid cancer. thyroid lotiana Ic ancer, myect.odvspbasti ynarome 04D ttumoru of mesnchvmal ofigi eC5f .itti)Votnoas and rd~odnmyosarcomas) mel anomna uvealmelanmna. teratocarcvnomra neurmbtastonma. g omngae m tumor of the skn .g. keratcanthoinas hepaoceduWr CarctnomalWol[ar dendrit c cd carcoa intesna cace muscleinvastve crcosecredveetmr pdra aninoma.o-r k spicesjact.bade acr head and neck cancer, stomach cancer Ove cancer. hone cancer, bra cancer, cancer of he na.ihary cancesnall bowman salivary and caner cancer of uterus cancer o tesices. t axcr Of coflntectite :1,e\e plroemdq y er~ rph vyeod'slai.a nsgN mnacroemlob~naeto nmenasopharygealneuroendocrine cancer.ynemalasc scmme. miesothelioma, angi Q5'a-coma K'npn N ur'oria, carcinoi oesophagogastc. a othn tub cancer. perinel cancer papillary serons mul leahm cancer. malignant ascies astntesta romal tuner (GIST), and a. hereditary cancer syndrome such as 1-1.

Eravr!enI syndrome and on indan syndrome (V I and wherin dhe cancers nontetatatic. invasrve or mietas at c According o at least somne embodimentsfhe prsen inenonther is provided any of the tore cog methods fo treting o prevention cancer conmgdtg admiristerir a ubject i need there a o ng pcn harmaceutical comnposition ping any one of a soluble orecule having the extracellhear domain the TMEM 54 polypeptides, or fragnment or vamflt (i honologue or conjugate stereo or polypepide, compri sing a sequence of amino acid. relies haing at 8e-t 0 % ,5%. %%6% 98a 99% 9 00% RXIWOucn MRdtY With inhiwo ai~d K4UqwCw as Swt lIth n (aneOfSYJD,4 or Won ProNk or a e sed snc ce eucodina UO n or g1 nexplCvw veion vyy N k d k 1otam teg neado fOrt~)C4 Oe hOr perdi comp ingnfe tfned co nroaoda aicord wti heeianteriaseected rod lviomseciase f i y electd Nnm a Uy cna a nt n i eRd n ima b) ri antcir n hos n a ed M t cance. an/or creajc cncer psrac ardins toem e s eryl ns themtu; pkrde oas nenoi re aese rvbedg dans fte OncUOvei mehds Ten tneamiiw OfOeentia degun e r heatd madlien re ca dsorderneemnathe. i n e eatma cn taise r isorde is seuir bea dependent a betes MelS; typo a aete dio a soase mrmbhnous gviornemri onepthrGoodpastu'treni d sea auoman~c githrsbcvpen i.s mdoatf ehig>c£1s vu tK <d.ho rlarabmry vufg0 ii defula egonaed poyi Wyay emtpoyosiis y ayoge..% W ax:riease AamiOsaruun A netrc yseos aresyin pu rpan to de denantli. pt tr siitgedlas.isiri derie den ibs sitn. on dats n rnnSstn G raderous adi Iphhalina a mue qese paoise nron emnj actionpat a:ollagendsee ankyloug spond Cu pesrhids umeaseautlarisepnd sad perndwehignsgarusciihos is , gra'iTomatoy sis omi oscopii poly yoni ics htronos kin ds, oyodesdirhinodaoieen disease. nJouiA cehilhaadgateomnh dewle men ofi eAuinmme Atah ctr VNI Anscieodin s in Acquired emapahiaA Co Aguluif n Dli.au nseveigetis Optia tiff Pnaci tjnmO liisasesn p spmnardtis ratiicufits, easr a goutis anrth ind inrskos orders di soce sa pempp aopid ecrpriasis aseichildhoodti eczemm n rosacn i wcana. an~d acne. normoc3mpemnftnk inicanlal va eundsti ar pw ndnit tnyvdisanti pitnhetaise sndrome. adnis macrophage activadaon sydrome. Becheit Synone PAPA snde a sY n dome o d a juv s s dkeaws cryI pyrinnp.ath Muckle-es syndrome fanmial dd-duted .ui-Imflatory syndi ne.nenratal onset muisavatenric iifannmatory disea se. nt at~ii Me'eraea feer chronic inf anil ne e ogoic cutaneous and aucuhesndrome. systeamuc flieni diop artritiHype JID jk ydrw.ichrazees syndron and ANFrecepto assorted paeric Sy nd e TRAPS immune disorders ansciatedith graf ansppntatno reectin. saci as acute and chroniceoni organ uranspiantatao ahogeniesteml Ccei tantisgantatioaatoloaons tem cell anspanan.ahone nmano tinpation. snat versus host disease aiatory nowel disease Good pasture syndrmomne pem tetorms ateima. au~(ton mne atropihc astrats, aleratns cotis miet uleersucers. croni t bronchis coe ui~n n pvsulnimnry o inflation. irtwey hyere repo~nsi veness. epuc shiockit aflam sin th sorders myvogeksis a. ndrcocalcknosis h o erc oedeamarnd gnumlmn. (078] Acording to othe embcodinents of the present immtion theme is povied on a o p elyclona attdbodies and Intibod fragno s and conjugates containing such, that species bil any one. of KRTCAP3, 'FAM26 QMG5:.49, FAM70A MIEM 4 pneins, optmde and preferabl by special binding a s eece'seled frm the group Consit o a ol SEQ ID NON 7,S 10 9 R 29-3 , 3 , 42-46, 127,2 1 135 r IMM a frgnn o vwast orahmlo.e r qeadge; dge alchad pardonelted im a - o ' steI NOsan ln K I00 or a hagmen oa vana:.nA5 or a hopioague ar an ew- tpe thereof or a secreted form andor d ECI theeof selected froi SEQ ID NQ:0 64 or a raen or a atidari o ologue stereo or a peptide selected fronm my onw of SEQ IT) NW)s I 16. 23 V. ese atibodies are potential useful as themapetice/or dasnosuc agerin o beta I Vitro mnd in vive diagnstc methods). 0791Acrdin to at leas some enbodments of the invenon these antibodies are useful Pa eeai and scetig tOb~~i- di--kty>pic nttdis ocic threowhich also pare d usful 0as theapeutleas and/o dianostic agents (bot n1 ro awlnd dsagnostuc methrods) 08j Accordina to (t least sone enbod inen of the innton. the antbod es and tmaeienttoselae the acdvy e knd by KRTCAP 3 3 FAM2.6P MGC2498 PAM7A 11.1 o~r TMEM154 polYpeptide, and/or are immune activating or imune supreing such as a i or fragments Mhat target cells via ADC( (antibody dependent celhMar cywtOxiCityI Or CDC icAompent dependent Cytotax ictUy) anti viter. [0081i in anotherbodiment the inventor icudes any of the foregoing anbodies or fragmns theroft wherein said antibody bok or inhibits the interaction of an~iy one~ of KRTCAPA XFAM26 MC32498. FAMAA or TMEM1.4 polypeptidei with a cnreponting coterpart or cell ponent Or tiue structure promoting an oppose a,"3~t it t1w 0082 n another e Ibodi nentO nioln iahdeN any of the oregoing antfixtxes. or ramnent wherei said anod or pla es or agents tr intracion o an ne of KRTC AP3 FAMt. 6 F C5& 8 FA47 0A or TMEM 154 poep0des Jth a correaponding counterpat or celR comrponent or tissuestructure promting 'An opposite fundon or act vitv lo0sa Accordirg tr at leastomeebodents of the p nt ventothem is provided pbarmnreetiea and diagiostic ensitios ant etornpri e a therapenay iiN o {iagNtclly effectiset ifofne of the.foregointg antibody or antibody fragmenm .10084 According to 'A least ote embodiments of the present ryention. the 'i 'vided parmaeutezd compositiOtthat conprse a thepeuticaly effdcdve fom of any of the aenoaN tomidy or anObody ftragmtlW and further Omprtong a phannacec acce(ptath e dtluent or carierO& [tI851 According to at least some embodimet of the present iavenfion there is provided any of the foregoinge therapeu nndl etwe poivelona or rionocion aitodtes or fragments or antiitipt cantnodiar sperdfc toeany of the foregoim Og or phamhlicestci com~poaition cotmpriong same, for treating or pavnigcoitiehen Oymy one of KiRTCAP3 FAMi26 MGC249 Fiil.EAMYAor fiM\z oy vpeptides, or its secrti or IRtwse fom ECD and/iae or V is ha'metogs thereof are difteatnIallv xptesseod s ncit cace aninhe ret ed condition Accordig' to 't last some enboanentol the present niention, there K provided any t te foregoina therapeuticaly effective polvetonal or mionoctonnantibodies or agents. or antdioye atiodies or pharmacevtca composion sam speafc to any UTcA3 piyptide ctediom a group existing of any of SEAQ 1) NO:7. 1. 0ii3.4T 4I, kUn1 12 I and/or agnento aants or homologs herof for treating cneurAcord/n to at east someemrtodnnens of te preent invention, there is provded any of the foregoing thlerapeuiicahy effedie polyrdonal or kR mnodonal ntibodres or tragnient.aor ato diotvgi athimds or a phzmacemtnza positfi n i g s saine to any KRCA P olpeptide. for tr 1ng ov nn cancer. rng ruce: east carnter n d/or colas ceci' According to at least some embadiments of thepresent inyentIon thee 1s provided any of the oregoag therapeutlealy effective poiydopaor monocknal atode or rrrnms. or and idiorypre antibodie or a ph maceat lc .osiiddn corensinge 1W peco nyof oe of M Fproes a elected nom agoup conamng 0of d ofW EQ 1DN&K 15- 1 K 53 3'7 wt 117111 ard/o anne or t lhats OnomoloA> erof for treng cancer and at hun eated conditions or diardersAcording to at least sone eabodinrents of th prsient 3Vtwanthere is provided any otthe toregoig thermpeutically effetive paohcionia} or monodoml antbodles O' tragmlents. 0 anthO dOtyp antibodies, or a pharmaceutiecmplOSinon compri.ng same specItc to any of one of FJNIZG6F poenfor W a ncer ptostae it~r.e acr meignona aute lvymphocytic lenkennia chonine spnocyde leuk;emia aente mfyel ogenous .leuktrmia, chmnicanoyciogenous lreemia. roodtiple myckmima, xodkuns lgraphoma or Non4Uodgkhf kmrphonma and/o imomnome renated cnditiornor disorders Accoding to atleast sorie embodiments of the present in\ertion.there is provnleid -any of dforegoing tberapentcallv e enibdi r ragmen o l t nooe or a plarmIactu tcal collpostoi compinsam speci to any of one of s:2498 potelns selected fom a group consistng of any at Q IE s 19 25, 6 , 6 25 Il50-15,200 andrtroe1nIs or variants oi ho ssology thereof. for neut g a cer andl/or ufi mnnm rein te enOaiioins, or asrd et. According to at least some etnbodients of the present.rstention there niprovided any of die fonregig therapeutically effective polydonal or monoona antibod es of faatenso ati-idiaotopifa bodies ox a pharmacendeg rposJitio compsing sa Speeic to co of one of MCT5248 p'otins far treating ynpsoma, especially Noniodg n Lvmlpho:ra. Multiple Iye leukemia, espeXcialy cell uiieea and/or la cancer andvor in.mmt elai ted Condkions ordsorder Accrfdin to atteM sonticembodinients of Ire preent0 lireriton, there s provided any ot the forgoingtenapeuticaiy effective pelcinna or ornoena antibodie or angens, or antaodiotypic antibodies, or a phamiaceutal compaloicomprising same specific to any of one of 4OA roteinselected fnum a group consisting of ny of SEQ ID NOs: 29-33 35, 36. 5459, 155160 121 186 196. 199and/or fagments or orns homlos ileeo, treating cancer and/or imnn~ine .inataed comiditions or c6I~sers $9 the fpanoi aterapeatcaly effeiIe Pnoconal or ocional anntodiea or O aFgetA r antediotyp aantbod . Or a phtreeNd l cmoii corag Sam peifi n of on of YAM70A proteins for etirrg Multiple Mveloniaidney er l t eor cneer ndior imeast n K sde iNr/) ltnmined caoiditons o daarde Accordioig to at est somne emabodranents of the present inveottn, teies povided anyfs the foaregairig therapseutically effehctiv'e pcsl sdantd or ruornocoial ttxtides or Issramen or ann-lkt spi . a prxaet cai CmO i5tin comYplSt n~e. Speclfc to any of one of TMEM 4 proteis ectd c ro Ma roup conlsi0gOi ainy 0 SEQ D Ns 42-46. 63. 6461 16219 191 and/r fragtnntr a i itn hto lo hereof. for tre g ancer and/or ionme related conditions or disodrs \cconiig to a lent sone emfodhnents o the present inventon there is provided any of the toxgarg therapeotticaly effectiye p~blelonai O ( onoln antibodates or fragments or anti idiotypic asibodies> or a phatm nau l cOnipe0sitli) co'mpri in gsrmie spectine to an y of one o 54EM I proteins for treating z vrphornu espevlat Noni odgk us i nphoma, anti CD20 Gxe Ruirnimab resistan lynhomnaMdpie Myona kidney cancer nd/or caneeatic Cancer, a/or: a rentedCond or drdereseciaS svte pO$VZ eydiemuatosux) I 0086 mording to SA otherembdiments thete is ovided a use of an o the t omVgs p-exfic anihodies and awbly fragmntis, and conigate theno and parufiac 'utnC3 coiposthon1 cotapdn i te U ~t modida ng ndagri or ihbeto unmtinxtyy (90871 AccondUng to .tii other einhodimnents there ispovmdects aibodies and antibody franmens spci"Xfic to po3ypeptdes conpririg discreet potios ofRTCAP3 prtis ding a frerent poadens of the extraswihdar doznain codosponding to reduNS 42-62 of he KRTCAP3 protein e qunce obtained in te segene of W93943' SEQ D NO:?). W93943 J 3 I 14QIID NO In W3943 1~ (5EQ ID NO a 312)4 P8 (SQ ID" NO: 3. or residues 115 -62 KI AP3 protein sequence contained i the se4qu elce of W93943P2 (SIQ ID NO)) W93943fPJi SEQ HD NOIt), and W939434' (SEQ ID Nr resoInes I-20 of the KRTC p rotein 1seq3cC conitadned in the sequee of WS3943 S! TN W 0 N Xcr podne tng' ano i d setence depcted i SEQ U) NO:49 or reidues 7791 of the KR TCAP3 pmten sequence contained in the sequence of W93&43-P13 (SEQ ID NO: 10) correspondin to amino acd sequence dekpicted in SEQ ID No:59 or residues o- of the KRTCAP3 protein setnce iontitned in tihequenc. 20 ) NOM or residues I5-7P of the KRTCAF poein seence ontaned i the de~tdin SEQ it) NO: A, or topo~vpPticu r )o ete og ed porn tail or head portn conipsr ay one o e no a sequence eh SQ ID NO 46 A o fragment theA 7 [)08&1 Acoe t til other embtodments of the present opendon there acep OYidd FAMK6 protein incnding di ffe porhus of h e aosn esin s t ofsequences of 72906 P4 ' )I>NO:a 4.eortsn ciinge n-to.atc emi: 52E 'D Or es doe 12 75 of ,eqtences of T'2906 P4 esidues 2- 143 enes of T829063SEQ ID NO, o16), sondin to ammo acid sequence depiotedi i Q D N 2 to p wypapdes o psing nyone o the nique set fo~rh Sn %l W 1N 49, o fragments there-of, mtibodies o anybody frments specific to po peptides comprsig discrete portions of antS24Si ei cuing dfen os ohe taofadoma ondr reIdus 1-55 of he seqAence A2D J24iP S C IfD NO, 1 5)corSpondig t o amino0 d sequence depc ted in EQ ID NO:0 o es des 94 - 0 of the sequences A.A2 13 R520 14 (SEQ If) NO:) 1.31 corsusponina to amino acid seqtnce deipictd i-n SEQ:( ID NO:61 or uridtes 1?4 of the sequences AA2 1320_P6 EQ ILD NO: 19 imr oN ".kl to den icl CtltC 'U:.VVt .v 4 Aaom o the Unique hnrdcge. ie~ ot taidl ort head nruon cop. s.uq an. one ofthe atmuro acd eno~ssttrni SEQ' I>O:..sr4.\ \amrt thenof> [K0901 Accordingz to sth other cmnodiimnts of the present in VnltiaO the -re provldle antiRues and antibody frgments specific to poypeptides compfisin discrete portions of EAM7OA noteins including differen portions of the e' eiulnr doma corresposgto resiue 510-9i of the seqenc Kl 0649P4 (SEQID NO3Xi06-49 P5 (,'SEQ It) NO:; ,3), or 10649P S iD 0 correspopnang to anin aci seqence depicedin SEQ 1) NOd:$4 or sduies .1 101 of sqence P10649. P4 (SEQ ID NO:3, corspondin to R . 3 cid sequncae depicted in SEQ ID NO:55, or residues 10-21 of the sequence FI0649 PS SEQ WD NO:33) corresponding to amino acid sequencee depicted in SEQ if) NO:56. or rsde 10-241f Othe)i~ sequenjcel F10649_P7 tSEQ IID NO:3; cor)onigt amno acd sequence depiotd SEQ ID N or reidues 51-65 of the sequence El049_P8 (SEQ IDNO:36U corresponding to amino acid sequence depicted in SE) ID NO:591 or re 13dues 223328 of the sequence F10649_P8 &SEQ i) NO36) or reduces 8 185 of the sequence F10649_P10 USEQ ID NO:32> corresponding to amino acid sequence depi e in SE) NO:57, or tO ol ypepides copising anyone of the unique brdge. edge porton tail or head portion nompring any one of the amino acid sequenCes set forth in SEQ 10 NOr;:155- 60. or iracmentsthereof, c9 Q According to sill other imbodipnents of the preent mention thereare pro ided andbodies and anetod fngmen t specific to polypepodes comprising dicrete ponien o S 4 proteins Anudn iffe re rt;ons othle extraceiui doiminicoespondieg to, nvsiues 2375 of the sequenceW38346tP3 P SEQ ID NO:42) or W38346.P7(SEQ D N0:46, corsponding to aano aid sequence depicted in SEQ I) NO:63 or residues 2 105 of the sequence W313346 P4 ( Q U Nd45 ofl5pond ng to anfO add 5eqUce depicted in SEQ ) N) or to omyeptes amping anyneof migU e bridg. edge~k portion. %a--d or Iwead noxnp.rtoin g any one t the n'an arid eecs set fbrth in SEX)- ID N 1:61 .-1621 or'i thereof. [00921 Accsrdineg to sn till r anodrent threis: rosid a mto opoueo [093] Accordiah tosi1 other rodimes there is pro edamethod to use any of Ohe oreong therapeuticay e ve polyclona oa zmonoclomd antibodies or ragrents or ant otyic at od its or a pharmacetcal compoton compsin sane, for treament or ptmseritOn of canc -er, anda r i rnaune related cndition MGM94 Accor:dio. to at least soeetbdtne~nts o>f th e, setnVerito theu" arevide methods ton Fdinv or preen canu tndmetr ene reated conditons eomprtstfng dn InIiru to a fitetiOetcty'33033 01t of toregoing antibodyo rgeto Accovrhd tgo at least sone 'mboodents of the ptmsent invention then: is provided any o e foregoing methods or neating, or venfing cancer ung an ot the forgoi g atibde or tragracomts r arzt cr, a coninnate thre-,o a nhrurmzceaicai caumpoit lion, corntprisittC same.

According to at least somembodineed te presennention there a provided any of thePooeng htds fOr trtad o Vt pargnt uung any O the fot\N rging atibodies or agtnents or aar or a corjagale there or a phariacertric zcopOSio comptrising samnerecific to ay *$f one of KkTCAPE3. prteing. wherei the catnCeI iWAY ttoimited to ovain cancer ng cance rat criwer andkr colonalVe werein the cancenmay be nMeasat on a eAn or In s Accovdg to at east ome enodimers 4 the preseni v nrin detre is povided any of the foreonng men fo eatn. orreveng Uaer ggr of thfrg g amrdies ortrmyrne t o a gae therot. or al hamaceuticalcompOtlin cjortpdng ame spedfic to anyof oneote FAM26F proei \herei the cancer is selected frot hut not imnid to ovarian cancer. breast cncer wostt cancer. renal cancermueamorna. acute we as for treating immune rented candiions or disorders inaung but not limited to inflammatory or autoimrnmmte diseases. tusp unt rejetiortand craft versus host dtiseaise. According to at least sorie ebodents of de present i nention there ma provided anY. of the forego'ing .ehdsfr t oaig r larswnn cmer anl~ lm~wll-i comniion:s or sorcier\ ung any of the forgoing antbodies or faigments or a variant or a conugtate thereof, or a pharmiacenntial composition cotm&Ying m eeiticato any 0a onet o the IGC52s49s tirotertaNei the cancer i ind 4 ao lomited to lrnphoma, eacs ia/I Non -odg ri phona 4tip Meomnv kema especial I ce leukemia. aidoralug canice Accodiya to at iast te mbdaenms of ihe present inventing theirs provide a' of t' toeig methods for Satia. or preventhi: cancer aMOr o rr nrmune heated comit ns r dsorer nnganyof the fogtotnag antibodies or Ergene or a variant or a comnugdae iereof. o~r a pharmacenuticai onmosiin ie omprising same. specrfic to ans of omnt of the AM70A proteins wherein the cancer is including but not linited to Multiple NJ clokna, ki dnei y ca Ir Iteg. can' cer, I ye;zr cnr.andior- breacner According to aticast omer mhodiietn of the p ent invedon there is provided any of the foregoing methods for treatiegg or preventing cancr using any of the forgoing antihoates or fhrament or a variant or a conjgate th eof or a pharmaceutical compositon comprising Sam sifiC to any of one of the TNI .54 protein, or its secreted cooluble form or ECD and/or portions or variants there whereinthe aces incudig but not Phmae, to Jymo especially NonHodgins Lymphoma. anti CD20 RitAximrab) resistant Ivymphoma, Multiple My$eoa kidne cancert and/or pacreatic cancer. and/or immuntine related coniltionS ort disoitre. especiads' SLE. [009)51 In another embil~odimienit the inention2 incIade~s a method of inducing or enhancing an inmmnne rsponist comripsing administering to a ptient in need thereof any of the toregoing antiboies or fagntsom and detecilng induction or enhancement of sad inmmne 1(0961 In another eilbodint the invntin to hindiO a i nuak hoc for potentiaup .eicondary irnsanm~e response nO* uigen in atie nt vih enol ed (opns ann imaterina efectiveri ontN an of the oreg antibodis agmentN Aanothe emobodonenit the t nO) inchides dh foregoing method w-e ianhe andgen & s ar ferAoy a cancer anigen. a viral antigen or a bacterial andgen and the patient has oponal ly teweelvd treatment an anticancer vaccine or a viral vaccine , [80971 it anot an bo mot the enti includes an antibody specific to any one of the KRTCAP3; EMh6: MC5249; FAMTA or 1MM 54proti or a fragment or varin or a homolog therof that elis apoptosis or aysis of aner cies that expread 100981 'In another .eirtodimnkt them erin ~dtid nv of the t-c voing antdas ow frarenrts. wherein said apTois ar activy involves CDC or ADOC actii ty of the anti body. [00991 According to at Jeast sanme embodiments of the present inventiom there is provid a method for inhVibiing the growth of cells that express any one of the KRTCAP3 FAMQ6F; MCCS2498; FAM70A., or TMEM I $ proteins in a stiledt comprisang aclrninistexlng to the sbhiet any of thencoresponding tfregoing antihody orafranrment or a vacant cornugate thereofor a iharmaceticua conriplostion cnrsn m lO010t] Accorditng to att least soine eraoimens te presetit i mention provides the oregoing and xdi and trment wherein the antiAnods a hieen hurnnizedo pra'naizozd Or tay monn nibodly. 1001011 In another enhtbdnnent the itenton nchades any of ie fotreoing antibodies or t'rrrits whk'erein te antigen bindingne eentainwtg from abont 37cntiguons or no coTis anamo aWos ro typteay ast d cl 10 tigo s tno tvonues nuno anid. These binding tet inelode omftama, ineY~' anton-cnfornnationa epitopes.

[O01tI2J cordingg tO anOthtbtodoment> 01f t ptaet inendat tYpOVdde1div agents and coqan ' tesifereof including bat notim ed to Fab. ." m os Angment [001031 It is aloa e emodiment of thet inventiona to dirctly or indirectly attach thesubject antbodies and fragments to markers and other effector moieties such as a detectable marker or to an effetor moiety. 1001041 in another embodiment the invenuon includes any of the foleoing amibodies or frnents wherein 1wTheetor niety is selcted fromn rdvg, an errayme (antibody direcwe enztyme prodrag therapy (ADEPT4 a toxin a radianudfide, alurphore, a therapeutic agent, or a dhetmotherapeutic agent. h01f1O%1 Ina nother emimenonh inounades any ofthec fregoing antibodies or ivavnntu wherein (he deteatabe matter is a :radioastope a netal chelator. an eun.n at unloresaen t compound. a bioinnescent compound or a ehetin nescont comnpmtnd [0010W6i Accordlng to at leat some etnixociiments of the preent invention there are rovideaz comndoui ind uding drtgs wvich modulate tagomnie or antagonize) at least one of the KWRTAP3related, FAM2.irlatedtMUC$249 lrted. AM7OA elated orTMEM14 eSaiox iologicai activi, Such tes include by way of example smal molecuk, apanex peptides antibodies and nments hot hind a of the po) peptieS $seted tm17 01- NO4, &l- ' J,%25,2130 2 .9 5646 1 Ail 121, 127. 12-.n.

4 662$ 186, 19 192, 196 199f 200. as we as rieones or antisene or sIRNAs wich ta e n lei- acid sepence ot fmaments or m atas thereof selected ftom any "f SEQ ID NE'- T 1, 2004, 97 l100. 8103. 100. 109, 124. 2 1 . 193- 95. 9 2 e mole20est my Oectd bnd or modlat an activ elicited by any of Me KRITAP3. FAM26F. MGC5249 FA\M70A. and TMEM 154 proteins or DNAIRNA or pomlins it Vti lts thereof or too inCreCN niodoute a it least one of the KR IKAPS related PMM26deeated. MOC2498 related l iO related, or NM related activtyr o lkding of molecules to ani of the KRTC AP3, FzAM26F 1 C52498, EAN7A ad TMEM 154 and potions and vaat~ herot wch as modulanng thebinding of ay of the KRTCAP. EAM2, M0C5N49& FAM70A, and TMEM154t its corresponding rflter receptorl edogenous gnd and cAn bw sel tou treatment or pevention 0 caner. rimrauine related condittons, inchading bt not limited to inflanimators and atoitirune dise s Insplant rejeeian and grnaftsus hos disease andorfor blocking enhancing imn srnaMton m0aaed y ini K.R'ThP A 6. M( (i(524% PAMYPA r IN M101 154 pPnq3oftdt According to the present nve a one of the fo anin MEM 54 ectodornara. at a hngmom or a varmlor w, hoolgu or1 a cr 't e oo phatnnaceucai composition compnda nim and/or specificantibodies and I o gcens that Wen too KR'{CAPS. NOUN",iP MC3S4PS FAMO or 'NPMEM 154 [Oh4 or emxruentdical cOmps~t{f on spmpn g sane, or cmpoimas inhi gNg seh a rr mi no a.apiners ppes hcharge IrCAP FA F. NIK D49& FAM or M!EM 154 poypeAdes as wed as rioz mes or aitiense or sRNAs vhih tarvg1 KaICA m MG s r5249 a FAMT{a r T aM c t n ic acid secuenoe or tragments or varnants hfereotf hich are usefbl fc treatmoent or prevenia ot cancer andor imlnirnn related conditions poay ay he used in comtinauo therapy with otler traitent aedihods known n the a ected from ie gron oning ofadiation thecrp nrody Iheapy chemotherapy p r , gerly or in combinatin therpy wh ote bioloica] acents oeaena dtrm aoamer aent, miwomappresaris eytOcc drgs chemotherapeutic agents.o in corohirun with therrpeuei agents targeting othe conlemnt rceidatory prteinle (CRPsy1 [00107. According to at least some eomodtnerts 0f the pOrsew dlain thesis piroded a tee of any of the foregoing KRTC\AP3. FA M26P. MC5249 FAMOA TMEM .54 povppoes ndo oluonde.n oaniodes fordianoss of a disease, hri disease disrdect d ernsce ads iiad e rgltedaconditonasa. effad e IA0O1O$J As used herein, the teral W'diAesi of a disease" en"rpse ereem'ng fora a dieass, roi of o dseae proasn and/o treatment tiafai/rrlpeo Opi~tiiti~l of gien N Neapy a. chsease Drnonit g the treat of a disease, indoor predjeting the ta of a therapy r speci c patients cr subpopnlations or detennig the aippropriate isn Of a t~nkrai Ntsic prodiu in~ jpat&ie nts orsuppuaios 10l9In atleast some enmbments of th present enn there s a use of any of te foregoing KRTCAP3, nAM2&6F M s s EMoA. rVMEM1s4 poiypepttdes1 and/or [00110) In at least some etobodinments often present in ventln there is a use of any' of the oregAoing .RTCA3 polypeptides. and/or poym otide and/or antibodies for diaignos fa cncer. seettd frow but Anot limited to ovarian canA ion C anl lcen lCnz ancea and reast andeX kltll in at loast some embodiments of the prese invention, there is a Use of ant of the frgi FAM26F polypepds, polynucetideS a/or anatidiAes for diagm s of a cancer. selected from but not mited to ovarian cancer, breast 0wCcr p atOetk cance ra cancer, melanoma. acute Qlyphcyic leukemia, chronic lymphscwic leukemia. acute myedgoenous Leuemnia, chroic myelogenous leukemia, muhipte myeom Hlodktin lympoma or Noi-Hodgkin's m kphoma, a well as for dtmgsis of immune related: condion. 0t11 Ma at least some emnbodiruents of the resc e io teeia use hf an of te: fpregobng MGC'52498LA poeptde d/orA polynnesenki, wAd0ar antibod es.f diaymosis of a ceaner.secetectfnorn but tot nuise to mtphoma eseal Non HodgkinM m phoma. Maiple Myloma. neukemiaespec y T celncer aner lur anter d sa a we as for diWaoSo of!mmune rested sondocions [00- nt leas eOn embodinents of the present inventor, there is a use of any of the foregoing FA:MQ polypepudes, andM r pynrcetidedes, andlr antibodiestfor diagnamsi of ascaner selected rna Nt not liNed to lyMhmpi a esclma killy Noni-td cgkiWn'r acanen uninan/reast cancer.as well as foediangnosisof finrnne relted ceodiorns tscvaly SLE U)011 in an least sme emdnents the present ilnton previs acei methods frda gosis of any of the foregojin, d eseiditdesoadiion s' C3mIpain th"' orniof MLM 15oloe oties ador p olvnleots amo nd/or an~ttiodies femordinnoS s sent ineion According t a t east onme se ilt eent venon Ak exncr Wio thenvratc ane changes o the epaoni o One relof the poipt or 1o01clenat henst m emodietsthepsekntnn ofn videsiJ iths egiard to a pamlrti ease, diordter or conhilon. The detection mat' conmp'ie detection of the epresion or ie ta specdt olypeptide orpolrnieotidie rn ae son' enthoioutts te orsent ne.fon . joyar means known int1eat and as dsre hetein tO0l lkl Accord og to one embodiment detecting the pkneence ofne polypeptide pol ynneotide isindicative of the presence 1the disease andi/or itseveriy andko it proeN. Acnirdng another ebodi t amet change n the pression and/or the do the pnl ode or pppde compared to i xpression a/ e i a haan eerity and/r is ogress. Ace o i itther embodimen a cange t theexpressio and/orevof the potlyncalide or olypeptide cmpared toitsevel and/r expresson sadsbect or in a ehotained theteirr n erlestage i ndatrreof th progre t ge disease. According to sid further enbodinent detectng the presence a/or relhtive change in the eitpossion auidihede astIo thet polytcktdad& o~rpolypeptidle is ruseful for relecting a meatnment and/ormnotring a treatinent of the disese Accrding to still rtthee e medetect the Oresende and/o rlative cm in expression anatoreve ot the olynudfeotcde or polypepxde is useful fur prediction of the sitahality ma therapetic product fr specitc patients or subpopublaions o determining the appropriate dos f fa. eaotic ptduet in atietit -rsiliaos.eouxgttill hnt-vhcr x ouet the method comprig quant veitativey andor qualtai determinng or assesng expression Ohe polypeptdes and/or pokudeons whemby differences i exprssion r ding e cose of therapy, is indiative of t cacy o optn activity of the th&'rapyv 011]TVhu, according to a east some embodnents the present iventon puvides 1w6thoda for iagnoisof any or the foregoing Cseasesdisorders o conCdon cosing deet an snbject or in asaotple stained frou th s bjet a mndceic acid sep.nc selected from the group consigof SFQ I 0Ns 9U 1 146 v6,8, -494, 9 .100. 101 10&. 109, I1ll 125.. 131, 19115 1971 IM~ 201, or frirnients Qr vainsor horlogs therect [00 1.81 In at least some enbtodirnents the present fnvention prid a me'thod for dugn of any of the foregnig diseases, disorder n jectdomprintg a) obtaining a ;nmple rom the object and ib) detecting in the sanle at least oe onuceoide andoroypeptide being a member ofaiS s-6,9 14N204.26 w. 3S41. v 97 l100 0 061109 124, 125. . W 195. 197, 198; ffagmen or vaiants or hotooc thedreof 50O119} In at least snie cnsodo etd of the present invnation th miethods are rtcndctd on a hle body 91091 In a lea some emibodneta of the present iintiOhe methods are cotced with a spe a ted frnt a object having, preAposed a or Aspected of having the dsease. ssraer oraondidoun hia east some embodiments of the present in vnis the sample is a ell or tisee or a d fn snple [O0121J In at art soma emnboduents the uhjectmvenion theory also reates t disgnostnmiethodsand or assaysfor dia nsis adise optonalin a bigcal sampe taken om asueje identi which is optIti soni type of body foid or sOfccrYotn Including but not jiniited to seminal plasa bl semm une. poastakic funid enminal id. senr te external secretions of the shin respirory intesina and genitoprinary tats tears. .eeebiospinai fluid. sirnrm aliva. mili. peritonealfluid pleural iddi cyst und bmche a en lageange o. tinreproeive sstemi mdr/or iavaae ofA any otner pan of tM body or stem inte body and stool oa tissue >anple' The tem my al so apjonni'y encompassarnpls of in vivo cel u e canients The ampk can opdoly be diluted with a estaule cuant befo conang the sample to a anybody anldrl perffomingany other diagnosissa [M 22 In at oceans some embodnents the present inenon provides a method for ciadosr of a disense in a sbject comprising detecing in the sutbect or in a sample obtained irom said subject at least one poypeptide sected fomn the group conss c-a any of SEQ ID NTs,. t9 'RK154- 'f) 29<13, 35 31464, (4 I ,- l 03-5. 1461- 19, 1% V t or a namoiog~ or agrwneor then-o According to at nV' some embodrnents of the present :avn there are provide adiagnrcstac mothods that inaciude e use of a of the feo' o g abomnes according at o esosome 'mbodiments o the present inention by way of amp O imnohitehemical assay. radioimagng assays 4 a- mmtang pos itron emission tomogaophv {PENf singe photon emission computer tomography (SPECTI, magrine msonance imaging (MR"); la Soond Optical imagine Comnpoter Toiography rdommunoassay (RIA. ELISA {nzmliked im uiosorbent aw"sayvX slot blot. competitie bina ng assays fluonmetric inagnig assays. Western blot ACS andthe ie Arcordine to at least wane embhodimentsimhe present invention includes diagnostic methods and dr aa'saywWh u v s of the ToeWginga andbodies o ragmeou that specifcalIy b d 2M, any eppp e hain eniine acds"aeece aet iortm i any one of SEQ D1 NON . 4, Pt R. 15-10.25WAYS,335. 30. 12M4. 127, 13:135W 140152. [14-il,121. 136. IN, n 1 p " s 9 ,019. de Oor a a se.r O hom.og. hereo deaotctithd Xi/O'ay frdtectn hepsncofalasone ofthe po vpeptides seated fron a group cons 01 SF )N3 5 76 4 1 32135. 14012, HU W. 121 W. 191. 9 19 2b, o a I~hnyirn Var w 3fDflr a OMONmte Alyoft 04R OifOJ in AlmV( in z iooAuai s10mpeo suboct. corapsntg C TQ On g he r n or to iN, "At an 090ig specficity foa aoaet p a aino aj see: slect e foam the wr t(YO$Thtll)5g of SIE< hID ' 7, S, 1- i, 15-1%'25,29<33. 35,36. 42-0s 27 132<1354 146 362. 1 15-il 2 I8S6 19 192 96, 1995 20). or A fragment or a variant or a homologe ther-o or ao blha on lhero? and detecting the birding of ny of the fcoing polypepi de\ in the Nunprlem (Vl bge uh't tonaid antibOdyf ~0 3 Accrodine to rme embodiments of the present nwenfon there are provided methods for diagnose f a deese comprising detecrg the expresio ard or l in a subject or in a sape obtained frn thesubject of a lat one of KRICAP3 FAM26F GtJC352498x NAM70A and TMEM 154 polypeptides. W00125I Acc, ordig to at leat sncembodimntts ~f thO rsetivewo therm poie ciaotiN eult t t ah s n of ates one of eA1 VAN42 MGC.324FYKAM7IA. and TMEMU 14 po'lynueleotides, selected fromn the grorp conislirng of SEQ ID NO,. 849, 14, 2a4 262, 041094,97, 1,03 106 20? 124I 1931195 197, .19, 291. or a tragimient or a vacant or a n o lo tcreot. by enmpiaying a N aT-ied technology. j'0O12fInmeaso ezorensotepee neithe NATased asay iW scted fr toe gnia p eensiatng of a PC I Real-Tne P4 1R Self-Susained newwe es egofn a meanne I i CR U Ss'MtUtc ction -1t Rpiae (7clitg Probe Raio.innedDNA, . RLY, aadysis, DfE G, Sing.nl Con formation Polymorphism, Ddeoxy Fincerprintint Mirara Fluorescence li$St Hybridixatn oCompae Genomic (00O127I i wmohe, emodMen the irnvention relates" to azs tlite 0yyt~Ct~. counlrismng an a pl con hag a nucleic dence selected froI e con ef SEQ ID NOs:94. 97. 10G. 103. !06. 109 124, 17 or a segment having a nudec acid seg enccact fort ja SEQ 9DN $: 93~ 9 7.1 201, or:Lagmrrents or' poly uceotides homolout there. [991281 in another embodiment the invention relates to any'prinir paIr. Cimpr ing a pai' of isolated ohgonuceotides capable of amphhyrig the tbngoing aMpliRon or segment [01291 in anyone embodiment the invention relate to the primer pair, conPrsn a panr of isolated oionuckotides having a sequence selected frm the g0ou constng or SEQ ID NOt: 02-93, 0-96 08-99, 1 0610, 0005. 107-10& 123123. 169-1 70; i3 168. 172, 001301 Acmng to at cast some embodinit of thet present ienion dtetnggany of te forgoitx Kk MOWS FA2&. MC524983.R 7A. andi'1 iMi14 polyvucieddes comp- eema primer mloopysing a. paI' of isolated ongonucleoti4es eapbise of spec aie . yhrbidiing to at le a portn fapenaceotde havo, a nele aci sequence as set forth in .SEQ 1D NOs: 9 1 2 2 ,-86 38419 909 00 l 0 109 12412 13i 17L 93495 197 199 201 nr polyncdeotides homnoioaus thereo, [00131U ACorduna to t least some e mental 4the present at thus tof ctoon i performed usin an cigonucleatide pair capable ol lybiding to atleast a potion oa nudc acid anene at least 85%. 90%, 95%, 96% 97% 98%, 99% bonroo s to the nueic acqd segence set fonh in SEQ TD NO: 1-6.9, 14 2024 26-28 3841 94, 97, 100. 103 16 109, 124.125 131 1 193495 I97399 201> 00D21 jAecording to at eat sone enb iwlents of the present invention detecdmg any or the toeing K'IpA P31 tAM426' MGC52 49 A MAN\170A, and M 54 polynnceoties accoing to at east some embodienis of t'h present inventscn centiprset enpioyitn a C a Q'r , pprisNit a padt of AAatet oUg vo d as swe A in SEQ I)O: 90 9 99 9 0102 105. 107-108. 122 23. 169- 70, 13 172; 17.3, 16 [001331 In at least some embded t th reent invenstlo provides a diagnosed kit for agnesof 'ka diseasecmpising makers and reagents t or detectirm nggu ieand/or quantitative changes in the express on of a polypepdr a ptym et de according to at least some embocdnnts of the present vnyits [001341 in at least aome embodments of the preactt invention he kit comprses markers and reageots for detecing the changes by employinga NA beed technoioge [001351 I at least some nbodimentrfle presentInventione kit composes at least One nucleotide probe or prm'nter least some cerodimcmts ofthe pcent invenatn, the lo cmas at east one prdmer pa.. .bgo ee e bryhdzdag to a nicsic ad sequence according to the teaching of the present invention. In at least some embodiments of the present invention, the kit comprises at least one oligonucleotide capable of selectively hybridizing to a nucleic acid sequence according to the teaching of the present invention. [00136] In at least some embodiments of the present invention, the kit comprises an antibody capable of recognizing or interacting with a polypeptide or protein according to at least some embodiments of the present invention. In at least some embodiments of the present invention, the kit further comprises at least one reagent for performing an immunohistochemical assay, radioimaging assays, in-vivo imaging, positron emission tomography (PET), single photon emission computer tomography (SPECT), magnetic resonance imaging (MRI), Ultra Sound, Optical Imaging, Computer Tomography, radioimmunoassay (RIA), ELISA, slot blot, competitive binding assays, fluorimetric imaging assays, Western blot, FACS, and the like. [00137] All nucleic acid sequences and/or amino acid sequences, according to at least some embodiments of the invention, relate to their isolated form. [00138] It should be noted that oligonucleotide and polynucleotide, or peptide, polypeptide and protein, may optionally be used interchangeably. [00138a] Definitions of specific embodiments of the invention as claimed herein follow. [00138b] According to a first embodiment of the invention, there is provided a method of modulating the activity of a FAM26F polypeptide selected from the group consisting of SEQ ID NOs: 15-18 in the treatment or prevention of cancer, said method comprising use of a polyclonal or monoclonal antibody or binding fragment thereof that specifically binds to the FAM26F polypeptide to an amino acid sequence selected from the group consisting of SEQ ID NOs:15-18, 52, 53, 117, 118, 127 and 149, wherein said cancer is selected from the group consisting of: ovarian cancer; breast cancer; prostate cancer; acute lymphocytic leukaemia; chronic lymphocytic leukaemia; acute myelogenous leukaemia; chronic myelogenous leukaemia; multiple myeloma; renal cancer; liver cancer; lung cancer; melanoma; pancreatic cancer; Hodgkin's lymphoma; and Non-Hodgkin's lymphoma. [00138c] According to a second embodiment of the invention, there is provided a method of diagnosing a cancer selected from the group consisting of: ovarian cancer; prostate cancer; 32 acute lymphocytic leukaemia; chronic lymphocytic leukaemia; acute myelogenous leukaemia; chronic myelogenous leukaemia; multiple myeloma; renal cancer; liver cancer; lung cancer; melanoma; pancreatic cancer; Hodgkin's lymphoma; and Non-Hodgkin's lymphoma, said method comprising detecting in a sample obtained from a subject the presence of a polypeptide and/or an over expressed level of said polypeptide having a sequence of a FAM26F polypeptide selected from the group consisting of SEQ ID NOs: 15-18 or a fragment thereof by using a polyclonal or monoclonal antibody or binding fragment thereof that specifically binds to the FAM26F polypeptide to an amino acid sequence selected from the group consisting of SEQ ID NOs:15-18, 52, 53, 117, 118, 127 and 149, wherein said over expressed level is determined with regard to a normal level of said polypeptide in a corresponding normal tissue. [00138d] Other embodiments of the invention are described herein are defined in the following paragraphs: 1. A polyclonal or monoclonal antibody or fragment that specifically binds to at least one of the TMEM154 polypeptides selected from the group consisting of SEQ ID NOs: 42-46, 63, 64, 161, 162, 191, 192, or a fragment or a variant, or a homolog thereof possessing at least 85% sequence identity therewith. 2. The antibody or a fragment according to paragraph 1, wherein said antibody blocks or inhibits the interaction of at least one of the polypeptides selected from the group consisting of SEQ ID NOs: 42-46 with a counterpart. 3. The antibody or fragment of paragraph 1, wherein said antibody or fragment replaces or augments the interaction of at least one of the polypeptides selected from the group consisting of SEQ ID NOs: 42-46 with a counterpart. 4. The antibody or fragment according to paragraph 1, which is suitable for treatment or prevention of cancer or immune related condition, by modulating the activity of at least one of the TMEM 154 proteins selected from the group consisting of SEQ ID NOs: 42-46. 5. The antibody or fragment according to paragraph 4, wherein the cancer is selected from the group consisting of Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, anti CD20 (i.e. Rituximab) resistant lymphoma, Multiple Myeloma, kidney cancer and pancreatic cancer. 6. The antibody or fragment according to paragraph 4, wherein the immune related condition is SLE (systemic lupus erythematosus). 32a 7. The antibody or fragment according to paragraph 1, wherein the antigen binding site contains from about 3-7 contiguous or non-contiguous amino acids of any of the above sequences. 8. The antibody or fragment according to paragraph 1, wherein the antibody is a fully human antibody, a humanized or primatized antibody, or a chimeric antibody. 9. The antibody or fragment according to paragraph 1, wherein the antibody is selected from the group consisting of Fab, Fab', F(ab')2, F(ab'), F(ab), Fv or scFv fragment and minimal recognition unit. 10. The antibody or fragment according to paragraph 1, wherein the antibody is coupled to a detectable marker, or to an effector moiety. 11. The antibody or fragment according to paragraph 10, wherein the effector moiety is one or more of a radionuclide, fluorophore, an enzyme, a toxin, a therapeutic agent, a chemotherapeutic agent, a cytokine antibody, a cytokine receptor, or an immunomodulatory agent. 12. The antibody or fragment according to paragraph 10, wherein the detectable marker is one or more of a radioisotope, a metal chelator, an enzyme, a fluorescent compound, a bioluminescent compound or a chemiluminescent compound. 13. A pharmaceutical composition that comprises the antibody or a fragment according to any one of paragraphs 1-12. 14. A method for modulating lymphocyte activity, comprising contacting a lymphocyte, positive for a TMEM154 polypeptide selected from the group consisting of SEQ ID NOs: 42 46, with a bioactive agent capable of modulating TMEM154-mediated signalling in an amount effective to modulate at least one lymphocyte activity. 15. A method according to paragraph 14, wherein said agent comprises an antagonist of TMEM154-mediated signalling, and wherein said contacting inhibits the attenuation of lymphocyte activity mediated by such signalling. 16. The method of paragraph 15, wherein said contacting increases lymphocyte activity. 17. The method of paragraph 15, wherein said antagonist comprises a blocking agent capable of interfering with the functional interaction of TMEM 154 antigen and its counterpart. 32b 18. The method of paragraph 15, wherein the administered antagonist is an antibody or fragment which is suitable for treatment or prevention of cancer by modulating the activity of any one of the TMEM 154 proteins. 19. The method of paragraph 15, wherein the administered antibody or fragment inhibits negative stimulation of T cell activity against cancer cells. 20. A method of treating or preventing TMEM154 positive cancer or immune related condition, comprising administering to the patient a therapeutically effective amount of an antibody or fragment or pharmaceutical composition according to any one of paragraphs 1-13. 21. The method of paragraph 20, wherein the treatment is provided in combination with another medicament or therapeutic method. 22. The method of paragraph 20, wherein the cancer is selected from the group consisting of Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, anti CD20 (i.e. Rituximab) resistant lymphoma, Multiple Myeloma, kidney cancer and pancreatic cancer. 23. The method of paragraph 20, wherein the immune related condition is SLE (systemic lupus erythematosus). 24. An antibody or fragment that specifically binds at least one polypeptide of any of SEQ ID NOs:42-46, 63, 64, 161, 162, 191, 192, or a fragment or variant thereof, for diagnosing cancer or immune related condition characterized by differential expression of at least one of the TMEM154 polypeptides selected from the group consisting of SEQ ID NOs: 42-46, or a fragment or variant thereof. 25. The antibody according to paragraph 24, wherein the cancer is selected from the group consisting of Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, anti CD20 (i.e. Rituximab) resistant lymphoma, Multiple Myeloma, kidney cancer and pancreatic cancer. 26. The antibody according to paragraph 24, wherein the immune related condition is SLE (systemic lupus erythematosus). 27. A method for diagnosing a cancer or an immune related condition in a subject, comprising detecting in the subject or in a sample obtained from said subject the presence of a polypeptide and/or an overexpressed level of said polypeptide having a sequence at least 85% homologous to any one of the TMEM154 polypeptides, having an amino acid sequence selected from the group consisting of SEQ ID NOs: 42-46, 63, 64, 161, 162, or a fragment thereof, 32c wherein said overexpressed level is determined with regard to a normal level of said polypeptide in a corresponding normal tissue. 28. The method of paragraph 27, wherein the detection is conducted by immunoassay. 29. The method of paragraph 28, wherein the immunoassay utilizes an antibody according to any of paragraphs 1, 10, or 24. 30. An assay for detecting the presence of any one of the TMEM154 proteins, selected from the group consisting of any of SEQ ID NOs: 42-46, or a fragment or variant thereof in a biological sample comprising contacting the sample with an antibody or a fragment according to any one of paragraphs 1, 10, or 24, in the sample. 31. The method of paragraph 27, wherein detecting the presence and/or the overexpressed level of the TMEM 154 polypeptides, or a fragment or variant thereof is performed in vivo or in vitro. 32. A method for diagnosing a cancer or an immune related condition in a subject, comprising detecting in the subject or in a sample obtained from said subject a polynucleotide and/or an overexpressed level of said polynucleotide having a sequence at least 85% homologous to the nucleic acid sequence as set forth in at least one of SEQ ID NOs: 23, 38-41, or 106; wherein said overexpressed level is determined with regard to a normal level of said polynucleotide in a corresponding normal tissue. 33. The method of paragraph 27 or paragraph 32, wherein diagnosing comprises screening for cancer or immune related condition in a subject, detecting a presence or a severity of cancer or immune related condition in a subject, distinguishing cancer or immune related condition from other diseases, providing prognosis of cancer or immune related condition, monitoring progression or relapse of cancer or immune related condition in a subject, assessment of treatment efficacy or relapse of cancer or immune related condition in a subject, selecting a therapy and a treatment for cancer or immune related condition in a subject, optimization of a given therapy for cancer or immune related condition in a subject, monitoring the treatment of cancer or immune related condition in a subject, predicting the suitability of a therapy for specific patients or subpopulations, determining the appropriate dosing of a therapeutic product in patients or subpopulations. 34. The method of paragraph 27 or paragraph 32, wherein the cancer is selected from the group consisting of Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, anti CD20 (i.e. Rituximab) resistant lymphoma, Multiple Myeloma, kidney cancer and pancreatic cancer. 32d 35. The method of paragraph 27 or paragraph 32, wherein the immune related condition is SLE (systemic lupus erythematosus). 36. The method of paragraph 32, wherein the detection is performed using an oligonucleotide pair capable of hybridizing to at least a portion of a nucleic acid sequence at least 85% homologous to the nucleic acid sequence set forth in any of SEQ. ID NOs: 23, 38-41, or 106. 37. The method of paragraph 36, wherein the detection is performed using an oligonucleotide pair as set forth in any one of SEQ. ID NOs: 104-105. 38. An isolated polynucleotide, comprising an amplicon having a nucleic acid sequence set forth in SEQ ID NO: 106, or fragments thereof, or polynucleotides homologous thereto. 39. A primer pair, comprising a pair of isolated oligonucleotides capable of amplifying the nucleic acid sequence as set forth in at least one of SEQ ID NOs:23, 38-41, or 106 or fragments thereof, or polynucleotides homologous thereto. 40. A primer pair, according to paragraph 39, comprising a pair of isolated oligonucleotides having a sequence selected from the group consisting of SEQ. ID NOs: 104-105. 41. An isolated polypeptide of TMEM 154 ectodomain, or fragment or variant thereof that possesses at least 95% sequence identity therewith. 42. The polypeptide according to paragraph 41, comprising an amino acid sequence having at least 95% sequence identity with a sequence selected from the group consisting of amino acid residues 23-75 of the sequences W38346_P3 (SEQ ID NO:42), or W38346_P7 (SEQ ID NO:46), corresponding to amino acid sequence depicted in SEQ ID NO:63, or amino acid residues 20-105 of the sequence W38346_P4 (SEQ ID NO:45), corresponding to the amino acid sequence depicted in SEQ ID NO:64, or fragment thereof, having at least 95% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 63, 64, 161, 162, 191, or 192. 43. The polypeptide according to paragraph 41 or paragraph 42, which is fused to a non TMEM 154 protein sequence, or attached to a detectable or therapeutic moiety. 44. A fused protein according to paragraph 43, wherein the non-TMEM154 protein is at least a portion of an immunoglobulin molecule. 45. A nucleic acid sequence encoding a TMEM 154 ectodomain polypeptide according to any one of paragraphs 41, 42, 43 or 44. 32e 46. The nucleic acid sequence according to paragraph 45, having a sequence as set forth in SEQ ID NO:23, or fragment or variant thereof that possesses at least 95% sequence identity therewith. 47. An expression vector containing a nucleic acid sequence according to paragraph 45 or paragraph 46. 48. A host cell comprising an expression vector of paragraph 47. 49. A method of producing a TMEM 154 ectodomain polypeptide, or fragment or conjugate thereof, comprising culturing the host cell according to paragraph 48, under conditions whereby the cell expresses the polypeptide encoded by the DNA segment or nucleic acid and recovering said polypeptide. 50. A pharmaceutical composition comprising at least one polypeptide according to any one of paragraphs 41, 42, 43, or 44, and further comprising a pharmaceutically acceptable diluent or carrier. 51. A method for treating or preventing cancer or immune related condition, comprising administering to a subject in need thereof a pharmaceutical composition according to paragraph 50. 52. The method of paragraph 51, wherein the cancer is selected from the group consisting of Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, anti CD20 (i.e. Rituximab) resistant lymphoma, Multiple Myeloma, kidney cancer, and pancreatic cancer. 53. The method of paragraph 51, wherein the immune related condition is systemic lupus erythematosus (SLE). 54. An siRNA, antisense RNA, or ribozyme that binds the transcript encoding any one of the TMEM154 polypeptides, and inhibits its expression. 55. The pharmaceutical composition according to paragraph 13 or paragraph 50, for use in combination with another medicament or therapeutic method. [00138e] Any reference to publications cited in this specification is not an admission that the disclosures constitute common general knowledge in Australia. [00138f] The term 'comprise' and variants of the term such as 'comprises' or 'comprising' are used herein to denote the inclusion of a stated integer or stated integers but not 32f to exclude any other integer or any other integers, unless in the context or usage an exclusive interpretation of the term is required. [00139] BRIEF DESCRIPTION OF THE FIGURES [00140] Figure 1 shows a scatter plot, demonstrating the expression of KRTCAP3 transcripts, that encode the KRTCAP3 proteins, on a virtual panel of all tissues and conditions using MED discovery engine, demonstrating overexpression of KRTCAP3 transcripts in lung cancer compared to normal lung samples. [00141] Figures 2A and 2B present a histogram showing over expression of the KRTCAP3 (keratinocyte associated protein 3) W93943 transcripts which are detectable by amplicon as depicted in sequence name W93943_seg7-1OF1R1 (SEQ ID NO: 94) in cancerous ovarian samples relative to the normal samples (Figure 2B is a continuation of Figure 2A). [00142] Figures 3A and 3B present a histogram showing over expression of the KRTCAP3 (keratinocyte associated protein 3) W93943 transcripts which are detectable by amplicon as depicted in sequence name W93943_seg7-1OF1R1 (SEQ ID NO: 94) in different normal tissues (Figure 3B is a continuation of Figure 3A). [Text continues on page 33] 32g nO1.3 Fiares d an 43reen bistoruin over ex prs o cc e. KPTCAP3 transcripts detectable by or arcardn tW93943se 3j4#21 arnmdion S LQ I) N 1 o aa des relaBve a cvaontl oe (igue 41 {a F of f Are dY of DN g e r h FZRc' P touyrpt ce wceaele Leweor cornespn toW993se3ads~ asratien Senc kedJ~ '71 e difra aored EGFsueigne 13s a codotmedateo f[ r iluke F EC presn hA sequente of KRTCes of t D NOT 2 noTA45 Ffused rno\eseeoe p corresponding to TCAtf lenthe serplengce of rotrl tob 'd teanl, REP n bold :OedtF quentermediaesUnd wgtenmsare Fjker egiao 04 rrntents te pnNA sequence of ) A Ppe EQDN, Figure B3 peree teNA see qinneace of H> NO: [imufv aC sqeence DNA KrCiRTCAP pt nSEQ ID NO, 12) [001461 figures 7A nd demos dMe ainao aof e KAPprc s of oe KRetCo \' OREi fuedbm or noued 8A dOEmonetsp byt sq grafa oesonce of toF thae tCDnier e~is t re und a- A powntRs n iokd posa,~~,k .,:jde apge oea gz wetxenOfe KRTCAPEK hOER3F prote in71tvM.-1:!sw a cuide i arosope igueQ B NO de nome\ates by red f reree nts.FP anadt sequence MFRE X.R C.AP protein ID~ U NO I I ) st7a) f igtRnre 7d 0Wmi5te dno aid seq uenTCAP3 2 ( pS ID Ot4) (SEQ NO) (2oaleo [001,471 igures SA and 91 demonsrte thelaltion o the K ICAPU rotef t o mebxe 1 e A d SAbyaes e-oesee of Te diEGFEPKRT\APT2 (SE 1D NO; 3 14s prote kicaltodhe el mmbrane. I upo exprvsic- in0 to93 I 1 1V els ,c1m a otiedu the, 4n:,v c~iobiecve of fth cortloca zucocp Ol Kg-c $93 byiotsrae h em lrsec of d-GE ffatdtha FORE FT.KRTCAPIX. P2 (SEQ ID NO; 114i fused pwiotnrnloa 0mt h rtth-f o non pemiebealized EGFP-KRTCAP3 HEK 293T tranfsected cekL Figure 9E demonimtes the. i tam0Jig with anti GFP of non permebahzed EOFP-KRTCAP3 HEK 293T itasfcted ceS I imnmuotain~ed, lTe absence of ant(FP~ red fluorecee {as comrpan-d with Figure Bh) indicates that the EGFPKRTCAP3_P2 (SEQ ID NO: 11 fused protein is positioned in the plasma membrane wi% its amino tnminn facin the cytosot. The images were obtained using the 40x obiective of lte cotnfocat mroope.' [001491 ie L(v A 0"D eonntaWese blaaligs using KR CAi2 Anibodies or 293 trnfected ce03 Ixares r Al shom WA anblot na wsm Lung Kdi~es t \odanad t rabits marked RBla5 ned P 2h) on KRTC' \P\Ali' MO9 '3W cl 5ZC ~'tdp31htiKU)-'r37 a 1 'V\3ttN zs rabb in R 52d B5259 ;nd RtB526 op KRTCAP3-IEK293T ce yetes an d ) ad (00150 Fwn ghas DAI11D demont)rat imntasiting of IIEK-293T cels -Umng purified KRT(AP3 antibodies Egsme- 1 kA:- B present imnnostaintng uing KWL 4 atbodies on KRTCAP3 HEK-293T encd ceia (Figme 1 A) otplRESpWo3 H3E 2931 nsfeted edi Fignre B), KRi4 antbodies shows a specic sigmal in the KIItAP3 nansfected Ces which is IAb in it the plRESuo3 transtected cea Figure D present imunnostaian-use KWi223 antibodies on KRIFCAP3 FIliK-2K3 transfected celik vire .11IC) or pIRESpum iEiKW t9Irandoeted cels (Figre i .10 FR z23 anibodies shows a specific Anal in e KRTCAP3 inosfeted 'eS w ichs Absent i the piRtSpur nseped cens Theinage was oboa>ed ith eu 0x A.r on echts of the conocal microscope {00151 atte 12 demoatrat. e t n se irnaohitoc emicstaining of an o a car inoma samblue otainetd nom a 52 ear old femaien nauig bod KRT22 The snaal was qat neti edusine a 04 sctea was gven the signal intensaty 2. [0015 21 gc 3 demonsentes pimmnent rmmtmohitchemica stairdg of an adenoarima sampe fomametastatice gasmtmionttsti tUmor obined fonn a 31yeart old fen duing Antibody KRT223, The gai wa tandfl using a 04 scle anidwas give the gnal intensity -34 [001531 Figurez 14 shows a scatter pkot. demnsrating Tihe expression of FAM2: transcripts that encode dvhe FAM26F prokem\ on1 a virtual panel of all tissues and conditions using MED discovery engi ne, demnrstratng overexpression of FAM2 6F transcripts breast cancer compared to normal breas samples.Y [15141 Figure I shows a recatter plot, demiomiising the erxpression of PAM26P trnscrpts that encode the FA6M26 proteins, on a virtual panel of Al tissues and conditiurs using MED discovery engine demsonutmiing oerexpresion of FAM26F tranticri pt in ovarian cancer compared to rinma ovarian samples. F01intmgres IAM 61- show a scatter piot, denonstrating the overall expelic oo FAkMT6F trnscrptin various drhase< notra and cane tissues, using MED discvoi' engine. figures I 6H re condgipous and i a senuendal order 00156] Fiates aiC showa histognn represents the oepessionf EAM26F tnserpts detetable by1 M FA2N, OF ZT primera (SEQ ID NOs 95 and Ci6 in k iey cancer oiver cancer hmg can mer N t L vmpohoamas and meanoma g es 1AC are contiguous and in a sequent oer t01 figures SA and .s show atogram showing the expression of FAdM26F TS 6 tanscripts which ar detecable by anpicon as depicted iraequence mone T8290 seg50F7R5 SEQ ID NO124) indifferent nmta issues (iur 18- i a coninaton of F 1g8re A) [058J Figumres I A and 19B show a hisSogrn n snowitng the expnvsi(3n of FAM26F T82906 by.alpwi ne deteiabe "m alon ay depited in .equene n sege 0F7RS (SEtQ ID NO:124) n hlood-specfe pand gre B1913 i a cotitiaon F figure I9A [001591, FIgure 20 presents the DNA sequence of die M426N P4 LAG (S 1D1 NO I /4).Inc FLAG sequenceis in underlined. [0016() F;ir 21 presents the ann ciI sc Se nce of AFA tE ID NO 175i The FLAG sequence in wnderlned, (06 1 iures 2A and 2218 demonstrate the eiul aictaiton of MA96£4 protein, 35 23A as opposd to an staid obsened Yong samne atbodies on p1RSpwoK 29 tra ected cell jr [00 e 6 eig or 2 he MG I29 p oe o i ul a e s n [m1641 Figue 25A o a25 sho a se 1 , de aln Wee io ro o tscn24t tnsan patodet e9 rOtCs2498e Ci ao a :vI o pane t annan aiin MGCin 2 M) 3scV enne.g whknsreaetnen o of bami GCca 24sdP ted euane cnaAU2el 1Al SEQ snnD N c. i funt nga 2a [001661 Fhgurs 27A \ d 27 T sow a hst oat. chOn1 s of, h yp eon of pro2t StvGC5t9 i 2A t e820dt QripS wa$2h rodtect on amprl f a ll d ine suen nam ANA21820 gI 2R2 SEQd 1 noo9t blood smpes anl Fr s ae [O166] F >re 2 A 23 present ea his Ani shme aon of seqwincme i,,n If N - 10)0.ii'Rd 0011 Figured 8A and 290 tspsnc io deuenbe 0, Dof Fias 4eT stance S N an Ae&2l nr LO (SEQ ID NO1) fermln iu 001691 Fitu eN 30A and 3013 rhowe a cua p uenet og the MGr of (Utii tsnte .9at ande91 no Fesert Ir A rotnr,o n ci sequnceo, Ul CL G JI conditins using MF.D d cyr<esndmn rtn vrxr~nno AIY :3its ng cancer saiaples con parei to aLd lag a0Bt eFie On i a C0OTLfywQani of hD cre 30A i. [~l 01 igue i 3 hows a catter pot d.&nnonstrainagte expression of AMghA ripts ha encode the FA'M70A protens, on a voaal paxe (0 6OUl and contiditic using MET> dicoery engine, ;-Ata oerepres o o FA o an mle cancer sa p es eCnpared to ooraIveW sampeks )01721 Fiuae 3A and 33B hrla Ceaoer ph t den au g of epsioA r7naArips dt ecod ethe Adeth. puiMsA la ;tal panel of alle c nd using s41MED dicoe *enaine\ dengstine.. dovcrexpussn of FATO tascipGA t n sadmpes corterc to mples fmpared snmp l dey s.nplay Nigu 33B W172 Pigurs 34 and 43 shw asttmerpo.demtaing the ein ofohy ot pain H20716~t70AF1064 tra entuh sratetbl b ng.io tdnsepcts ineyncer slscm pared9eg0F Ro nomaSidne sample'rs diferen n3ormy cnnue mson of cnu 33A)4 [0174 Fi res 34A and 3N show a histognm showing the eapreon o1 ypothetical paein 07147 l6FA1M70A I 0649 mets which are detectdble by aicoe as cepseted in sequence name F0649seg10-1 2 IR1 (SEQ ID NO 103) in c diffe pec nt'ofl 1001741 Figure 35A rn he DNA sequence of hypot LeIce proepi F1207 IFATO: ,A F169 VA 3ok 'tc 'wihare detectble byaipic a depiodeted i'n seunenm l(d\~~ SLQ IT) 'NO;) lO n blood s.pecn *panel' titgure 35B a 35tnat' nv~-IA), [(Q151Fiue ii ep36 as tl; INA k ecuemt:ce of "AM7 kl __ Q FLAG ,3EQ ID) NO: Gene xpecl sc sequence coflesponing to the trgens fullenthsequence is market in bold faced F I seqouence is umbold 0176] Figure 3 repsents the anno acid seqence of EA OA PS FAG poutn (SEQ o) NO; 120) gene enc scopspnn 1r i<c full enghseqe of the prtj is miarked in bold faced. FLAG sequencersunnbold, [00177i ures38A-38D demonstrate that th FZAM7OATlP5_FLAG EQ 1D Nt120) fused protein localizes to cel ne rane ;pon expression in HEK 2931 cells Te m ta ne uting t 40x ObjctAve of the confocal microscope, Fgowes 39A and 39R peen the specicty of antibodies raised again:t selected epie o FAM70A. FiRe 39A and 39B present the results of mmuno-precipitation fOllowed by weszer blot analysis uwng purified serum from rabbits 663 and 15664, respectivey, and FAM70 HEK-293T the inectant ceAl lyaes as well as HEK93T nontrasfected cell states Lane 1 represents RETK,293T tmnsfected cell iyat:es followed by P lae 2 repesens HEK 293T non rasfeckec cell plates followed b(y WP lmes 3 and 4 100 ~~ ~ ~ o Vaiu eOI Usingeamunsye no pausedn prset thewhol cel on ae43 on.* 3 trzissec cteed cel ls.140o d Din (9011} J hae -40 A40i1 'u(trtaioo ynj el yo~ anti [Ar~It a tbodes rabis 63 . lis u 40IA and 40B pnte te revsults' on li-El&2931 iransfected cells, uMys 110 0 or h ltNOY) d~uin..e~~~v Iiues40C( ani 40r) prset hereulson RUMM w.% i'nntonsface cells esmJ~n 1:'200 orZ I LXXfk ) di ,ios respecle I re 4bprsents the results on PHOK ( AC(, Ci> cells and igute 4010 present de res lh on MNI/CAR (ATC. CRL-8083 cel Silar results were obw c wg rab 56~fshiu s664 data nut shown). D nstrate reid Signl nceo a ofn293 tran sfc$td ceis fbiowe b in abo wth 5Q, 16 50 6rtign 00ppt espc(y ce-s fow ed b ncubaitn w h 0 5tines s50 tmes FAfNV O peptie respectlye 42 shows a scate t emnsttac 1 e es f NI4 tranwripts that encOde t TMEM154 prot ns, on ao' panel of4 dw rs and. coinsia loMt <uscover) engine desmonstneowag OverIxp 1-oni 5s4 cnRw Uh.Mz- discovery Jrepress!on ransersotsi kidney Cancer ssnp iecomlpared to norma lwkdney sanmica [001$01 Fgures 43A and B demontrae the epnzsim of TEM l54mnscripts that encode the MEM 154 proteins on a virtual pael a tissues and conhlon using ) discovery f3in. sr shows a st pkcs. eosrtigoec Ow rrusron WC TMEN1154 in pascrpc -t aeas cacer pk'p coinpa, " to norand pancieas sanps Figure m-31 presents Kapl an-Meer s-rival curves of uxinab treated hllCL n corlat , o MEM! 154 exoneiom, - In (kgar 4313th rnes. Tow in el e oi line ~se s m1 expraa n l esens Low TMEM 14 nres uasnaonn [ 81 Nw2A and AB sw a in am shown the 0 ito .U M 1n54 X8346 } crptws which deectabe by anu-on as dePicted in sN4trnie ~MWO %vW334_cbQ-0! Ri SE) N:I0)indffrntno depcined sequence nam 38346 _g&20F Ri (SEQ ID NO: IO bin seefic panel (a re 5411i a connti(dYn of FigusrdSA) 31 Fure 46 eense DNA eeeneeof de TMEM 4 TKFEARiSEQ ID :NttlP 189) fj-AG eecei in uvInievnet [QO1$4) Figi 47, pxsn e- acid eqe ef TMNII 154_ MF AG SEQ ID 00105 eues 4 and 48B peunt te lcalizationr [001 F ard 4B preentte spci cell saing loca s to sie cel inendnue, observed using TuftedTM21 antibodies Won TMEM 154 nsfeeted cells Figure 40A and 41 pee the results obtained usg T embodies pu iiedrmm abbt *6285 and ra 462S6, respectiely, 001871 1g ures SA and present the specinc ceI s tang localized to he cel meebrane, observed sing pnfir~edTM 101antibodies on TMEM 154 transfected els ies SA a $0 present duls gained vxingTM10)1 aiodi ned n ibt #6248 and rabbit #6249 spectiv 1001381 Fiulsss I Q -5l C p sent thevreults M01 cell g 'air' wndse d using pallied TMZ I and TM 101 and adies on the ng Nd "e control pIREpurk3 EK29 trafected ells Fgures 51 A and 51 present ie r els obtain ns 112 I anti bodes purene frmaubbit J4628' and rabbi #@$6 erespective. Fiur n t R-7 the results obtalined Miln F10 atbde uiid ~n abtr64 g,9 [0018) Figu e5A 2C present ec& e sting locailed to the ce1 inenbrane. obere usineoied TM21 ad TM exanU des on three d afeet cUe v Figuen 52.V 52A,4 nesera the us on CESS A. ct :I B{90) cale igures 52B 513- presentte result on RamosATCcat no CRIN 1923ces and figures 2 C 1 520 3 presnt themret on DAMd (AT7 ct no (C1 3) celWs. Figurs ANk 1 nod 520 2 prest the resu obtained using I21 anibodies purfed fr N abbI #685 and abw. 68 spetivi. figures 2A and 52A 4 presnt the restate obtained sAing TM M nbode prified ont rabbit #$ 2 and ra1it 06249 rese gures 52d and 52M-2 parent theresults hand angn IA4 dAes pid n rno rabbit #6255 and rabbit 28 respected. Figure S 13i p resents the reAl'Ssda nad using IMI Antiodis prind fom rbbi #648 ore and $2CW present the results obttnteri using 13M21 antibodies purtied from rabbit #6r2Sd and nribbit 06286. espeetivelp Figuere 5203 presents the mle obtaied using TM 101 antibodiesTified fromn abbit #6248, [0oi90] DETAILd ED$E:ldPIION OF ThE TNVENTIONC 0019-t] The present iventni a fome enedingents, ret to ang one of t poypeptdes referred to as KRTCAP5. FAM26P. .MIGC52498 IAMTON TMM, po ipeptides. andits corresponding nuCdeic acid sequence ad frament and varits antd baoogs thereof. and th ue he as a theraneuti andh/or ciia,anosti tariw aerin to at least some embodinents thero are pro'idded uses of these po ypept ides d ds cret portions thereof as a drug target for the peuee aa mnlecues peptides nubiodie atisense RNAs. iRNAS nbozemes and thetikt vcording to atlat sme e abodiruet the rwenitum <veles in diagnostic and Fh-rapenac poiyenal and Otmocilml anttboies and fragments thereof that spcciilcaty bindI Kr I F AM i MC5249 AM70A u 154 polypkeptides and potions and variam tereo especially those that target te ncelular domapns or o varnits thereof or the niq e bridge. edge tai or head Portlonh Of nflgmn3t o(r vanmt tlepaOf Accaiding to at east some enbodbmen the Inventon prides hunsan Or chimnia mnorcian-r1 antibodies and agents tereof and aw idrotypic anods h bnd speeifcaUy to a'y of the amit acid sequences as se foit A SEQ ID NOs 7 8 104 1 I. -PV25 29-31 354. 42-64. 11541, 12 n 127A i2 3m, 146-162. 186. 191-192. 196 199 2 ad ovarian and fnmtent and hon ogs thereot [001921 According to at least tome embodimens of' the invention, the antibodies are denved from pantcular heavy md light chain ernuine sequences and/or comprise particular structural features siuchi as CDR regions com prising particular amino acid sequences [he invention provides isoled antbodis methods of aking such antibodies, immunocnnjugates and hispecifc molecules compsriing such antiodies and pharaceutical and diagnostic compoositions containing the\antbdie5. immnoconjugates or bispecific rdiecuies. Accoina to at least soe em beOdnts of the i wen hn, the specific anubodies vay be usd IS the treatmentand m asMS of cacr andor mmnereed condition ts described her n [00193J be prrder tehat t h e Present i entio maor ready understoode cera em ame fitrsc detfvned, Additiona &.efintis are st ft~ throtetbont the dietaile ,d descri ption.i 1941 Te ten "KRTCAP3 protein",n edheren n \ ma proin encoded by a KRTCeAPS Per u tcun knovs or r "Wildte protein, aen'y se Vd thero any other yarns (here-t or any irents ilavof ramin d o o a anyesre pdon hro) [01951 b ri "KRTCAP3 pptd* fee to a polvpeptide encoded by anty one of the nuele e acidsequres set loth in any one of SEQ ID Ns:l*-6. 994. 9171, i93195 and farngmnts anid homologous thereofg epeca y thoe posseYsOing at oatZst 8O. 900 9. 96. 97, 98 99. sequence identiy therewth. These nece sequences are refered to herein as "RTCAP3 pelzucletide" The term also Afers to any one of the ,oltidek othi oe ot U- t NOs:e 8 .10-13 -(te ' on Net to in tuy One of Q ID N -i; sucne bridg edge piona ti oro head paron thereof. set fords in znt' o ne of SEQ T.D NOv-: '46- 1418' provtein frcee seetd fro n' at tof iso4 p0l 3k)tkka.do that m:c used flor rabbit. mo:-se Q., otliti lnlnremalitrurnwi-zaion and! specific aniodie prodAnon st oh in any onee. of SE'Q ID NsI I 1l arid tfttttttien and homlog h especallv those possess g at east ) 9 5 96.. 97' 9K3 99% seuneidniythrwt. 'tetra'8.ICX ~tncei.d ~ RTCAP. potvpeptrde N as isd herein, fur~i' to an om .. .ttsn ovncetie n polypejpidest respect le y. that are dieretniydl expressed e g n cancer fnhuig hut not d to I z cancer, breast cancer colan cancer and ovarian cancer wherein the cancer mayg be non'netatutc. in uvirie of rnetastatsc [001961 The term "KRTCAP3 variantsif. as used heri'n, refers to a proteiu encoded by anyV one5 of the ln-cleic acid equienceS set trth in SEQ ID NOs: 2, 3, -4-, 6, 9, 94, 171, 193> 191. andi fragments and ho-mologsous thereof, especially those possessing at least 80, 35, 90, 95, -9. 97, 98, 99% seg uence identity there wih. Thie termn "tKRTCA P3 novel yvarianta)", as in further refers to any one of the proteins set forth in nyno SEQ Ns:10,, I, 1, 3, 47<51, 146s-'48, and fragments and homologous thereof, especialy those possessing at least 8 S . , 90% sne ceidentity threwith.-QI .001971 The term "KRTCAP3 proteins" as used herein encompass any protein within the g o ot RITCA P3 poy peptide" "iKRTCAP3 variantss" and KRTCA P3 novel rw antMs' [00198I The term "FAM26F p4ti1< 3 ussed Iheret i inddes ainy prOtein) encoded by a .FN2F iWneW product.. n n - o w type rei a s e vints themof. insy otiier giants thereof r i ny agents thee ciding batnot fintied to ay eI elat potions there. [01991 The ten "FAM26F poypepde as used heren, referto a polypepUde encooed-' by ty one: of toe nulic acid seqen csse fo in any eof SEQID NO,-s: 14 125,97, 2Zt and gments and hono neeot peclly those posss a least t0 $5. 90, 95, 96 987 99Y sequence ident therewith These nucieic acd sequenes are referred to herein as PAM26F palydetd s The term also rlfers to any polypeptide set forth it any one of SEQ ID NOs:I 5- -I xtraceular ponions thereof, set orth n any one ofIc E 3D4Og;2 3 1 que brdge ege p.tio, ui or nead portion thereof. set fiorh in any one of SEQ ) NO-:I27 149; protein fragments selected for any ofl he i-solated polpep"tidep that are Used forabbit moew atr Other i5iuiutmatiianiztit and soc-cp~ef nibodies production set frthv intns 0 1 SEQ fID NO,% 117, 118; and f'agmen-ts und nd niogoustemef especalv those poseening at least 80, 90i 95. 96. 97 98a 99% sequencdent hm ith he te FM26 i u-eotide or -AM26-h potipertide. a sed herein. -fiuthua rv.rs to any of the foregoing p nleoides and poivpeptide. resectiely that ar differentially e-pressed e n came indudinbut not sted to ovarlam cancer breast cancer, prostate cancer. renalancer nenoma acute npohocytic l ma, chronsc ly-mhoc - leukemaactet rnyeoanous leukemia. chronic~ :yOelOgeo leukerria multiple triveoma. .I-Iodkin's lisphomia or Now Hodgkin's lymphorna, wherein the cancer may be non-metastadec invasoe or nastadc as 42 er' hostdiase [(02V01 The Qrtn GC5249 potein ssed herein includes an- prot encoded by A Gvj49$ge e rad includig Od nown or 0W type proin any spee varies t ne'eoa,as teretoraytas tednf (ndin t rothued Ko [00201} Te teirn a0C52498 pppt.ad us-d ein, ree to a polypeptid encoded by:any one of the uce acid neqnces set ath i ye of SEQ INt 27, J09 13, 2 and gents and homoaoou there espcallthose oengat leno SO855, 95 96, 07,9 -9&. 99%, esea eitityv etwt heencecai Seuce:s ar refe red to here as "KRICAP3 poIyecttdes. The term also refers to any one of the polypept des s th n any one of SEQ M 1 2 q. ; 35: xtceha portion's hereof set foE in any one of SEQ ID NO,:60-2 nq 5d54g pon on fintnc"nts aw oornos trfl'~ p"rtcclly 'hoot Sossrn V- 0, 55 ,95 96,' 91 989 NukIn yllt efeo th Tlun t ii .. 1,MGCS249h pl-ycettttdde GC 9 poly5 pept- asd e ' o ncrn futbe' " rtee to all of the f poynxteleotidn and poiveptidem ievp'et' Mhat a e differentdal expressed e in oan=r biludino but not ii'riied vt' butn",-.4 uttllIe't" tnMO 15yOulyl$ma, copw ilA non odgkins Nophom euke epe cel eukema -ere the cancer maybe non-metasta invasive or metastatk as wel as non-adigtar disorders suh as mmue elted condition or disoders nah din hut nor limited to infaumniaton' or .artoimmunne dtsass. tnoiarareecion glart YCIN U a~n om, [00202. he term 'NICf 2 4 98 aiant as used henn ers to a protein enctdi by any one of theuleic ed$q~lt mtl1 lt n.W SEQ9J N(s22.7. 109S,201 ., anid tagmentsand homoogous thereot esecanyl those oesse at8.east W 9. 9 96 97. 9.8 99% sequence identhy therewtthe term "Mit novel varat msed hern fuirter refers-to any one of the proteins set orth ui any one of SEQ ID NOsl-9. 25 W0--62, 150-154 200 and Oagments and homologous thereof, esecirly those psesding a least 80 5% 90, 95, 7 999 se ente id sen tha the~;tnpsof' 4 MC529~ olpepide'>".MGC524Gh varM WYv-and AM4j&2498 nK3VN [00205] Ihe er AMA70a pep hn n d a ) t ped naOd b e ;m ody t.l in ho le otein. 1ns 22,r, 26 28 103, 197s 198, o angi nadomol therh)O eq eAiathose pnsnat leat 80,5 90 95 9 98r 99r sgnc itrerety Thfse naci2ele e seqrnces "a7er po lerte' as AMed pelync ete t e a potal: f on g eoo ill any one,: sof £ one sof SiIT) NOsz2gk eagt portion; tailo r he-ad portion ther e f u c in a.'y OnI'e oaf SE 108 515 ,60. 96, v99; ponei fragments lctcd semncyes setfd Artrh i. em iddgee an6bodfi:s production, Se t forth in atny on.e oEQ D NOs:,1 56 d agnt 1and 197, 1 h g toesciy se posand nog oA ath ast 850'.Ci 85 90 9',v N\fl at 9 eas 90. 65. 9 , 95. 96 97ei , 6 J9lw~lete iftt ten- "FAMth., I v nA mc rtA polypepte e aused t herein, asne irfers toayonesof The term also r elec (taondes otsih plypeptdes respsetivo thnat 0e iffet ifl N p) .3 i 3 itmccr indkzig I'moo no iwd v"lung cancer tvr ac bretastekrIdIncy cnt multip ,e ml pin andtherel f set the can CeVr ofmaqy n nsiver me as. ede ailor ha, poro se orthin anut'onde or drders nEQeD 5 d [002061 The aroteo ftAM70A arom as of hernrefeprde eed axr by ny Onit o ntd seque anodies prodctI set Tort N1 a2y 9 T ) N1& and 186,rtnranints and hoxoloottereoe y up ose p ssg at least 690, 95, 90. 98, 96eq0sec 0e ciideti thereith. TeAM"70A polynuoti as ad erMin ponhepideto any on f the rtein. ,er fers any one of theID NfO36 p~ynclo~resae o~epiei. epetieY.tht r dftrri~zli apese 44.t 1969 asidag fnwents and honoaloous hereof especia v se posessi at tea 50,PA. 90. V5, 96. 97, 8, 99%se'e*ei nie dwih O2671 Ae ral 'FAM7PA proteiuo as wed heei encopss any proen WA te rnups Of tAMOA POppudO$ er$,'A* 0A ian o"FAi novl (0208I Thetr IMM14 protein> as sed he ns i nchldes anly, Croui encoded by a TMEM154 gene ceduct nudng the knowa o d type" poe an sp v s thereotf ati other yariants tiiereOf. 0o' ay tragmets thereof " ding butnot Pruited to any emxaceldudr portions thereof). 10209 1 he ten "' EM5 polypeptidet" as used heren rea to poypeptide enoded by anr of t ucc ac sequence eth ooen an one of SEQ ID NOsf22. 38-41Y. 106, and fragrtents " n-- \AO-O' T5heeof Cseitl hs a>55t least IS0. 45, 0 95, 96, 97. 98,* 90 squen\' oen t terewvih. The se i ecacdN . m k0 art eferred to herein as' NIM '4 " 'nadC id he (ern also refers to awy oe of nhe paiypep6dtideset fot inM aia'y one s t NMsE4Z& edracellar porutLm teL ot, set forth in an et of SEQ ID NOs;63. 64 nkue hd ge, edge ponioin OR or head port on thereof h iet m o aa one o f 1.D) 11) N s, 61 o67 protein frnp nent; Scested fion a;n of the sted poypeptdes ued for ab or mninand spCi antiodeas produdn. e cti m any one of SEQ ID N's191 92: and fragonns and hlotologo$ teeof ese those pOssessig at ast 80 5 90. 95 96 9 99%) seci ence emy where oh 1 he t erm a'<TMP i 54 po~vnunceolte om' -v' mI tt olipapude ns used heaena nhe rkevs to anime oe te o di u41 pol auodeN nl poin ppdes scimed toi airy tmmune adease.s4 inapinct. incnudn ta not HiOited to kiney Cancer> paneadc cancr w dil exlna l'mnphworn especildy iurn*odgkitv lvrnziho'rn, whr t cancer tnay be nnnisa~.ivsv rm sal swda .nownal~tiamt diordesuden 1 33111 inunne reled 'onditos rdiores nluawht o disease specifically SLEP [002101 The termtoi he ' hele actodomaiCnEDY o1 "eotoon W "extfeelutal ectodcmidan in a K It Atapolypepwi-e rer to the polypeptideSequecet isted below or the ceorren nace acd nuesnce nc do not cOmpO-e the sigmd peptde and die 'TM J rarnermbrane porto) of the KR TCAP3 po peptide: T wo ECD regiam of the polypeptide W93943_P2 (SEQ ID NO:7): W9394P2262(SEQDNO:47 sequence :TV LRH VANPRAVTPEYT VAN (and oiionay bridgin amino acids of any of one. two, See, tour. five, si seven. eiNht, nine or 10 amino acidN on eiher side ,starting anywhere from residue 32 and ending anywher-e up to residue 72: and als nonlinear epitopesncorporating this sequence or a rtn thereof. as well as sn OF=e two, three, tour, f ve. si, Sevein, eight. nine lior o now contiguou\ amino aeid of the sequence 943 P-162 (SEQ I0 NOAS -equence LAV&L:IANCOiRNOADNiJOLLDPI. VPLDEGPO ITDCPEDFiLYDI and opnnan bain g amino acie1 nyat ote two tee five ix energeda nine or 10 amino audisneither te. staitnamy-wheretironresidue 1 and ending anywhere up to redue 170 and so nonlnear epitapes Incorporaung thi sequence or a portion thereof, as Wwe as any of one, twoht fou e. seen. eight. nine or 10 now Zol ouN am. n ds of the se ndc ECD o'F die p e W9394 3P13 SEQ INO 10): W93943P13 -20 (SEQ ID NO:49 sequence RRCSLCAFDA AROPRRI \MPan -gamno acid"', of any io fone. d o? y fi ed svendighi ni 4 m or 10 amno ads, setting anywhere from residue and ending avyhe-e up to resdue adalso noninearepuopes aorporating thss sequenceor a portion there as we as any of on.to' three. tor ie. siNt severk deb, ine-'o et t)nonwl'< us an ciis of the: sequenCe \-VO9394 L3 7-O l SEQ ID NO, 50)-- sequence:DPGRAPGEPSRP (and option niin aino acids of any ooe ue toi ve evenight niger o0 amino acido 0n either sid starting where from residue 67 and mding aoweCC p to ninidae a0 and also non -Iineat cpnope ncorpora 4 mg tis Nequenceor a portion thereof as e Les any of one, two three four t seven. ght nine or 0 oncon Mous amin acid of the sequence W93943 P 3 1 8 NO 48 sequence aptasnay briomnig amino acid of anY ot one twol tree tourfive, six, seven, eight, ine or 10 arano aeid\ an eher side sUrttng we - om L e n e 13 and endnig aanere np to aidue L98 and Amo nonine isencorporaaw is sequence or a pordon thereon as we08 a, n o one.y, two three, Mrin, Ae sI . SeveNOm. Ophl, Ie M J() now contiw moasds ofte eqence); 8cc ED reiwof tbepoxpte .. ,fO N :1 : 9Vk)94 1 _2 6t5Q ID NO< heuce: iVLRHVARGiiAVTPE'IYA and pi i wi Jn a Q So amo q Y4 pl c on? iWO 41 . tourw . t e, I . N1, eeNo 1 Vnt. one O 10 n & acs on either side g an vWhere loan rv u:2 and ending anywhere up) to sidue T; Ond O t S incorpolratin this me(1riC nrpurtii thereof. as weS as n' oW toe, twO. Ahme. tur . w~ e. sNm h ln or M ors, aduitiOUS amio acds of thMequnen W9393 PQ1 62 (EQ ID .NO:4) sequence; AVSrv AN R .ADDP~ d GPttDcPDTRIYD land optmonally burkleng zunh~o AcMd of any cf oxus t rlee, four. five, si:x, seven, egt, nine or 10 "uynuno acids1 on oithe sde awtn V wam r4r 'd\dl 105 and o4d anlywihen Up to residue 172: and s n n atina seence o prt thereof as wel as any of one, two, three, tout f e seen eight nine or 0on soontieun aamino acids ofte.sqec) 'Two LCD regions of the po ypeptide W)3943P SEQ NO: 12) 93943 4262 E>0 hi NO:4 sequeceV ANPRG V.PPEYVANa opt oa bd no acids onb aei a on f tne two three ad ening hee p to rsidue 72; and ako nona near epitages incorantrin s sequence or a portion hereof as well as Any of one t aree four fe x seven eight, nne or no oon "inn"as antino acids of' ~esnec) w1B94; P3715-162 ($T,-Q If.)NO:stis) une LAVUIVANO.RR \fD fPGLLDPLVP EGPG iTDCPPOPTRIDT and ontionahy r n Ro acids, of ay of one. two thee, 011r five si even, eg, nine or 10 Anina Aids on either side, staring ainvhere na ie 105 and endin ywhemY up to tindoe 72 ndlsoOnna( eptopes iicorpomug his seqiunce mr a ordion thereof- as e as ny o one, two, three, four, five, si, even eight, ne or 10 no contacuons anino acid,\ of the aeuence) Two ECD regninsof the polypeptie W3943,,P.I8S (SEQ ID NO 13)): 4C, W993_P8_762 (SQIN:7 serpjmence: TV IuVANPNGAW VTPLTVAN(and opuo"n iy hdogg amo acids d any o oneqo nee .i sA n, ereht ine or uIino acidn either ide ain; no whom fr reside 32 and e iidiq anywhere ut to ire- 7; 'and alson ar epilope c ir io ati fi ae X- f n hreof as we s any tf one, tw the, four, A mw. sevn. eil tins or I Oion wThgous 3n no W the \egw'nie \~934 A 1 EQ5 1D NO: S- seece: CCVA AA T 1.R (IV4C R K G LQK;L% MW PKR 1.QLK DQNQER ASQRS Ys Vadg qoa (3br phX of, any A" wko, w:nwop ng tuma :ns roe three, our.ny. X even. eig.t sote o;i0 anino acds on eher Sde. guin anywhere & usid 105 and end aIyvhere up to reside 8; and also .nonear pkes norpontng tissequence or a potion hro as Well as any of one t four' fie, six, seven., eu ne or 0V an cdruonsamtln acid h nuen le'-t 90% at least a east 96 at last 9a least 98 or a least 99% sequence iet Ibmv su 0 ofZ IAM26F pt,-I3pt de rter to the pffly,pttd seuncslitd bielow or Ahe (iAe~t~ndfli66 l1(di d seq, uences'. (which oo~ not copis hesgnal e toid n thelTM itpitvcibarc 00:1 01 thVe FAMZ26F palyplidtiC -11 6IT) egipn of td SEQ I NO be W0 T82906 3 4 40-48 (SEQ ID NO 5 qunce: QCPCSAAWN (and optonally brd g n eithr side, striganweefioni ridt'k 30 nd endin.-g anOwiere, up to residue 5%; and al noninar epopes icoPOtin sequence or a portion thereoa wel s v an , o on, two thwc fon five i. seven tignt nine ornunontignous amino acid of he se6qu2encer1 Nd eqene EUAAT1OSAFAQR\ LOGRNRSCAA IPLiPCNQAKASD)VQDLLDaKAQSQ nd ilndn .o0f any of one. two, othCO toni, ien 1, s iw or 10 ainro acids on ihr ie srtm antywnvere fr-ont resid ue 15 and rnieayhr np to reAdu .ISb and also nonlinear qi topes incorporatinq tis' Sequence or apomion, - * 8" thereof as we y a of one two. three. R I a. StI , ieen. eigt Ine or ) non( cnttos ammo acddsof the seq c); One ECDregion of the poSpeptide T829063 (SEQ ID NO:16) T2.96_3 _2a43 (SEQ D NO: 127 sequence LSPV SFLQLII KF IY LEQ EQQItKSK ATEH A TFELAKE&N IKCPE EGJSB PKEYNTPS MK EWQQI.SSLIYTFNPKGQY YS SMLHKYVNR KEKTHS 1R STECDT VIPVLGFVDS SGINST PEL (an~d opt'iol b~ridging ain~ifo acids of any of one, two, tee, four, t've, si\ seveB. eight. nine or 10 amino acids on either side, startog anywhere from reside 17 and ending anywhere up to residue 03 and also nonlinear incorporating this sequence or a portion thereof. as well as any of one, two, three, five, ci seven, eight, nine or 0) non ccmihaguous amio acids of the sequence and iaga ents and vagrants and honologs thereof possessing at lea' 80%, at least 85% at lest 90% at Sam 95 at least 4" at Wea 7T a st 98 or at least sequence identy therewinh8 W0211tl The tern th swolb ertrlonai mIOI retdm:no c)% eodma of a MGC52498 pa pepd refe t he pol- ypeVpdeu s ed or the carrespon inclein cid sequiceres tocs hh do not coprise the ignal ppde and h T tranembrane portion)of the MiCS2498 pRtenO: hree ECD regions f the polypeptde AA 382 l P4 (SEQ ID NO: 5 AA2138203P. 55(SEQ NNO:5 e-. ence: MSG ACT \SSl QEVVRGPSClP :4AAVFCCGFEDHK.YCDHSPYPKUS (and option.ally i g g amino acids of any of one two three fou. ve seven, eight, nine it 1O uno a ,dstariag anywhere from reside and ending anyhere up to wsndue:65'n alsoN 'nrtincar epkopes incorpotidog this sequence or padnthro a ut~upr,-un ti 3- prtio ote weB as any' of one two Maree .fr. five. six seven, eightnine or i onoeoti in acids of the sequenc AA2 13820 04, 9190 SEQ ID NOt I- sequence SSK Pi'l ~-ITK.LDLCiL$.,LDi-X . CVNT(1MAAEVPKVSPLQQSYSCLNPQLES NANRCEAVTNPP P (and optional bridging arnin acids of any of one two., threeon fIve, seven eight, nne or 10 amino neidso enher sate, stad n anywhere fron residue 81 and ending anywhere up to residue 0; ndiarpope incorporating this sequence or a portion therenf as wes any of. one ~o ihtree~ tour. ine.MXevenrt. " ait.ne or 10 nona giou i inoltS id.KL o he sequence~ AA2 13S20P 61 i(SEQ IDtNO:62)e MASLW PS ALTFTDA P F LT RLV L P N LPAPARCSGALIG gad opti;oall bridging amino acids of any of one, two, three, four, five, S, Sven. aght no or 1M amino scud on either de, startin. anywhere fom esidte 51 and ending any where up to residue 81:I and aho non- inear epitopes incorporation this Sequence or a portion thereof, as well a n ofoe, two, tht e. tour. fve. \ix, seven, eght, nine Or 10 nonc~ostiguous amino acids of the sequencee and rnqreaments and vaiantos and hominogs thermt p igae 80% atleat 85% at leto 90%, at least 95, least 9 it ast 9%7 at lts n9 or at east 99% sequenceient themw . The tean t ab ecdod anu EC r*. "3' ectodo m o>kxracel ectodonaein" f a FAM70A p pude reae to th;re tpyptide sequences tited below or the conespondng Ie cd se ence b t not ls the ssignalpepde and te IM {tran merpftrane poronl othe FAM70A potein: Two EC; regos o poioepideP10649 PSE. ID Noh3(Th F10649 P4 1-59 IfS EQ I) NO54) se(nence PI'N V nd optioadly bhdgig amino acids of any of one, two, Ore, foMr a sX, sevenegh, nine or 10 amino acds on either ide starting aywhen fron reduce a dndi o annwher up to residue 09 and also ineatittepe itncorpomtrn this sequence or a portion thertof as well as an Yof t". io thre, {umr five, six. Neyen, Kigt nine o-r W0 no-aoniloso acis of th. sequence); E 064&9 l 10225. 5SEQ ID N:5 sequece DOVPAARHIDLKPLYAN RCNYVPKTSQKEAEEViSSSTKNSPSTRVMRNFQAARE VCP1112RfCIPaiRCNKToEC ILYNCtNNVIYE Y 0ilV$SCQUIULHNLL VSA (and optinally n anino acd f Oy 0o ne" o three, fourfv sn. sevn eigt nine or I0 amino acids on either sde. arh tig whet frna redne 100 and ending anidaere up to redue 35 and also nninear epitopes mcorporaung this sequene or a potoO thereof, a weon as any of oe two, thrfolar te ru , si 'en s sita nine or 10 noeontiguous amino acids of thelsequnee Two ECD regions of the poieptide F10649P.5 (SEQ ID N 33K Z-'Mt F10649 PSS -59 (SEQ SD NO:54 sequence: TTRTQNVTV (and optionaN brdging amino acids of xn of one, two, three, four, five sim seven eiAht. nine or 10 ammo acids on ieitner side. Stava .rmngwhere from residue 1 and enAdjg mywoere up to fCndwe 69: and also nr-i near epitopes incorporatinlg this sequence or a portion theneof. as well as any of one. two, three, four, five, six seven, eight, nine or 10 non-contiguous amino acids of the se 9 ence.;0 ) eqe~e P5110.,1 0 1 fnp() U! NOW6 l AP \ 1 HifKPLANPNIUHVPKTSQKEAEEICPI SRECTPRN NT C) N\GNI(AR\ I WtiY IDVSSCQDHjiL intly WN 1a Koaily brin 'arminv Wcd\ of any~ of ane . te. w toni'. fivSe, six. seven, cogt 'bne iv 10 a id crs o ih ag or~n sn es whe we tr r .. a . 0 m e a tr m ' a w s wn o t ei due ia n I iso ( n i endfn anyher ren tec.>$ n's -e21 -, Te a no4ne nar ep tope ncorparating this sequence or a poaron threo as we1 as "y OfN one. wo. hre fur five. six, sn, eight nine or 10 aoncontinuous aMe ad 0 te sequene Two EUD region of the po Ipe fide P10649 P tSEQ 1) NO 5: _10649_P .59 E N~4 sence: FTRTQNYTV a'd optio'ly btddg ne mmuno ZactO\ of )-ny ('4 omt to' t how.*u fie Wax , sevn..'' e inhtl~ nin r1 0 amrinox acidsi on either side anl anywherl fle n i andending an up to reside 69 arid -also oninaepue nerounNthis sequencek or a porton twhere xl as any of ome. wo. thre, tour, five. , Seven. eigt in or 10nK cniu)srnir cd of lre sequence F1I 9 PT 110- 241 tSQ 1) NOd equ e D).CY fAAR fDIKPIL YANRCH YVPKTSQKEAEEENPTLPALNCS Vf NTPT SYYIP QVASYNTYYiASPP PPYSA-, DFQ SUVFPSSPPSGISDEPQSAsPPYOSSAP RYIS>YYPPFFIPPP 0 do na amino 4sf one. wo. thre fou'.iv,, sever eight, rime9 o nmafino acids on eithersidesiig arywheee from resione 100 and ending anvwhe'u up to esidue 21; and rlso non linear epiopes incorporating hisequence or a oro drr-of, as Wel as ny of outwo tre e, fer fiv si.seven, eNi. nine 01 10 i NVil': I~l amino -o hesqu'- ")' a 7 eO . Uc.$l 1 dek'N0114 Net1elde Iwo ECD reg ons of the p u pegwide 10649 . PS iSEQ ID NOt6): F10649 PS -5165 SEQ D NO$9 sequce TTRTQNY V)YPG and opdonialy n alnino acid of'my oft one, wo , three. fy, I o ai onl ithe side i'ng anyhe om redue 41 and ending anywhere np t osi 7; aid also non Ainear epifpkesincm pari tins sequene or a potm tehuen, a, wal a an otone, two, three.ht anaie s.seen,cahi. nime ofir lowcflailnon\ ainno acid cif thre sequence i Em649_t2 32 iSEQ IID NO{:57- sequence: GOFKDMNPTLPALNCSVENTIPT VSYA PQV ASYNTYYHSPPHLPPYSAY DFQHS GVFPSSPPSGLSDEPQSASPSPSYMWSSSAPPR YSPPY YPPFE KPPPYSP tand optionAiy briding amino adids of any of one, wo. three, four fim si. seven, eight. nine or 10 moe acids in either side, \tarting anywhere frm rescue 213 and ending anywhere up to residue 338: and aSo non-inear epitapes incorpoiring this sequeceZ Or a portion thereof as well as any of one, tw, thr, four, five, si>: seven tight, nine or 10 non, Ceotiguows anino ida of the seqence ' one EP region of the nolyp epride T1 f"10 Sfii WS NO) \ ):' 9 10,30-15 (SEQ 1D NO )- sequence s FKDRI MNPTLPALNCS VENTIVSYYWN'A RAPQVASYNTMHISPELPPY SA YDFQHAS GV FP~SSPPSOLSDEPQSASPSPS YMWSSSAPRYSPPYYPPFEK PPPYSP aad fost:oan,(] brioging ;lflin auik 501%' oft'e olvitwo Olnce. oor five, sieen ell. nli . 1 Ro acids on eit sid start anvw nre tre resfde and ein ere up to reue .195 and Amionea epitopes nocnporatng this sequence or a portion rhertof' is well as ensy of one'l tw.thuee.u fivei even eiht, 01110 10no crintwtin' ame acdds Of the equiece and fragnxertts and ovarian tsand homlogsi therof pos sensing at least 80. ateat85% a least0: at least 95; at least 96at least9 atleat s 98 or at iese9% sequence ideot therewith [00,212 The terna the suelecdomai (ECD 'eT cadomn o trm-aca ectodornan of a poiypeptide 'TME M i 5 refers to he palvpeptide securences beow or the corrsondlna nucle acid sequences which do ntcomnpse the siga pepti and the TN tracnsermbane~ portion) of the TMEM 154 protein: One 131) legion of the o lypeptide WS3-46-P3 (SEQ ID NO:42), W 346P3.975 (SEQ ID NO63 seqence IXLNSGDTNESERPNKTIPSTF AY'KETh NANTNShFA PDENQLI (ard - tinaltlridging ano acids50 of any of one. tWo Sthre, tour le. six. seven, eight, ri i ;r10 anW d on ns qo Wdn di anywhere op to residue A and asno o ee or a Paho thouf. 3S elIa k" 0 Ono. ma. tAe. tur. liv. ~A, noeIeo. eiahW. nine or 0 on Ono 0 no Qc d i seence One ECD rh peptide W364P4 (#EQ ID NO45 NMNRNAWD CPT K KLESN PS D&S ad opriionasv hridging atno acids any of oe. two' three Mclv . i 01 sene. eight. nine- or 10 afmninoacd nehesie starting anywhere from residue and ending anywhere up to residue r and ao non> lia eopes ncorporatn is sequence orapoton there as we as any of one tw three. four; five, ir seven, eight. nine or 10 nousano an of the en OneECD region of he popepide W 346 P SEQ AD NO46) EELIN$SGDTTVESERPNKVT$PSTFAAVaTKETNANINSTNFAPDENQLE (andi b~ bodgng ;iinnO acid ofanv of one, two, ote fW-, fve. six, me"en, eight.nh or 10 aninoaci:& on either sid e starting anvwnere trom resde n 13 n anwhre up to feddue 85, and aho nonlinear eptopes incorporate hs euence or a portdon thereof, an well as any of one. two.thne.: tou, fi-ve. Wix, ee eight. nine or .1 no OI~i> Oli lltilO e> 05of them-.Cqunc)ei. ndl 'ra'nents and vas nd~ hon es thereo possess atleas 0. east 8 lePt ~f:Qatlest 15 at lestn 96, a est9, at leas OSr at least 99% seuecieniy, WOR1'3i1% The m imm response"" refersf to the action of, for 'eitaflite lympnhocvyts 0 nten esen Cells, phagocytic celL. granulocytes, and soluble acromolee produced" by tlhe atove CAlS or cells Produceds by the lve or spfleeknl (inluidirie atiodie-s. estOkeet75 and cot puenent)ha reuts in selective arane to destrcio 1.o vnau fm the hunan hotly o in-o pmags cll t infected with patoces. aneros clls o in ease ofritlfilllt or tsathioqical nljnna pnrmad human ca, o tinraes, [002. Tc i atibody as tened in 11 I tIO iden whil pnl," "advt and mnonoi'c niatijodieryand any' antigen bindingnfagnient ( inti genmbodin portoni or sgle chains tereo An anybody" refes ta glycopotern co ig a est two heavy' cains and twn lgh{(. an i se-connected hy disliie bond or an antagen hinodig pnon Thereof Fach h Suc a comised a heavy chainvariabe rYin (abbre\ ated heain as VI and a ea chain constantegon 'he hea chain constant Yea in compsed of three. don C =01 and (03. ach e dw comprised <i a light a ha n viabe region hhreiatea heren a m and a i chain omntpegi. se tNght chan constant eyon is mfi otn donn (. fhe V ad reions can b , her subdi vided into gions of hypenaiability, termed conpleinentar determining reions (CDR) intrpersed with regions tat are mocoerved ternd ramewok regians (R Each VH and V1 is composed of three CURs and four FRs rranaed from aminoterndt to carbovwermnin in the following ordeER. CDRI, R DRZ CDR 3 Pl D, CJRS FR4'he vatialie resigns o0flte heavy and, ight chains contain a niz domanthat mectNs wihn leiane The conant on of tie antibodies inay niediate the bidinag of theimnogfobulin to host issues or factors including -vauios of the immune system (eg effector cells) and t irs component (CPg of the assical (002151 Thec t trntige nd biding portion of an antibody (o(r simply "antibody port as ud hemn refer to one or more fragtnents of an antibody that retainlrh AIDIiy to specieri bind to an ntigen ;e n. KRTCAP. PAM26F MOC$249$. FAM IA. TIM l $4 poiypeptides and proweinu n t has been showm that the anigebindng function of an Wx - be perndby rgumnt of a fllnt nbd.*snhso binding fragnents encompaused within the term antlgen'incin pord& of an antibody include (i) a tab firaaynent. a monovaent fragment consisting of the V tight V BeH Constant ighi (Cl) and CH1 domains leb) fragment. a biant fragn compnri5n two Fab fiagmns inked by a dinid b dje at the hinge region; i a Fd angnoumoent ns tof the W and (21 domananie Fv fragment consisting of the VL and VI clonA A\aon a snsle a'y)ofIan anu c%' v dAb'famn (Waird et l., . d Narae M4 ) w den \onsts of a V do ann Do ariolated cniplementantv deteinrning region (CDR Fuhne slhot the domains ofthe F fragment. V and VL are coded fo r separate genes they can he joined, ing Incominm methods. b a synthetic linker thatenables them to be made as a sigale protein chain hich the vt ao onovrream molecules dknO~ as single chain Fv (sc.Fv: e e. Bird et at d%198) Srlnne 242:43426 anHsOn et at i1988)l Proc, Natt Acad. Set USA 85:5879A883). Such single chain antibodies are alo intended to be eona sed within the term "antige- bndt6i portion" of an antibody. These antibody fragments are obtained usg coventional techniques known to those with skill in the art, anId the frapnients are screened for utility the 'air e rmumer as are inutantibodies 190216 A, isoaed antibody .A ed herein rnended tore to an antihdy tt suhstantrdlvre ofother s aibodies as ingt frn auntoic Spoe.Lncitw gfQ a ohteiartd r enh d t: specaaiy bin lKRTC NP PAMP. MGc539 AM7GA 4- .1 54 proteins or .t.CA.. PAiM26MC, 2498 PAM Y1A, or iM polype-pudes is substantialy tree of antibde tant speedicay 61nd antiens her than KRT'AP AM26 MGC5ZQ9 1AM YOA TMEM154 pten- opo eptides respecnve y An soted a ody at speicaiiv bind RTCA. 6A MGC52498. FAM7OA TMEM 5 oteins rpoleptides nna however hae Crs reacisutvto:W othw'r antj-ens. wuh as KRTCAP.13 EAM-2t6F. M0C52498. EATM7QA. TME 154 proteins or KRTC rAM26 C52498, AM70A or TMYM 154 paoeptides fm' other an jsolated snilbo y y b so bstandaly -free of other cel~anmateinal and/or chenmicas [(IQ27 The terms "nocinandady or "nonoe-a antiodcy position" a used herein refer to a preparation of antibodg tuolecules ofsea molecudar comaposiaon. noe na anbtod bo mposito d sjinys a single bininad spei ty and affnity ta par Ktbar e tttOpex IOO2I81 The ter! "human aniody'. as used herein, intended t include an-fibndies h vi uirs~ vartabte rem-ens Inre td b th fraw,ork 'ari CJDR reinse Itiv ed from~ .. nv' ,.,. Iqznnaozlb h-misun germnu mmunoiobun sequtences. Furthermore.t the ntibody contains a -ensn taein. (he constant iron also iS derived born hum a gernn-e. nmrnuno hiouuhn sequences The hunmi anbodies accoiding to at least sme eniboiment of the intve1nion nay include amino acid re-sodes not encoded by hm g inc irmunoglobuli sequences (e', gntations intoduced by amdom Or tte pec niutagen. into or by somaic nutatdon i However, the terma "human Inibody as used herein. i not 4tencded to incde antibdies i which CDR seegncesdert Dor the get line of anotern anaiaan speces such as a mouse ave ben oaled onto huua.inraewni seg ence. [LIQ2191 The tant "human monaochonal antiboy refers to antibodies d ipaying a singe binding specificny which have varable regions in which both the framework and CDR{ regGon are derived freim humam e~nline mm3nngi ohulinl sequences. In one e~mb~d~ient, the human nmonocdonal antibodies are produced byv a hybridomna which includes a B3 cel obtained from a transgenic nonhuman animtak ea, a trhanIeni mouse, having a genome compising a human heavy chain irangene and a hight c trangee fuaset to an inmnrta Ii rd cell, [002201 The ean recombinanthuman auibody" a u'sd herein. ci des all hnmn antibodies that are prepared. expreoedceated Cr .soe rcnan means sen. as Ia) atusbodies isoated hre an anniral egg a nouse hat is tausgenic. or transchrornosomnafor huan. ienmunogobpnun gces or a hvbridoninprepared therefrom desrbtned ther b6aW-. (b) antibodies" a td fmm a host ell ttopnmd to express the huanantibody. e. gt from a transtectomat (-) a'ntiodies isedated tro a recombinant combtnatorial uman autiboidy library, and (d antiboedc prepared apressd created or isohated by any other means that involve cnof "inhm an inumnog obuhn gene segences to crher DN:\ sequencessuc corimtant huan antiodie havevatiah.naions in which tae tamnework and CDRZ regions aen derived &rosthmaan gemniine (onmunogjtin aoence n certain embodiments. however sch recombiant human antibod ies can be ubjected to i viti :Indagenesw for whn an tansgrnc for human i sequenCes . readhn ivo 'N omti t a2ng0nesiad thus the iino acid sequences of the V Vi and Vi regionA of the recomblnant antibodies a sequences that, vhe delved from and related to human germine stand VL sequence may not naturally as is nn tbe uman adbody rnnune repertoIre in vivo. [00221 As used heen sMtype frefrs to the di body h N-1 oha s wcuodced by the heasvy chain ck3oNtn eine 100 221The, phrases ' an antibody recognizing an antigen" and "an antibody specifc for an atten" are used nterchanceblv here n with te teru an anibod which binds pecicaY to an antigen [O§223 Asused tert as antibody h speificaii indsf' e h n KRTAPS FAN MaGC2 [A O ,n ate pegae nte to ia to an , tibody that binds to htan KRTCAP. FAM26 MGC52498 AM7 VMEM 54 proteins or p :yeiaes optionany oae th a KD of 5X 0 -I oes 0 AMOiWor less.Ior nwom10Yn) NI orrlass, [ " he trm Kaso oa sa as used heLen s ende to refrto te association ta ie otuar a bofngiad c' a to e term KAI5 or snit en interacon Th d tern ITD. uaed haem is ntendedt rater to the dissociation contt hkh is obtained at in a and is eo ressto as a molar ~ O cotentao N) I vakw fur x ants~dis cambe tenaxt 0550 :iitods wellP stablished athe are. prefered tethod fot dernnia the KD of an andbod iby usin 5inCe phAnfofl esonane ooalL aina a bloacnsor ysten uh a Iuia ce) system. (02251 As Used herein, the ter igh affinity' for an IgG odnbody reens to an rdbody having a RKD of 14' M, or ks W eN ss or M NI oNe- tess for taat nge However hugh affnit b indung can Vary for other anubod Notypes. or example, "hkh Ohnn's biraing~ for, an IjM VrAr to an :antibodyv \-i a RI) ofi I(Y NI orles, M N on lass [002-26 As nsed boontit. thOW' m m'ilrers to, a pntsa stece at thes end n-Ia ainin Otd sequence that sn I qe to a spc vasuant aceotiong to the present inventin Therefore spice -vaa han ving eh a ta may optionnydy he considered as a chera K that least a first pmrdon of the sple i arant icaly highly homtOlO (oftenI00% deicaN) to a portion of the corresnding known prten e h a least a second portion of he varant cQompOSestne tail UM02271 As usecd hereint term head's reth to a pepide ste ast the be ginnig of an aOnoo add sequence that is aique to a varint aCCordito te presentinvention Theroenea spelieariant having such a ihead may optionaly be considered as a cfmera i that at least a firs portion of the splice variantecmprises the head, while at least a secnd portion is tpila hil homologons (often 106% identican to a prion of the co-rrespaondana known protein [00228] As nsed heirem the 0erm "an edge portion" refer to a connection) between two photos f1 a splice varianA according to the present inventionthatt were not joned in the wiold tpe or known protein. An edge maty optionally arise due to a jom~ between the above "known protetin potion f ai variant and the miitsfar exmple arid/Or may occur if an inremal potion of the wild type sequence is no longer present, sucih that two portions of the sequenflce re now conftiguous ini the spl ice variant that were nom contignous in the known protein. A "bridge" many optionally he an edge poirtiion as described above, but may also include a jOin between ahad and a "known pr-en"pOnion of a variant, or a join) between a tail and a ^'known protein" portion of a variant or a join between an insertion and a known prote Q portion of a variant. Ise emibodinent idge between atail or a head or1 ,niqe insertion and a i"nown protebt portion of a vaant, cones t iast about 10 tot acids in some embodirnents at est about 20 onunniids or in somse emboiments at least about 3 anino anN. or in some embodmens at least about 40 anmno acid, in which at least one amino acid sorhe taw/head/nserto and atieast one aniin acid is f r he. on protein portion of a vmant incm embodiments, the bidge may omprie y numbr of anino acids from about 10 to bout 40 amino acods (orexampie 10.1 3 7 33 39.0 amino acids in length, oray nater in hetwee [,02.301 it should be Noted that bridge cannot be exended beyond the length iA toe sequece in either direction, and i should be assumed that every bridge description i to be lead in such manner thathe badge engt does not ed beyond the sequence itself t)231 burthennmore, bridges are iescried with .regnard to a ng window in certain conexts below pot exanpne. certain descnptions of the badges fature the otowits mormt a bridge between two edges (in whiOc a Po on of the kowouteOin iO ot psent in ne variant) many option be descrilIed a tos a bidge portion of CONTIt' NAME .t epresceitin the natne of the protein (co'nprning a polypeptode having a enrgth 'n. wherein is leastabou t amino acid in Ith optionalit as about 20 amnino acid. at least about 3 amino acids, at least about 40 amrino acids or tast about 50 am-no acids tengt w at least two amino acids comprie XX (amoacids in the center of the bridge. one f-rii eah end of the edge) having a stniture as w (mnberig acurding to the sequence of CON MIK MEXNA Pi P a sequence stating rom any o amino acid numbers 49-x to 49 (for example); mnd endOUng at ny ofamino ci $52R numbers 50 + ((nm) - x(for exampN in which x vnes fi no 0 to 2. Ai this example. it should also be read aS including bridges in which n is any number of amno acids between 4-50 minmo acds in length. Furthermore the brdge polypeptide cannot extend beyond the sequence, so it should be mad sch that 49 x -for example) s net les than , nor 50 + ( n-2) or example) heater than the total sequence ength, 2)ZZ The termd neuac as used herein should bender i od to enconpass aov ne dlstc P lcase Bvhether invas ye or meatatizk which is chacterized b haarmalandn nnconnmOed celivmsuen causing ane wt or mner. eindtng exainples of cancer which may betreated wa cotmpaiOn accoding to least some emd tdenused threat sona d Umors, sarcomas. hmato cal m ignauces, including but not Hlimted to breast cancer e. breast carcnnat. cervical cancer, ovary cancer (ovary cam inomna\ endometrial cancer melanomna. bladrhi cancer (bladder (.rtinoOt d ~he cancer tadt acemrcminorna and nonsmall cell lug cncer paceaetic cancer (eg pancreatice rcinowna such as ex:rine pancreatie caucio mac olon cancer (eg. coitretal cartinonau s laseoton adenotareinoina and colon adenea.prostate chance including the advanced di\es himatops.eoe motors of lymphoid inege(e g. leu-emia acute iniuahcyvt cm eun caroie lymrphecvtic ienkemwia. 13cel I lynuphonen Bnrkitt' lytnphoma tmuit-ple nyelonma Hod,..kinrryphonm, Non-f-odglin' s lmphoma, anti CD20 (is- kuRi nab) resistan yphona) znyeloidleukter for exarnpe, acute dc s ia)i thini cancer. thyoid foicular tcanceri .mye iasie syn:ronmeOSC) tumors of mesenhaal ori (g fibrosarcornas nd rhabdoa agosarctns> n e anona. oven) melauna. eratocacunorna. rtnflacauct i anaiIdeI alure-ci Oea uphern esophageal quamou cea cnacnoma, hepatocellular carcinoma. fiocular denac celi carcmnra, ints'anal cancer, muscle invy ae cancer, seminal S ale tumor, eidermal carciina solee cancer. ladder cancer head and neck cancer stomach cancer.lier cancer, bone cancer, bzin cancer cancer of the n:tina. bliiay cancer. seall bowel cancer, savary gand cancer, cancer nte oImit Cane. r of test~icles, cancer of connective tssue, prsectatu y tr nplos'splam Waldensroems .mac-rglbi naemin.nasephniarneal neuroendocrine cancer nvdodysplastic\ srcme. mesotheinma. .tioaroa.Kaoi.er. a.. carcin oosophagogastric f'loinib cancer, permtoneai cancer papilryv remus mun etian caner, malignant ascites.

gasroue~i~ni srond tmortC8hIand a Ohadtzu Cantois roresc s1 raaine :n a .drnre an Von Hipp d a asIdron HLI [Q233% th reca- too o ar Cancar The disepse seted rnste go tensght i eid t'orimarv and tetastc cansit the oyava. i Ang ettheh A cn,'t anMr YOU an semv m enendomenrr cleat cA m se epithena. and Wf cusenti cannon an and irene a rtumen a we -as other nom-pthefeneoplasns oie ovar tnhdnigau gene cell maligamcie s not nted to p;esarv and Mnetaae aner of the breast. iicudirig mainirary carcinoma such asInflaing Ducral Caretnoma Ductal carcInoma inait fikrating Lobxuar cacrtra' tlrt acn :1w-situ lnflarrrmov bratcnQ re~adsaeo e breast andI other non--eilheliai neoplasos 01 te breast.ncte dng fiosateoomas, 1-c ~ o ers, rhapdomuyosarco az angoseomtasoaonooma ohy Iodes. W i regard to lang cancer, the disease is seleCtd frdm Gt grup consstUg of but not hruted to aquamous cell lime carcinma.ung adenoca oma caniioed small cel Lw"' Cttl .xf rort-aai cell lung cancr [0t 023M With gadancer e disease iseleted front tegrp c n ot nt united to pvmary ani netastatie eaners of the ler and ntrahepatic ble duet gar to renal cncer dieasis ected omm the gop' const bat no ted t prary and metastic cancer of the kidney, nteladn a renal cell ovary. mcindianephWob t n~ (ie Wiestumor) tasiRtanal cell neopianms of the rapes and aus saras w nal g With wan INo coovancr, the dsease is seectend from the group C esiatig of" but not lWited to rimnry and metastatic cancer of the eo. ie ddig rhanocareinoma muneinous caruinman icludin& geliven e and medarqu carnmaN t r'rid. smal cell carcinoa, sqaaxiriouas cell o aftinomtx at nedifrentiated careneoma.s well ittoter tiner elileophasomt of the coln. .ninin lymophoa.

cora ing of nt nited to and mlkseatWcans c e wano(etWa p a neiingude nocarcinoma, erot35 and. tiWciOUS cystadenocarinmzis aciria cd cari iA 1'di ffret atee 10 aarc <i catcobiiasmronu an i e ni o o i i tmo rs z uch a so nog arai.ae gcesd be otIoe tc s13Vand 3nmeasiai 3i~ f~l 3untenma 03Clidlg Lut s anaa c as sperfal speadin 5 anena. nodlar meanoma. ralIe naos 3Ceum2 Nand ktetigo rishguna mehtoma as We as -,icsa meianoa itraocula meaoma, desm tc/ne.m i men maand a ana of Safn pars cearc sarcoma) 1002191 Wit h kr 'aa to pros"-tat c C k r. the iseas-e is-. steeC tei d fri t ,zhe r:Op -o sng imep the al neop t ~ itjci p aden~on} hyperpiat, pmiade adenrozrenoma, Mucinoas or si: n-tuor adenoid eyse carcnoa prostate duct creinomna h~toco hueremia ironicc knaphctic ienkemun it acu ~Jte mpnthol bstc ema ace eeoenou 'ea'ernia. chronic vaelonencos ieulsenisa. ntre p n a B d lymphoma such as IHodgkmas lyti homal23 no300-d-ki s igrmphoina NHI1) ~ti C:10(ihe. Pitixnman)resistant iymphom~a lowgryade/foi edarIN~I-. small cel fmI T NH grae diffue NIH' huhi dc. minu b i- hoy'- (SL ' Nphbai NNL high E grade s mll nc'enrclc NI-L bl disea e NH-b mia i a y on cosa-Associated Ln ahe ise CA Nmph ma -AkL hArkt phoma \-edastmd tmge B cell Umphcma Nodal margnA zone B tell lymphoma $ NMZL Sp enud marginal zone lymnphomadSMZL Etanndelm dna n B cll, iynphoma ntravascuar arge BR cel phoma Prmary efso 0> Enmptoma Lynponatoid eranomatos B-cel pro.phocytcjeukeia. Pec-ussr B cAwD-miated ly tphomua and Waidenstism's [O0241.. The ternt omor: reited condele' as rused herein wil renompass ny chirese dIsorder of condition elected finn the group incinding init noat hinnted to asatiie scierosi psornesiso theumtoid ardhitis: peeristic arthritis sstemic us tervhentatosus rSLEt nlcenniic oliis; Kohns disease; bandign yphocydicangiis. thomiboetopaenic purpurxc 0obentoistpi idioath c thnmbocytopeda iopadhc aoznimnune hCnit pure red cell pias, Sjogren syndrome rhiuneI disease. cotnene issue disease imTiaiuatcy itindbod t srn degenej ai dv r1~ iien x,,-i odA exti'ac i p -Dir uasro nerureunti atirits aiitslouct nueoa d e ian tihcinic pOiyatrthies crycigtbtalnemic ascuit. A NCAassciated vascul itis. atiphosphol ipid y rame. yvatthei as autounmnrelheentoijde ,:cn~ae Gud Iim arre sddkoma chronic imne diabetes. Addison' disease memnbranous glomevukmrepropathy (ioodpastu\d d~es 9aitammun ga pc'ou5 anaefi a pemphigus vi s .ithosis pdm ay luonea ctoms dermatomyVu ti wot nyoasts .bronIyosiis. mygIelsi, clac oieae, iunrogiobulin A epipathy. Feioch<)cnonlein pu pun .& ans svnadrotne stie cemenma systenic sckrodenma, atho aleergy, pm t aearyecrrosi ishmato iv~dttis. oritry :iayedeii 5yV iftetC Ophitalia aduOl liunneO uiti segatitts. chronic action hegatits. olageny ditsases. .kylosing \pondyvlids eria irdis .amieroseapuaa5, panartets eodosa c indro.nsi ge gBaoniot P . nicroscopc polya i chrone urticana. lkms skin disrcdes. pemphigoic topic eczOm. Ditids diseas childhood trtoimmune hemuolyc anemua Refractorgno chronIc Atoimninume Cytopenias. Preention oft deVek men Cof at oei mat Anti-Factor VII antibodies ia Acquired Hemophilia A Coad Agginti Diseas e enivellts Opica. Stf Pro Sy'ndronie giegivitinpertdautiais. pancrenting myocrtrdis. ascrubis. sastitisgo gouty t arthritis. and ritflnnory' skin disonVer se ected fromni e group cnsisldng ct OsOriaitgi pe derimaitl eeems aatitt.U a in. and dem, nrocomp etenai urtier la ivascuti.pennardiis. m yosm anti-synthetases sgndromne.sl 'thiA macrophage activation syndrotme Lechet'syminronie PAPA S adromeic BIuus Syndromle gout. adus andi Penile St I 'a disease Crympyrinopnathn Nbwvt rW 'I id' Oit ttiCt an Ca o d-iUO{I rdan O naevssw ne o atal neutroogac, cutneus and itituar syndrome systemic jrve~nie idiopth arthritis iyper dIl) syndrome. schnttie} syradcomie and I N acepor-associated periodie synrnte I RAps inf lammator oel Isense. Good pastnreY syndimndepenidousnemia atrnatunte amtroi e io.uertis eohias. ised connect e iisse disease. pananrmtis nodosa. pogflreive Systeio Ese'Odermfa. pepti ulcers. ulers chronic bronchis. came o aY ry gimav inammnon rwam hperrsponsiveness, scpe shock, inttunaior skn disorder, s .yogeosis, chondrocacos thyodit. dergc ea, g oastunne does asocid ihgrantsphtntion tejectio. sga as a te and carnicrejccon orar transpantaon i6gerni SteP anpnan itiOgOOOsa\sten ten 1Tra phiraT~ImI bone ianTO iEnnp altida and gratt versus host As used herein the term treannest 0 refers to care pnoided to reeiehesiand objec e a, to iprev~ Or slow dowa (Gessen) the targeted pathologic conditions or Osordt hosc in need of treatment in e hose already with de disorder as we ias ihose prone to h tie thu;EoIer or those in whoIm the Adisder is to be pr cnted The term treanenta used mhrei fes also oranimnae theyy. wh iA a toen that is given to keep a pahorcgi eenditiott disorder trom coming back aferit ha disappeared folkomg the [00242 he tern themapeusat effeciveanount refes to an amount ot agent accrdln( to the parent invention that s effectvv to treat a disease or disorder in A used herei he ter ti diagun reters to t'e process of I ent i a ed d ag pr3 ioctd t, xding e. g- detecting the expression ot the n.c1ei a d p - ptpdes acco .g o at eat some emnbodinme.ns af the invention in ta biologeal sialm e inl cos, tissue nc rectum as defined below obtatied ffCni an individn Putenl inh ts used hereid the term dhiagnoS encompasses screening fr a disese det cuti a presence or a seeity of a dsea distinguishing a ease fran other disensesinluding hose diseases that may featuee one or more similar or udentical symptons pviding rogosss of a disease, moruto disease procession orlapse as wel as assessment o treatment efficacy and/or r-eapse of a ies.dsre r conldiiion-, a'Is wet]l as, see na therapy aid/or a treatment for a dsease opmaadan of a aen heapy f&r a disease, mnotorin tghe reat:rmiet of a disease anuotr predicting the sawabini of a therapy Ior ptie fnts OfWpopiatio& or dertn igte apprate (losing of a therapeutic product in patients or sbpopuhations The dignosti procedure can be Wfored in Al ar inVt Itro shoud bentedthat abitcoogicabample obtained fmom the ubjeet may aso ptionafly comprise sampe that has not been physicay r moed fom the subject consecuve eiAnytrtion of two or mre med eationskery ohap t ea a n e disease Inpart cuiar the term refers tothe use 01 any of the polypetides poy neotictee itto co:dbiatti Ithat least Ott addition fledtatof nOf thertlerhstreatmen of a disease uina theagents accodng to at least some embodimentso thepresent nveauon my be combined withtherapies ll known in the art that inclde but are not ited to, radiation therapyantibod therapy chemotherapy or sueryo.n combination therapy wi Other biokaictal agents, Conetoa ndrugs anti :canceregtu Snoosnpprttsan cytotoxi g: . . f uncaer chenotherapeutie :ient\ Aonxinx to a least some embodiments. treatment of Multiple Mgelnma usm hte agem according to at( least somle er odiments of the present invention may he obbed tar agent indudin but not limited to Melphaana predasone. thalidoile (MPTor combination Bortezonab ~eicadelmphdar, preodnione {VIP) or a Coinctt of Lenidomide plus kwdose dexnmethasone. According to at least some embodiments. teatmet of ovarian cancer usine te agren ts accdinge at least some embodnets othe present inerio mat be combined with an 4 .~ tio rinithet tOachQatgl aod. Miplain Accord ng to at leant some eintocimets treatment ie-nm atoitd arthlitis disoider in the agents accorn to at les sonme embodiments ofnte riresent inventroinmay be cornorned with but not imited to a rst ine cotbination tatmenit With a drug suoh as ,spi n abl cotone..rt....eoidst wicn e used to reduce prun and inf-ammation ad on me Mosecnd4ne combinaion dr.s such as gold. methotrexate and hvdro'vc hlovoqwuine ajuen promot Se rase issr and prevent progressve i nt destrion. Acordi to at least some embodimnents, treatment of rhetuatoid arthriti inchulacordin to Zud d order may option-aely feeur air gent accda othe \tsent ammdenl~O comnedi with an agent indingi butnot limited to methoirexate ard rituximab. As used herein, the term "sbject" includes any ho an or nontrumnaan iaIl The term rrnnman) animal" includes all \tebrte. -eg, mamnls and no- mArmrnad such as nonIuman primate sheep, dogs, cat horse cows, chicken Nhibians. reptiles. etc. 64 (OO243i arious pects of the inyenun are c etibed i tte dead inthe fboano [002441 NC EC ACUDS {024 A peleic acid fry aart'o an < t onetde" or a Tpo incietide" arfe sed herein eedaingeay to rene toa polynier of nucei acid :residues A polynleodde eseqneit iag to at east sorte ernbdients en te resentinente tuters toe sinre odon e stranded rele acid rigisene wmn is isoiated and rrrvided in tennue of a .RNA sequence, a complemnentar peilynuceodtd sequence fcDN At agtenomic psnneleetie seqesnc ior i cotipoe olneofide. sea ences (e, acoonatio of the aoye) [00461 Thu.the present inventionl encompasses ttcli aidi sequences described .eteinabav- rnante ee ofo ienc-'s hbridi ane rhcrrw sequendes hooz acid segucnces set ferth herein" neqtunes encoding sino iku gypeptides with different Ccde asae. alteed sepuertes am~tet'tziea Is tmaatI's'' d as deetionnertinor usttian~ of one Or m~r lot eseti l th dt SNl OCCerng Or f3t num Id e ther randomly or n a targeted fashion. 'The present invemion <do encompasses nomnologtous nudeitc actd sequences Q winch forn a pat one poly udeotide sequence according to at least sme ernbodimen of the nresert nt 'e't'on shieh inviude seqttnce reg$iS uunue tote polynaucleots according t at i'at somte embhodimnenrs or te prenentaan [a047 In ases where the peivnclde sequences accoonn to at least .otm emhodmnent of the present invention encode previously mniek ted polspeptide th preset invention also encompasses novel polypeptides or portions thereon which are described elnabove. [00248] bt the e presen itenn'rn also encomp~asses p ppptdes encoded by the polyaleotide sequences accotno tos least some emnbodinments of th preen inventio, Thepresent invetion aso elcompa ses hootese of these iosepde sncn honiolane an be at least ) i atest 5 Pt 98or 99%or more hoolojgoin to the* WIN 565 amino acid sequenices set orth below, as can be determined using iasP software of the Natonmd Center of Blotedmology hnferiaion (NCBJl) using defacit prameters. Emtay, the present invemin alao encompasses fver cents of the above *described polypepides and plypeptidest having mutations such as deledionr insertions or substitutions of one or more amino acids, either naturaly occurring or man induced, either :rndomnhy or in a targeted fashwn. [O49~ igonucle~otde de fru casrrvng heethods according toa t ast simoi ernoi*n, <,3 the present invenirod n for .. e uece poa a~e tae'e of auesID ted as dke icdbecl aboue 1a5 genet accod ing to aboutnacletide synQis tocd known nthe art suas emn c syhe or sod paesnthes EYment and reagents for executing so phase synthesis are conmmerciadly avalabie from. for :a t s nthesi of the ogonacleoddes is we withn the capabiries of onesilled in the a. 002531 igoc leetides used according to is aspect according to at kast me todinents of the present intention as those having a length selected tmn a i nge ot about 10 to about 00 bases national y abou t about 50 bases aut 20 o about 100 bases. or about 20 to abo ;e aos e s . inenuon many comapre heteocyd c eWsides co istin of purines and the yitriii dines T02521 PEPT W S [O0253( The terms >peptide " petide' nd >roei are used itearchani eata herae to refero a polyoner o am no acid residues The tens appij to amno acidip nlner in which one or miore anino acid res the is an analog or mioeticofa~ corresponding atualocOcrrn amino ais cias tnatuna1l accurring ano aciki aleo s Povepie can be modified. em by the addition of cabtohydrae residues to forni ycvoprotets.lse terCo yepti . potptV as o incle 0o<oei wseflas non-giycoprotns.

[002.54i Poiypeptide redacs can be b heniically nthew: :ed ment as b\ implnsg sandard solid phase technoues $iuch methods mndu,,e exclnuvse solid phase snthesis Winthd sonld oktse svntlens metood, baDnmer cciderisauon ztlssicl soluti snhesis These orthods are optionalysed when The pepode a relanely short e, 10 kfa) and/or vw hen it cmaot he produced by' recontbn thnioes ye. not encoded by a nucec acid squWe) and th\eresore in okes stfditreint c nmrv [f102551 Soli phase poivnppide sfnthesi procs-dnire are we known intet and further described b ohn orow Stewat and \ DAliaha Yoana Solid Pha Peptd Syn Ieses2ndtEd iee (Tnitca Co Ppn 984. [00256 synthetic poptd can be *rfied by preparaitv high performan iiqtdd chomtai.rphy c ta 1otent inres and moeua p ie. Wi Feman and Co N i ndt composion of wh"ch can te confirmed ia amino acid sequenaing, n02571 I l whers gmlana of a polypo eae desired. I can be iner usmng .eo mbnanni rechuqes such as described by Beittr et al- 197) Method in n3ol $ 5516-544, Studier 4t al (1990) Mthods in Engvnot 1851602893risson et al, 1984 NaWte 3J0 5 1 kama u a) (1987) BH) M T (2 07 Cozi e 084) ,MBO 1 3 671680 and Broi e at 1984 Science 224:e8-4t (ureg al., 986) Mob Ca Biol 6559-65 and i act & Webach 1988 Mthos r Plant Molecuar Biolog Acadec P s NY, Setin V4 pp 421-461 [00298) ft will be appreciated that peptides accordng to at east some embodients o the present irrvetno may, be degradation product synlei pesptides or recombinant pepides awell 'as peptkcotiec typically syntheti weptidcs and peptoids and semnpep~taias Nwh are peptide analogs, whihen ma haw for exangue. modificatins enderin g the peptides more stable while in a body or mof capable of penetrating celhs. such modifiatinst include but are not HOnn to N e asterminnoeion C te'rin mocdtiatondepn& bond modiictionnne b Cnimited to (28 N H 2-h C:i24&0 S O. &:Nfi CR24.) CiH H2. S C. NB. CH=CU or CWC badkabone moditcaoons. and reside modifliuon Nethods for pepaing peptdomimetic compounds ae we known in thea and are speci dd forexample in Quamitvaie Dr Desn CA Ramsden (3d, Chapter 172, PE Choplin Pergamon Press (I9) whic i incorporated by reerence as if fuly set forth herein Krthe" detas in this respect are provided hereinumder..

O tideo) within the peptide may be substittedi for example by ethylate~d bondN (NCH3YCO), ester bonds -C{RHC--CR)-Nfl. ketomethylen bonds vCO C2 u -aza bonds CNH-NWR& (CO w R s yl eag methyl carba bond CH'-.N- , hyIrox yeiylenO bndas . i-C t CH2 Mio Kaid boards K-CS N oefhorc doube bonds fCH=CH retr amde bnds -Ci Lt peptide derivates i NtR YCH2tO tw ~herein Rf is the "normal" side chain naturally presented on the carbon ~0O260 h .&e t' oditiaon tan XCetir at ;ntx oln theaods atong~ the pepyide- .hane vurit aC0ey ofal 2iat tbme 0',6' nmec. W0261 Natr aro m ano acids M r and Phemay be sub-tted b ynhei no--nrum acid mh ;as Phenyi'yne 'n naphta-ietne Nob i esyled dervtives of Phe halogenated dervatnves of Phme or onireth-yl'T [eU2-621 n ad]p oitOrne ao iye peptse4ain a 0east > e emboiments the present nventon insy ayino Ihde one or o modifed anino acids owr on Arire non-ano acid monomers (a. tiat- acd. complex carbohydrates etc) [O0263 As -used heIin in the i ican < andls section beo tem ammo acme' or amno acids tin undersood t Ade e 20 naurall ' anino aids; those utno acids oien inodified posit-ansiattionadi id oi inldiggjor eanple. bydro yprono; phosperine and phosphothteontne; and other -nusug n a i dM anclina, but not onnited 5 to 24mina~dpCI ctd hvid narxyvlysnne. idestnosine norx San, norunne and ornith e Punhermme the term no acids iludes both D- and L animno acids, (002641 The peptides acco:dwi to at east some erntodmentsof he -resent invention ntiaht cide one no. nr--natiral o t -ntralr polia ' iids incuding, but not Homtd o se 'wtic. andi "heo wich Are capabl- of pqnptide sofiz)iJt o t teir nydroxv-conntang a- de cham. 1002651 The peptides according at lcast sortie ofoinents orte presentOhoeion can be biochemical ysnthezeld such as by ung standard sofid phase techniques. Pese methods include excolsive solid phase synthesis partial sofid phase synthesis methods. f mtent condensation cassicad solution synthesisThese methods are optionally used -when the poptide iK kiti~ StoOW 0 C.I)ka n/rwe i antb rdcdb uwovas am~hent cemistr [W0266I Sod phas iepid es proedtres kw n the art and uaheo descridy Joi Mow Stew and jan DiHtha onna $h Phae Pepide Synthess (2nd Ead~ Pirce C2hesn i mnrpany 98) [002671 Syntheic pepddes can b e pid by pie htilgh pesrrance I <ad chinnt aorahv f(2ghtdon '.4198) Proteins. rnun suatd mecla principles WR 14'eemntn and o, N and cooion iE wich can be confirmed via ano d [00268 i- ases wher amoun i peplides according to a (a som embodients ofe fix en ivw ton a dease oi ane recotinat teh~nsjoessuchas dese"xnbed by Bitter' e.L i '7) MdN:,Orkho& neni 153 16544. Studier et aL (990) Methods Enzynot W.,608 9, Bron et 1984) Natm Oa31Y 5 1 1-51 faka4 atsu at it (9$?) EMtB) 1, 6:307-311. Co- t i 984 EMIBO 1, 3 36711680 and Bogli at aL, (19843 Science 220838 43. Oud et a d 986) o e ol. 55t565 and wVibach weec Me o Plant Mloleeur Baogr Acadenne Press. NY' S et V.1 pp 42463 002691 RECONBINANT EXPRESSION OF INLYPPVFIJDES 10(J2701 Mekdeiria fixr iltoacuetion yf heteinlogoswn v ae e nt mmvl n e e en now4 the art and include dciaasendiated : aMet on alcium pinsp.t precipitation. po ebne ameiaed trnstaction. rotospla fusion.eiectoopoatio encapsudation of the yin o bilisue inection anddirec lmnject n of the DNA into nuclei. In addition. nucleic aiad molecuIes may be Cnrodced 0to mamm an calby vInd a etors Mathods o nfoing ad are wA known' in the. art, See, ma, LAS, Patent Nea. ;92i649.200440<1 ad.915 which patentsare hereby incorporated herean by refence Methods Itransfong plant cels are web known in the art ineladag. e g..Agrobacterhn ad ae d transftonrnauou. biii sricAEDQi trnfomto dte ~ sne , ci etoporation anvia trand fclmntiovt etos of intnftmung bacieral and yeast celi are as w~eknown in the art. 69 P027 nadia ce ilinei av ie a oss to eqesson e w known nI the art and OWNchde many immodad cell We, avib Wn V g the Amaeri Type coae. Coecon( c(t. Tee incde. iitrelCieseamseroaytlO cclos, Nsoar5P celks lHK-297 ceti. NIW21YT3 cell . HetA.: cells, baby hamstrkiey(31)cl, otiy dney cells R hut he ate a cenci a ce p &g (24 A549 CeAN. Y1'3 cAil. and it umber of other Cell lins. Mainnahmn lost cells incude huvmn Other cell lii , tuk mlay' be se at,' insec celhusuch as SOV celamnphin cells bacrial cell p ce and a c hen recobna nt expression xeo' enco ng the polypemide cording to a least some embodments o the n or f ments threnare- i' rodce~d int lmnnumaladan hostels, th. lpetxde are producek-d by cultune the host cells :iolt a periodl of thaesfiin to allow for esrsinofth POpepde in the ho.t ce or apreern N ne o he po ypeptide nto te CIe medt us n ndard rotint prUOCtion methods unt fg CeILS Mchd etc. Nicotiana.Arabidops duckweI dO' Whe potato, e: Bacteial host cells include E ccan Strpto ces spec e east hos co lk of thr i(eitow otherietie wixedtrxrton;ltompoumc0i mel (" an Ne wt- 'itlus a auunbbtr of know techniques. orm rrl ~ glutnilne sttase gene" ceramn cn ns. The: Gs system is discusse d i w'holo on- part ill '2onuetot- vitS pean Patent Ns 216 846, S 2560 5, 0 33S 841 and 3 997 he nuceice acid rnoecie teue en. or conpng (he n acid sequence prdeder h ga e t ( polypptie Am grtk eenarc parit of lh n intant in veato. reatdlos of their" olvosvlationl pette. (002C4] VKCTORS [00L275) Accorch K to at lst soieeuhdi-ste in-vention rvdss'tr com),lprisinjg thle nucicucv now mnlc Tthat encode th fpoluetides fusion teis n dpo~i peptidt .s. and plp de agments 01 at eas so- n emtodnens t aLIQ1 T etpress th poypepddes uscerding. to at casi neo aenodd ments of the fyetotfJ A mI e therof.DNAs ecodne.. partialr wAlhe g repdefo tained a sedbed ae a ierted te egresn Ytfors auch that the geres are onT Wked to trascrtiopnai a ue r ltoaconro sequenes. ien vectrs Nincdeh p ads rettoi ses atlensrses denogassoared iues pV.l3ant urues such as cauim W mosic sobacco ssi. vs cosis ?A AV der episode ad the lk The gene igaed ilto a vrctor such that va oipional and transiadonalomP suecceswh the vector Se t . fte dedacior 01 egdaog the rncription and traniuon of the gene. The exnressica vector and expressio contr setdenCes afCe choseu to he cnam tible Wiith tiw *xpmiol hl Ce( Usi The gene inserted into the expsson vector by standard miethoadegigadn o fompimentary retrction SIleS the gene fret and veetor; ior bhint eud lignaun na restricto sites recpresent}. [002771 A convenien sector laone that encodes a f tnadd om;nple te sequence. wit app Dktt itsIOn Sites engineevd so that any seonee can beensl insered and expressed descbed abo-e P denaation nd tinscripton tentoaton occur at na chromnuri sites downstruany o i the codg g Ion he re-emrnbinant expnesfio vector can a so encode a sgna peptide thni tatase etion Of the polypeptude from a host cel Th ge nmyne rusheconed in the vectormhu tha tiesgna e kei inkdi~aet h airline tcndott'is f the gene [002781 Ini ad iifinto th W0e7~ aci :dioog to u h tvt om etorert of to~ iyn vtt r0. tion xotutv (tX xrsOOdVston carry tt0d.atory sequenCes 0hat ont Xi the pioinS' ot the gne in a nost cell R w11 be apprecated by inos illed in the art that the design of the expres on ctor nchding the section ofregdltorvseepones' may depend an v'ch tactoXs : the choice of toe host cel to be launsforned thie lvel of expressing of jxrozei desrest Okt Prteft'rore 4 )tcniettr\ sequne fon rinla oteU peso include vira elemt that direc ht leels of pmtec nrss in InWIaMAhan cells" suerf as prooters and/or enhacncers dernved frmrtoial LTs i.ytonmegakwimns (CMV snch a h CV n40te ehanc ir 4. Y 40 sc the 540 pmorA YW ade n iw eg., Jhaw.~wv~~. o , p .............

polvonma and strong mamm4aom promoters such as native nnmnogeimi ancd aetnm promotdersm' ot her ddertptteo n o\ vial rtdaitory ele1ment andi se4uenkcs tlleret <ee at, UN Pid Nox. 5 W 4AT 245. and 4.96.65. each of which i het\ i rncror ed by itre:ne. Methods of exvpmBg po ides in b:clerial cdis or fugal cels eg ,,east ceis are also, well known nm the art [002791 i addtion t te nceic acid accord g to atlst se emiodinens of the inventuon and tegoldory sequences the recomiinant expression vectors acctordng to at leatsme embodimnts of the ientroinnuy cairy ideni sequences. such as sequences that regate :S ntiOn ofhe tor in host eilns my. mg i Wrepliatior) andkctahle ner enes Teseectable mr ene wc Nitates selec O of host eeit into W& h the ectorhas been inthduced ac. e, (3 Paty NU. S99 6 4 $ nd SJ 9 C For e upt, typicaly the selecle mker genetsores t'neto dogssac &G S hgg~rmvcin or methiotrevae on. a host eln iNo whih the vector has ben itroduced Prferedseectabnle aikere vnes include the dihyrofolte redutase DHFR) gen the ne S( r G418 seledon and the tmatesnthetase gae [002801 PROTEANWN MOMi CATIONS [002811 FUSION PROTEINS [002821 The preein mwentjon .icompasscs fsin prte {conjugates for useit therapy.e mpesftingre thT TNUVI154 soluble portio s tehud5 the ectadomain orxpoos a adants thereof. Por example the invention encompasses conuqates wherein the ECf) ofthe Tb'EMP 154 is e atahed to ananl ngk in or ragmen there The ieaton contemplates the use thereof for trrtnge caner andlou immne reletd conditions, dieases or disorders described herein (0t253 Meording to aAtleast some mbod:men a fudon protein may bepared from a protein acsording to at least see embody inents of th e inyentionby neisgn with a paortion of an im unogm tin comparing a constant region of an imamnomonn Optioall the portin of Mhe r nsnut'Jobtiln sconrrtis a hea vy chain constant wlcvtefl w ii eqntui.,A and more peembly a human heavy chain con~tot ein The heavy chtn al contat rgeeon is optionalsly an it! heavy cain constant region and opinaav an Fe chain, or an IgC; Pc gnt t com ses m an dmansAtoug apy sbtYpe ma optionally be usedthe IgGHubtype i preferred. The Fe chain mayoptioall e a ksnon or "Wd of muutamsOd are descibed U Patwt Application No. 20016034852, pubised on Febrary 6, 2006, hereby incorporate by refence as if' uHY sel forth herein. The term "'Fe chain also optionally compri\ any tpe of Fe fragment [00284} Several of the specific aminO acid reidues tt are impoirt fr anybody conthant regioni-mechaited activity in the fgG sublass have been ideiierd. haclusion, subsitution or exclusion of hse specific amino acid et e allows for inchnion or exclusion of specific immutnogiobmlin constant region-mediated actsvity. Furthermore, specfle chags may result in agiycosylationi foir exsample and/or other desred changes to the Pc chain. At least some changes may optionally be made to block a function of Fc which is cersode txro tobecdesMbic, such as, an ouldsirabke immnunel sytefect, described in getttr dettii below [00251 Non-idoi itluative examples of uniatias Fo hh may be made to moM te Ma acth iy of the fv sioni Npotein J in die fol61o ngh age gi ven with 01 o a e sequence nencnatu as ien by Kabat frmm Kabat FA et a Seqences 01 -otins of Terest. US Department of' Healtth and vamdn Services, NU I99) 22 C S 233- ELLGGP - > .EAF.GAP; 265D > A preferably in cobinato wth4 434N A,, 29-TN - > A (fi example to block 3'-cs 'on)' 38422 E)KCK AYCA; 330133AP > SO ar a combination thereof (see for exape Ad Clark, hemica mnriol and Anibody En eering pp -3 for a s'reption these mutations and dheir f ect he construct forhe Fe chain wich featuIs the atve charges opoti auxad prefeabty comprIes ecombmie on of the hinagre mylon ivth :the (2 and C W> domain, [002861 The abo=e mutados many opoition ey npkttd to enhance deed popertns or .aternaei to block dodeied properties. For example aglyco:yiation of anti bodes was shown o ma.naiin the desid hi ending fhinctionrali r whb bhk depletion of Tcels or t eriei etokine release whicda optionuly be ldsied finctions see N1, (hark hemical hummol an Antibody Engeerdg pp V13 .Sufbstioriio" of gi pixiim ne for seiet may bock th ' to actaae compiemnenb w many optona ly be considered an undesired funonr s e M Chrk, hemical z:umno, nd Antibody Egepp -3 Chanoitg 330a0m n"s ombintion Withia chant> fmay -Alwa (n:Wance tOe desiredxi ef f) blekiii Whe Ziihy (0to aoIC, tZ lt.Oi.

0029u1 c 235 and 217 wa ntn ed : iHt n~i~taed vtoos(cttADCC). sut that ean ;iiw te bock of resiue fan 23.3 ws deacobed OisVnalso block stwh actlvVif ADC( i c dered be an undesia futink [O288% iiekae224 i normally a csteire for Fe len lG wAc is he ste. a which ha chain f an o covale linkage id t cha Otna di redue may be harmed to a serin tavoi d Any i of covalen ni (ee I, Can nal aAol andAnody EQix eing pp 1-31) [002$91 The dove angen to reidues 05 d 434 may ptiona beim e ed to mucci lokbNadii~nc: to th P eeotor which cmva ojp(oon-al. tv bloc"\ "~'* funtinaltyofRc relxda it t senesse fiwkedfoas (see 'Boig<. gG i rc F Reeptcf'r. Shdiel Y Vo 2706 pp ti59 6604 100290 The above chlangex arc intend as itstraon only of optiona can e and are not meant to he Inmiting in any way f-tenmre. the above expiaoation is prtwded for escapae purposes nly, r oW to be bound y a gehypothesis. (002911 ADDITION OF GROUPS [002921 If a prteIn according It- t- A serokt inIton ak mnoech is to place VvOinjos tticttcinsi gromlps at vanom;u poltt on i liermeclwicae suscepbt;le to or suitawble for chemia modi cat national gro ps can be added to the m o' linear homs of the protmil accolting to at estame emboodimtsfthe en~~boti~~rnents. toe tutioiiet. h rega to one r more chanicteds ncldng hot not rton d t mproveme i stabulv penetnratton through celular membranes and or tissue se tis e coalition efficacy decreased clearance, decreased ton itvimproved seliectits improved .esistacc to p buyon byi itcuar pmps, and the like. Forconvenience sake and without wishing to b.lNflne the. fre'e -eriof ot one of thOu ence contained in tfelu, O~tin accordn i to at least some embodiments of the nveion W be teamed as he .Nlterniins of the cornmositou and the free Cterfiial of the Seqw:nce wil be consider as the C> tnruas of te contposi dr Either the Cterminas or the temins of the seqeitnices. or boc. c'an be inted o arboxvc acd tonloctm gvnsps o r ani a ionM gI: :rspecivtlv [W02931 Non-irttog t>:ampies of suitable jmetional grups are descried in Green and Wu "Prtecting Gmups in Organic Synthesi John Wiley and Sons. Chapters 5 and 37 1991 the leaching> of which are incorporated herein by reference. referd protec-ng groupsrthose thtm Wacil te tra nxt of the achve ingredient attached thereto into a cei, fo example, by reducing the Ayrop"hicity and n h ipophilicity of the active ingredient these being an examxpe for ta .moiety for transport across ceflular membranes' 19112 he moiet as C optional e ceaWed in ~v either by hydra s or enzvaya e'i~~ the cell. (Dumter 1t a P . hardn Sdf 57:83 (1%8) D>ite etih at Sc' 828 98 Dter . IPhr Se $&557 % K 1i . nhl~.mistry 26,224 { f-}'~indjher i t Du Meobdsn} aind 1 wn72K 11 (1%99); and Te de et.at-Biochenm Phan. 33867 1 988) rscon et alt Ah. Biochmemn. >39-538 (1985} and Singhal et F A . P220 P 19871)),f fyd (rottin gromupsdcdd est cathtmates and arbamate mwoteeng gro~ap An protecting groups include aikoy and arykvxy carbony groups, as deserbed aboe. Cr -terminal pOtecting! grcaupsCarboxyhic' acd prottng gnups includel h tic benzdie and aryl est as dewribed a v for terminal potedg group' in onembodiment he earboyl ic acid gronp in tc de chain of one or mor guanIC acid <yr artP'iC acid reZ'shu in a composition acrdin to at Jeastome enbodilmts Of Ohe pree invention protected. optionraly wfh ,a methy ethyl. benz I or substitted ben!z ester [0(935 Noniniting ilustratve exampos of termin protect g goups nc! de acyt cupt-CO- Pd) and wkojy earbonl! or ryo- y carbony oup -CO-O-R. hein RI is. an aliphc ituted ibpht. benvi K sbitd bey wromatic or aa ubptited te0 group Specfic eanples of acyt grous include but are not mited to acety etthx CC n-propy>C t -opropylCO- ?'dyu QCC se-e buty C- burytvbC hr>-. I ornyl. pairiwyIovlysrst Oyl.tarioesunv('- spbhse oylsn-GO, ben yb(~-an st Nd bs-enzy )lCO -sampolr- of dkoz ca boryl and aryioy arbnv orum .ie~h C*de c 0-CC- ehe C) o Co n-propeo o ( o)sprops -C C nOut -CO e i-O uty-O-CO-, plny C substituted pienyiOn-C- ntd enib-0-CO( ubtitue hen-z O-. Adamanta. naphtale imyistoleyl tolsiti biybenys amnnmoy'l iEstrben to duovh DarOy benzoyl. clohexane. onormane. or Z-apro ins oder to faitate the N-acylaton, one to gyicne residuesean be present in the N-terminus ofthe moleule [002961 he cao ap at i te Cerinus Or c und anbetrotecie fto example b a gmpa including brnl liilte e to an Amp N i n tvcly erno ks h Creisi replaced with AN H. ~NlH arid NP R orester dc the hydroxa oup at te -oinih e placed wSh -0A121g R and RI aoe o .i idial K' an ahaz: heterocy cte n'ing wi houttit 2 addttoia heteo sch anroget oyen or sufu.nwleinm sute. ecampe f ntdhee teroeee 'n'1" ''er vy py'onyl.inrohno orn otenlro o iperaroyt kExmpesc(>erminalpioutmg ups include but are not limited to N -NHCS .N(CH; NH(ethyl N(ethyI d i nt 1ey ) NdC alky p tn~()~{; 0- ehyi pQ-r opyh0 nu b dl-N~o gp0 2t*(sece bayl (0O2981 A "tpinit 'g Oraw rw ovyt" Ctn riunt'be sobnt:Wt'vd for am-,ino aodO ridl inth coinpositronl of this bwkriveiti oto anS conservalivo and "teni-otsitt substations. bhese moiet es are also tempted nonvnatra mino acids" and ay optonaly revpaee amidn acC resdee amio acids or actas spacer groups ithin e pepide in tieu of deleted anio acids. Tha pettidzimed aide moieties optionalv h'eatleri eIeton or etaniaurationa proper ti" similar to tOe placed imino acid and such pepk mti cs azv used to eTplace aina a ds - thI essential position and are considered csoservativ substttnai Hweer uch sininaritnes are not necessaritv irgiuredi Accordig-ito at least sewn thodimentts Utfte present anttlYCDo ola2 Ofre peptdominetdcs am selected uch tht the composition at least substaniy retans its P poloical activity as corned to the nativeroten according to the present inrentnon 99~ PeptdonNineds a y optioialty be used to inhibit degradationh e peptides by enynac r other degradative processes.le peptidornunetics can optonally be produced by .gnic syihe technique Nondimiting example of suitable peptidOmimtt include D amino acids of te corresponding L utin acids. teta (Zabrocki et Antghemac l:875580 98 isosteres am ide bonds (Jones et al. Uetrahedronled 29 "38S356 14981 Ld anipo;2poenidne'carboxvi aciKemp t at, Or, Chem 50:5834-5838 1985r ano are stihwn in Kerp et aL Tetrahedron Lett 29:08582 (.19881 as wel as [Kemp at aL .].eft 29:5057-5060 (19880 Kemp t a. Tetrahedrou Let. 294935-4938 I1988) and IKemp dt aT I. Org Clen. 4:109-115 .1987> Other suitable but exemplary peptidomimtes~C are show in£agai and Sato, Tetrahedron Lett, 26:64>650 (1985: Di Miuo et at. J. Chem, Soc, Perkiri Traes 1687 185): KAthn at aL, Theraedroni Lett 30:231 t [989: Olson at alt J Am. Chem. Soc, 1 12:323-333 1990>: Garvey et al J1. Org, Chem, 56:436 (1990. Further suitable exemplary peptkiummetcIs include hydro <w ,,344etrahydrtisquiine 3carboxyhtte (Myake et aL 3. Takeda Res, Labs 43. I 1989)> L.22.3 etrahydro- sogohne-3-carboxylate (Kazmierski et aL 3. Ant Chem, So. 133:22752283 99 ); histidine isoquinoloRn carboxyiic acid (HI Zixhchel at i.. int. 1 Pep. Protein Reks 43 (1990)): (2S, 3 ethyl-phe'nann (2S R athy'> phenykanu> 9R 355 an ph evylaatne and t2R [003001 La mp[ ci l-. ustratie but nolimn g a vctora) amino x id inshid beta amio acis etS and beta? a2 ho rmtnto e cybe amino acids>maattje Zmin acds. Pro and Pyr der'as unbstitutad Aamine der vata veO A1ine deriivtives inyg substituted Phe and Tyr Der varives hinar core mino acids or diamio acids. They are atvaflabe thon a ane I of suppliers. suchas Sigma-Aldrich (USA) ur exap [003011 CHEMICAL MOfl ICATIONS [003021 In (he presen ne tton any part potein accotr g * t a some ide sequence my opmonaly ' modif ed, alhou s described be ernativey other parts ohe protein wa option he moine n addiAn to or in phae of the side amoaidd res-idues. Rte mnoldiaon .. ay optiaall vy be partor, md di ea a syfnhesis of the.\ moe Aei a chemical Syndheti proes 6 olwd for etcarnaiw by ddct a <,mca1 marcheI d ambwn acid, tlowevrernis mdfaiofa an amninr we it istLread-s present in the miene in su nodiaalo posb modied according to any one of the obowge eempry types of modificaton Irn the pade coraa vewe as '>chermaly wdmed nii exermpa type t .iO6Cit fitiiG include mb u yuethylaton acylauonh phosporylatori. lCoMylion or fauy acyaktion, Ether bonds can optionally be used to jAIn the rme or tnineihydroxyi to the hydroxyl of a sugar. Amide bonds an opton ally be used to jon the glutamate or aspartate earboxyi groups to an amino group on a sugar tGare and Jeano. Advances in C:arbohydrate Chemistryand Biochemistry Vol. 43. Academic Press (1985: Kun Ang, (hem. t. Ed. English 26:294-308 97. Acetal and Petal bonds can ao optioilly be formed between amiWnoacids and carbohydrates aty acid aol derivatives can on be made. for example, by acylation of a free amino group te.g. .ysine) tToth et a. Peptides: Chemisry, Stracire and Bology, Rivier and Marshal' eds ESCOM PubL .eiden. 10784079 (I 990 h. [00304 As mce here the tm cemical rdifctlon when mfernrg to a protein or Ipe ie acecrng to the parent inOtiflon, efme to a proten or peptide \her '- t Vtone ofits Amnro acid residues is moifiaed ehiwtr by natural poc.se5 such as po ig 0r oher ostraislatromna otilntions. r bry chemica rodificatin technis.uer vic satr Wl known in the ad, Exaples of thea Ireneroiassknown m eodifieadons a tc n... Is cincde bmt are not mited 1to)tea tion angdnion APIibosynede ycosslatlo. if anhor fornrration. covalent attachment of a ipid or lpid deiyaive mtatn iunvistylauion, pegylatronm pren ytatior. phosphorylatron, ubiquitiaulon. or any similar proess [003051 Other types o'f modifcatins optonally include the addition of a cicadhane moiety to a hidgicrnorecule. such as a ocein as insnbed in PCT A tppicaden No. NW) 200(050c herebi uconted by rferencer as if f'u"et forth hereindheSe mtflties am designed for use w t bionmIwctes and ay opdonally be used to fmplart varcs properties to protein, [O(03061 l-uermore. optonatly any pottan a protein ma be modified. ior example, pegjl-lUot of a gelycosylaion mnoiety on a rte'oavn ma oy opiona.l v be pedirnted as derie n PCT Applica No, WO 20061050247 erby inornom'ted blx reference as if h sfuR et forth herein. One or more polyetfle 'ne glyol (PEO) groups may optionally be added to O nked and/or Nl iked glyoTsydon he PE group may opto be reached r inear Optionally any type of a-at ralubte polymer may be attaied to a .ycosy atin site o a proen tRnuh a glycosvnAtink [O077 ALTERE., 1) CLVOSYLATION 3 on cI to at leaerN Nko e N ue Tj eae altered prrmntXc oreoiaaa or auhr nyod'e to hae anM aedxc p oalata he dn nate seune r ya atcm glyao.Syladttl "wtern. V~ Dsed herei. Wad awre'meashvrroeo -otcrorda noenaeeetedae hman e esa o e 1o e aded the o id e sOeO9 3 ocpp vdeaequn ofna proeins ds tcnali eiten Nireor C he. &nied seer toe a tnnt of th carodat oetr to0 thesie deain ofd anaornn saences foN ke acdecept e a te T Neeno ma Un e at b W he o d h a ot oietv to the tparaie sid chan. TVup the prsneo of cite e these ei uenres apngypde crats a poem!a cdylduet hsite. pne svcohae frefer to yt zt hnen yf one of the sugch Naher atosre nee0Sydofxiogro tos uhy as ams af idne otreonrnor eeor ypronne ttmmade MOdMes h the invention is cnvenMy a o nwsplghedby a() the adminoy aof sequewnce -of the protemo such-that it coaainson or moure of die toe.dsce teipeptid e seuence nNi e dio ites). Thee pranoan moay r aso be made by te Ohe or rrotcein for 0-lnked giycosyla, stes), Thkwtenkiun c- sqec mnay be ' eec yieN dui changes aft -i'lN 1 vei. ( 00n 39e 1 ar0 e enle to he Votn'- euzik ewlOdd"' easia te of torr emsu e by> ctte"'-kca1 n er?-v mynza~c couli nkg of gltvcswn f n ruoai eie'~t~ooe Dpn 'w~da on the couphne mode ud.tee saarsty be attache,; d to (a) aetn n hON, h ti' eah\- roops"' ""0 sn-bvk groonsme a those0 vtte (d) fre . vroxy vis in'np such as tlhose of scoine. threonme o virrvrll.e aoatc residuies uc as to-eof (0hnkain~woie rtvpohn rf tlhe amnidegroup of; z tare. I'T ' a ithod5, are de sci'-hed in W() Ae 7/O05'330, and in Ap:n, -and Wrimton. CRC Crit'. Rev. lu. 2 2$W 306 (, 1W x VhISIZI Riemnoval of ant cabhdaemoieties prt.M on'if proteinsa cco-rd41on to atlewa soone, embodirrents, of t-O v nt txrtvh accornphisec henii or enzymlaticail or an eovAent conpouid. I ustetetrslsi'n the cl eava-ge of mo st o-r -alsul r except the A1M ir 4 Ngzycdlne o Pc ygl actosam n g e h aind®n ad sequence nta R6f0i3 Cemnica degivcosvanois deseribed by Haronddin et at.Ax lioeun 2 198 and Edge it a a BMY xh1e000 111 198 BUILlnaN: cea5 e carbz tovrate mauSSiS0 pdstttrateans he aeed Vthe use of a varietyo eo> and si0mt "Odn\es as desced by Thak.ra et a h nm 0 0MI4 METTIODS OF TREATMENT USING TM.EM.154 POLYPEPT IDES AND PRO'NEIS wo at Maust some embodiments of the prsn nenino ucleiic a0(d ow rice cx intnents hea epecially the ecdni~ r*ers~ form"S oft T'IM $4 ptsad po,-Ivpept ides, cani be msd to oreat cacranhiio u ot limited to Irpos.epcal NosWdodgkin's Lmpho s.ant Dl~ {ve Ritu irmal .ssstant~ uyphomna Muidl N-1 abcid and taeat Co V Id Co i'a Ox :rn5jtV 4 Ito Or c~ ornso ete o nn bc prdt 0d3151 acoc to at let sd the present sventhere n nh bt [003161 As tumed herein the terr "treaongr refers to parenting. mir~nsx. reversig ateutie ll~itisn ;r~r S 5Una~ ( N\ e A O 10O h ikttlt5etts 5 tsbox'edesribed diseases. disorders or condomR Tn he temtsttneta ue hri rfr to therapy" which aun a tregvee ta ke a keito iii eonwcnrn sanrer ows hoenu s asns .o alt s p it hadre a fasddowie be the initia 003171 woti can h e ctd by sp(-c -Mcal spsrezuiatng the expreikm'on & a least one of the noypejtaides mcoronf to at east some 0 0tk31Th Ontionahix 11pr.-muiationl may be effected by adinseigto the sis ect at least onae of thSe p01spepudezs aceorduJiss to at least someesboie of th'Se prese. t inv-enoon" <V ~ non-orot wsvtttite or m active Portion theeof' ;as escribed' hkttr, kiOflwet, c vn rotm he diedtonr a d enet di u rmum RTAPnma3oA26 MGC o 9 FAMptoe 1 A rutnh MEMed 59lpeptie Opaments egbo acueno acs wast see eoivnetd nf haen aind re adnwgk in P3 FAM26i MOa ATU rwpde aIy I a ona0y bat adnterd at a p a r Xn COrtica3o clsc- 5e 9n Ane eA30 nfIl belodewacrdi t .s sn emOd)15 men lbeatecas ta eamn of the n n piob ~ieone cesc moeof dise afornog tohe rsnt om o abcrniemihohrretetnehdlknw nteat 1003201 ~ANThRCPANI-TAM26F, ANT C529 'ATL-FA'Nt7GAt A NTL-ThE. 5$4 ANTU9OA AS W0321 The tiboies cording Wo at fes oeenoimnaof the in1vention incudig tose tuR '38 tiv P~aua ilvrrcnne. ooocu nibmdie"s c -rceiedb ats uf InC don e Neteatesc p tCresthe pancibtes. Fodr, epampe C anedmelaogmand emd ogi ma~uanie sch anp ndimynpho their Wajoheid specrcaik to human KRTCA,'P3. FAM-26F, MG~C52.49d or~2'.K TMIZ 154 pouilsptima nthi an aiodN dn to at ea m ebnoent of .0lw h'tib brts to corrt 'pondiqnn KIV{' AP3 FA:2F F\M f Mt4 '.7A Aor T .'EM1.54 poispeptah', wh high atI' inato e "afnNle 'tkh. a 1KQ.) of" TO S NIortss or 10 -9 M or es or ten 10 -10 N orte. lt, , 'T'h AnORTXl \nT FA.M6F And MCS24 ndi-FANM A, Anti -TMLKM ,',154 antibodies according to at least (.n embodimens of the ae optionnaly enhibi one. o mrore oA the (003221 6i) bui~ads. to o Otecorrepodi hunnn K AP,3, fAM26. PAM70PA. or '154M 154 poly-peptdes with a Kf) of' 5N 1 0 -8 M4o es (10323j (II) Fd 0oeoiteKRCP.N26f.1c MOC$2408. FAM70A. o 'EMEM 1)4 ntte expmRsed. by cancer fei~ nidn or example Ovatnan cancer. lung cancer colon cancr.bras canzer, kinycacr iver. canceir. paacrematic caneposae cell1 lumkemia. but does n ot 1abstantiaWle In d to norm al cells., fin aditon, OPt Onav thes aidhodie and cat gates thereof wil he ecue in ecinig secuvg. kiPing of sach caner cells and for mardittmsc olid rsponW~%fSt'evolved ira ato irtg and cancer l~003241 Ci tiOna, the aatbody hirds toe cesond1g humar. Kin oA Q,. FAM6Sf M0C5249 AM a a u atigensith a 0 o( 3M --S' o. owthaKofItx 10 -- 9 14 o >s or with a9I f0 2 - NI or ieSs or, wit K) Df 0052(10 -->1 , nIo c r w-ith a i.) o wc V -9ad110I NI. [003251 Stadad assis to evah4te & at o Oe anibodies lward KIUAP eM F M 248 A 'A E poiypeptidesare known in he adar.ifc1in m er eszampe. eBUSM West 'm biou and RIA. Snaabe assays are descvnbed in deta 1wi , Eh.wLtnpmkn. Ile binotr Wwc y,. Fndngs affhv of the antibodies also (003263 i poma, 'aduto n of Rt KTCAP3, Am-FAM2F ni MC524% Anti FAM7A Ati-hIE 54andhody seqwences onm antibodies can hind to KR'ICAP3. FAMOF26 M0C551S FAM70A or TM 54 the V and seque ces!, b e adt read ed to create other udMKRTCAP3, kA12F. IGC.2498, FAM0 A, or TMENM 1S4 bnii olcesaccording to at lestxmie: ofoiet teiv~U KRTCAP3 FANMt26Pf MOf::524%, Q:\4 NAM70l or TMEM 154 bh ng of ch "rn&d ad nahed anodeS can be tested aann the binding as aa described aboe. e. i SAS) Qtinnhv bn~ VP 1 arid VL chainN ame Mied and m.athed. a VUsg ec f-ooA a paxtcar VI/VI p iria replaced whk a srrtls a -nar VHI seq-ueance- i-.ikewse. opti~ta a L se frce omn a particlar VkHA4.- pawIg i s rewplaced n- t. stutu y) SW~ M =W cwUlC~re. ape the MW- andN1 k. eune fhmlguaitxi&es are 0027 PARTICER INE SEQUENCES the invention mp a eav chain vaiable aegon fon a particulr geine heavy chan inmonogloh$ anelar a .ijht chain viable region fran a priicuta gnodne lght d7 tiarunuOOgtdobti~tgcit (0029 As used here a hrani antoibdy conorises he-av or light cha v vaab Ogions tMy " l We prodl a" or fdi ved tt a ia gernne seqfe:i variable regions of the antibody are obtained om a system that uses human gernmlie immeolobuhin genes Such systems inciade limmL uang a transgenic mouse carrymg human immiunoghabuin genes with the antigen of inters or screening a human inmrmogobuin gene ,Ibrary dsplaed on pha ge with hme antigen of interest A human antibody that s' the product of" or derived from" a human germline imnmunoglobun sequence can be identified as wch by comparing the aino acid sequence of the human antibody to the amino acid sequences of human eqnine im amunaglobins and selecting the human gemmline ammunoglobuln sequnce that is closest in sequences hi, greatest % dentit ou the sequence of the human antibody , 50 I A hn umnan body that is "the prduest 9 8 or derived from particular hr mu 9mIne Imnnlobtin sequence may entain a7%9no acid differette a5 compared tO the -emlin sequence. due tO for emntpie, unatrayo rr.ng 0onmau Wiuinad itntional introion of siedirected mutaton. Howle a iecfed human antibody pvecav is at least 90% idensiid in ano acids sequence to an amino nid sequence encoded by a human genuine inrtnaoglobuhin gene and cOntains amino acid Residucs that identify the brnan aiody ab ing hunman when compared to he geniline omunr hbi ano aid sgne of other species eg murine gemne sequence) Scrtr cases.a human antaibod ma beaeast 95 96 or 99%; or een at leas %%C; % %, or4)9% idened in arnno acid se seence to the amio ri seUPence encoded by fhe geTi~ nnmnogbin aene. Typicallya human anybody derived from aparticular :n~an germine sequence wil dispyI no more than 0 amino acid difference Iron the ami no aceid sequencde encoise by the hnum germnc insumogobu:in gene. in certain cases di hunntiebody may display no mnore than 5 or' even no risorethn 43 or ansino aid dfference irons them rsnsoncdd segvuence encoded by the germssne innno moobui in en'e [f493311 WUOMO GO(U ANTWBODWES ff0332] in vet another emnbodiment an antibod' 9 according to at least some esrnbodimnscns sequenices foa are homobsio oisaiated AntiK.TCAP3 AntFA.M2F hAn MGCS2498KAti FAM7OA. Anti4MfMi54 amino acid sequences of preferred Anti KRTCAP3. Anti FAM26F. Anti M0C52498h AndiTAM?0A. Ant LTMEM 154 antibodies. 5t45 Ct~iI. w~e~ui se atibdie reaintedsrd snto'alonetc ftenrn antibd 00-331 As ued hMAT the percent hevadog between wo ammo ad pequece, s egoalent to the pereo identity between the two xequece lhe nerent idenniv between the two sequene \ a timeio of the ,urnbt of Qid al positiys shaed by the Wquence Le. %homelagcvw of identheai yotion total y 01 pes't" . 100h. talig lflt neZCOunt the nis1)i'0 o ps aid the length of tach g, whic lAh nOrd to be ianrducesd for optimal ahgnwen of the two sequence, The compansott ot sequences and deternnm:n ot percem rrknuit biweten tw ese 1's iral be 0m ao Ipihedslnearg tihadiai alrtlin as descr elbd 1o th tow n .l, [00334 he perct derity between two mino acd sequence rei be determined unng the g r of E ee and w. ,er icat.Apfr. oseL, *:11-1: os8 Wih a een i rporatedhito the AUGN program (ersian 2.K sting a P M eit es-timai a gaP ltngta penalty of 12 and a gap penalty of 4. lat z dtto' )en ni between tWO amno rC d sequences C rn e R Ned theNe e t Wanseb A. M.idol. 4; =444$53 (197 U)) .Mjg2pritlult Wiihwasa been- inwof porated into3 ti Tme in the ca sodwe pa kane av e onieriafls' n, onetither a foss 6 ta a PAMN2M atrioad a gap naw16, 14,, 1 engthweit ofl,2, -3, 4,ti (00-131 Add4ittona1v or ahexhr W d pnseti Cui~Sicoltgt a es 0 "mdrahelinat of the present lCanot v' bater be u~sed as a '4nexs seqaeunxe t einhm encc aa~st pn ta'haens related S such searches can h reformed usig deXBLASTI progamero 2,0) of Axch at 1990 Mo0 2ol'; 0 0 BLAST protein se ser an be performed Wht XB t ie X ST progam (coretn xv orn qth43 to obtain amino acid sepuces homoloyu to he 'ntibod le e eol to at lsoe e Iln 1th invntion, Ia obtain capped anes mo comparnso puposes Gapped BLAST can be utzieod as deserted in Aktchnet a 0 997') Neck-ic Acids Res 25 1$38943402 Wher uti Pon hi g BLAS d. (lapped BA progrms the defat pareters of the reptx prga g XmAS1' and NaLASI) cni he used. [01J336 Antibodies with Conservative MNdifica3.n& 184 [00337I in certain embodimente an .antibody accordmg to cat least som-e ernbodiments of the invention compares a heavy chain variable region compiskin2 CDR , CDR2 and CDR3 sequences and a light chain variable region comprisug CD 1 CDR2 and CDR3sequnces wherein one or nore of ihie CDR sequences compoise specified amino acid sequence bate on preferred AmtiIKRTCAP3, AntiFAM26F, Anti-MC52498, Anti-FAM70A. AtiTM EM 4 antibodies isolated and produced using methods herein, or conservative moudifications terof, and wherein the antibodies retain the desired fwnctional properties of the Ani-RTAP3, Anti-FA M26F. AnLiMGC52498. Anti-FAM70A. Anti TMEiM 14 antibodies according to at least some embohiments of the invention spectiv eny 00338} In various embodiments the AmtiAKITCAP3, AntiFPAM2:6F, AmiMC2498, Anti-FAM70A, AnthMMS4 an.tibody can be, tor example. human anbodies. humanized antibodies or ahimeric antibodies [00359 As wed herein, the terin cnexvaue seence nnxificanK s inendcd to r oe o it nodfadons that do not gnifiantw affec or alter the binding characterfitis of the antibody containing the amino acid sequence Such conservative moodicatdos include aminoad substtuinms addidions and deletions Mndifications can be jntroduced into an antibody acorAing to a least sogne emabodiments of the -ivendin by standard techriiqugoS lkno in the rt sh as siteidirced ognx; andR med mutageness Oservative amio acid substitutions are ons in which the amino acd ntsmue is replaed wth an amino acid residue vlng a siilar side cai qn nims of an acd rsdes having smnniar Aide caun\ haw, been octned ;in te art I esv nins inlude amino acids with basic side cha (mgi.s'Isine ar1ntne, hmtd WOOdc side chains e g, aspartic acid, ghramic acki red pouvarside chain (e g glcne, asparagine gluamine. srne tiweonine tyrosine cystene tryptophan nonpolar ide chain e g alamie. Aibie. leucine, isoleucine.p" ine pheya-ltane. dtbiinn beta bosnched side chains (e. treonine, saline. icolt einid and ainmnatkeside cha sc rvrosne. phenylaianne. irophan. histidinel Thus, one or rnuoe atr-ino acid codues witdin iccoi fm niod arding to least somte embodiments u)te irnton can be repacsd d h other amnino acid residuers foen the saine side chain family and the altered antibody can be tested for ret-ainedt tnction ie. the functions set forh in te rough () above) using rhe functiendiassays described herein, [OOMtA ENGIEERED AND MODIPED ANTIB.ODWS 003411 An aribody acCording to at 10ast vot icnsonelets Of the idvention can e prepared usng an antibody hving on or more of the VH and/or Vt requences derived from m AntiI-KRTCAP3, Ani-FAM26F, Anti-MGC52498, Anti-FAM70A. Anti TM EM1S4antibody starting material to engineer a modified antibody which antibody may have altered properties from the starting antibody, An antibody can be engineered one or more residues win one or NOh varinbe regons i ni and/Or L f W example witin fn or mor CDR region and/or witoiri (ne or more framework region s Additionally or alttmatively, an antibody can be engineered by moifying residues wthin the comtant region for example to aber the effector fviviions of the antibody. [00,U21 One type of variabl reinegnen.khat c e k rtne is, C.DR ntng Ant bodie interact wih target antigens predominantly thrnaug anmino acid residuies that arc ocaed in he i beaNy and igh chain Fon0p1mnefnty determining myons CDRs Fo tuis' reaonkte: amIno acd s equlen.ces wt' CDKNR arere e divers bet\.een individual andbodies than sequences onutide of CDRs be'se CDR sequenceae responsible for n os antiodyn-amtgen nteractlol dn s podibl 10 tixpt\ recoinbittn ntibodies thtt :mi'mk> the pn'ree of SPOUcic vaurnlfr mca fn niiho s by Ons""trtrcingxmso vectrs that ndlde CDR sequences from thi eped M natay occurring anbody grated nto franework sequence i a different antibodyy ith different qvfpfpt el (see c Riechvaman. L, at (1998) Nature 3322322 oes WP t al (1986) Natm 1 re3 522 525 Quien.(.e all [989)f Pe Nal Aca, See. U.SA $6 00lTx3;: US. Pat. No 225 39 to Wnte ie ndiS 0 at Nor 5330 05, 0 69,3 !i an d 1, $3Y0 to Queen in &k 0 I3431 Sutable mwok equences can be obtained nm pub. DNA databases or pudlished references thaincnlde gerrmline anttbod veane sequences For exnmpe genline DNA seqnences in human heavy and light cain vrable reagn geo, cIan be tond in the 'Yasehnma germnne segueence daabase I vilable on the nie.me t \ as'l e n \ abat, e t at 991 Seinces oteims of rnmounlongicaal iter tn [dion S Depammetdnrf'Henh and Huna Servie N I PubAlitic No '32 Tom ntsrin, I MI. et 4 * 0'992) The Rpepatoire oftuma aetline V SequeN eseal about Fifny Groups 0f Y Segments with Diffemnt ypceriable I cops I M l .io 227:776-798 and Pox, A a. 994 A Director f aHhinan Gtermine VU Segments Reveals a Strone lasun that iane [t. fI mxtnal 4:l8136& the ciets of eadh of whidhare express ncorporaed herein by reference. UJ00M41 An other type of variabhe region moodfcation is to mutate armmo acicd residuest within the VH and/o(r VL CDR (1)CDR and.or CDR3 rcegons to threby improve one or more blinding properties (e~g affty of the aintbodyv of interest Site-directed rmtaenesis oi PCR-mediated mutagenesis can be peformd to introduce the mutations and the effect on antibody binding, or other functtonal ppesrty of interest can be evaluated in approp:ite in vfiro or in vio assays. Oi ycervave modifcat ions tas discussed above are introduced. The mutoations mayt be amino acid Nubstittions additions or deletions, but are preferably suibstitutikms. Moreover, typicaly no moee than one, two. three, four or five 035 Enirneered nbdies according to at least sone ebooents if the invendton include those in Whih umdimadons have been made to mIees.des witr -I antor ! mg rnome te pnes of ueaatibody-. yp tsuch tamewor'k mocdieations are made to cease the immunonen1clty of the anybody orxamp one prei i to r artate" one or mor aewo des to the Je spodg ertie sequence.More spec~ificay an antibody that has dezronesrnatcnmaticm may contain fnmmework reisdwzn that differ ktro de gerttine sequeinec from wich ahe indbudyc derivci Nu resdues can he identified by cnmad the ant hody niamue WOr sequences to the gemiine sequences from which the antibody i derived. [003461 In addition or aternative to modicatins ade wthin the f&anIewnt or CDN region antibodies according to at least some embodiments of the invention may be engirtee -to inc Jtkediheoos w tIin the RC region ypicry to aler one or more functiond properties of .he antibody, such as scram if 1ecOm plemno t fiwiator F receptor bindingand/or andzendependent cetutar cytotoiti. Furtermorean antibody accordiw to at least sone embodients of tie nenn nav hehetnidcl nmdified t. nore more chemical moiees can be attached to the ntibod eo be modified to after glyoosylaton, again to ahe rne or more foncion properties f the antibod' Sth embod ments re described father below The -mer n of' iestes in the Pc region is that of the EU) index of Kabat [00347 n one em hdnOent. t g ing of ( i odified sucd that the. n r ot cestn resides in the lince region is aered i eased or deeasei This approach ideseed rther in Na 2 godmer et a The muoer oCystein@ residues the hi e in of (n sehed Io for example faciia wasnem of the. fioht and heay chin or to niram Or decease the ability the anti bod [N1341 hi another embodiment. the F1c r egioa :n antiboo intated to deeasete biooical haf 4 of he nbody e speci aiy, one or mo 'nmi a fmien d inh t h ody has npa sega NAdcoucy protun A pI btnd g Ye to nbte. haSpA biwh a ppoc i tcbe nI ahi'dti in) U. Pat. No, 6 165 b Ward cia [003491 another emboonet the antibod moifed t crease it tbiogien had Rkc Variouts nporache' eossie. b or eanp e one or mot of e foUnwing mutations can be introduced: 152L T254S T256 as described in US, Pat, No, 6277.5 to Word ernatias t inram he biotoateal half lie the antibody can be altereds ithin the em I cr esiOn tO contain a savage receptor bi nding ei ope taKen foame to loops of a CI12 domain of an t region of an Ga descrbed U S at. o. 569046 and 6 ".U422 ha 0Pr'est( alii [0035 in yet Mier embodments the d reori is atered h iadbg at cagnjp amino acid re dueith a difr amino acid esdue to after the efect nmo of the antibOy. For example one or more aiino acids selected fomti amino acid rsidtes.23 4 235. 236 , 29 318, 320 and 322 can be replaced with a diffent: aino acid resie Such that the antibody has a altered Affinity for an efcftor hanmd but retains the ntige binding ability of ie. parent antibody. The effeto d which a iltered can be. for ~ a 46otFtcepo or thpr1coitoent S-t coo oe matUas approach i de iIn:ed anilher detan i S, Pat Nos -624,21 and 0,648,204 ot by Winter et ad (00351 W another examIeA now or moe a mino acids selected from an i 1a Nid i es 29 33Y td 322 can be replaced wh a difetrt amino acid reside such that the antiody hai alte'ked iN g andlr r reduced or aboh shed compiemdat dependent cytoto xity ( ioprch is described in further detalin U Pat No. 6,94 5 by dusoge 00-321 in another erm on or mom amioacid residue hin an'ino acid pOitios 231 and 23 are altered to thereby a Oe the abil of the intibody to fil COMfiete' Thtiis appwleach iS deehOd AUidbti in PCI' PabHciati$O 942935by fadmea et 3 03531 In 'et another eaamle, the Fc regionismodiied ticase the ability of the anttibod to mediate antibody dependent cehar cytotraicity ADCCI and/or ki increase the AffmnY of the antibody Fr an Fcy receptor by modifying one or more amino acids at the following positions: 23& 239,t248. 249 252,< 25, 256, 258, 265, 267, 268, 269, 270, 272, 276, 278, 2 02 3 25, 26, W9 290, 292, 293, 29q 98 3 307, 309, 312 31, 320. 322, 324, 326, 327, 329, 330. 31. 333334 335 3 338, 340, 360, 373, 376, 37, 382, 388, 39, 398 414 16. 419, 430, 434, 435, 437, 438 or 439, This approach is described further in PCI Publcation WO .2 by Presta.Moreover, the binding sites 00 hunan IgofMr Fc gmrnuar.F gamma R. . tigniaR U and feRn hav been napped and variants with ioped bindhig hat been dtc ed (see Shield, R ,et :At 2001)J. Bin, Cherr 276:69 I66010 Specific mutaion at posidnns 256c 290, 8 .3cts, 33411 and 339 are 'hown to imarove binding, to FeyRlffl, Additionaal5 th-e inini combination mounts we shown to 5inrpme F:ngtama RP binding T256A/S29$A8 129$A!E333A 298A1 Y224A and S298A/E333A/K334A, [03541 In esu another emboent, the eosyition of an antibody i modified For eQanpie. aft aiycosnted antibodv can be made ehiS antibody locks glycosylation) OyeoyauO) cn be atend to, fe enample, :frede ft a ityjr anien. Sach carbohydrae mdificions can be accomished by for example. aien aan omote itesalicasvithi h ai the antibodysqcFrei enexns saino acid suub io n Lie iade tiat r 1 i eimnadior of o r a Wrimb region framework glycosviation sites to thereby Arninate glycosylation a tbat site. Such aglycosyladnmay increase the af of the *aitidyf fNav antien$ Sucidh u a p ar ah desaned Iin erther det ail in, Pat. No s51450 and 63t8&1 by Co it ad [0N Addit n1.1v or alternafivelv an ntibody cans be ade that bas an aMeredtype of glycosvati' such as a hypofucosylated ntibody having reduced amounts of fiY reinkes or an anybody having increased bisecing iNac structures. Such altered ekcosylaf tion patters bavo been demonstrated to increase the AO abiLty of antiodies, Snch carbohydrate eiodiadons can be accomplishedd by, for example, expressing the antibody in a host c h aored aycosvaticn machine.. Ces with altered glcosylation mpachiner .bae been *4kscrbed the art and can be usedNa host els which to express reombiant antibodies according to at kast some embdients of' the invention to therehy prduce an antibody with altered glycosvlaion. FEr example, the cell line Ms704. Ms705, and Ms709 lack the faccsyhransferase gene, PUTS Xalpha I 6) fccsyltrnsferse such that antodies exprssed in the Ms704, s705 and Ms709 cell lines lack fucose on their carbohydrates. Th M4704, Ms 7 05 an yf0 FU{I cell lies are created by the targaeted disruption of the FUT8 gene in CHO/D3{44 cells using two replacement vectors (see U.S Patent Pulicastiun No. 20040110704 by Yamsane et al and Yamxane-Ohnuki et .al (200(34) Biotechnool Biengi 87:64-22). As another example. P 1J76195 by fHani et at describes a cell e4 with a functionally disruped FUTN eee which encodes a fucre yc transferase, such that antibodies expressed in such a cel line exhibit hypofucosyation by .reducing or eliminating the alpha 1,6 bond-related enzyme. [anai ea at asio descri6e cell lnes which havet low enzyme activtv tor adding facose to be >acetyiglucosamine that nbids to khe Fe region othe antibody or does not hav the tyrno n activity. fmr eNzriple the rcm ello R cel hine YB20,AC CRt 16621 PCT Wblicaon WO 0 35.835 by Pirsta describes a vaidrintC li' e c ced with revdud abizl to attach fucose to kn(29nlked carbohydrates; a resultn ik bypofucosadoa of antibodies expressed in Oat hostce ise also Shields R a (2002), iel Cham 277;26733-267401) PC'T Puliaion 0 9954342 by Uioriset aL deselbes ell hines engineered to express glycoprcteirmodfyg pyecsy tnfeaes ge4 bea l acesdgicosaminyvltrsfeirise 111 (GnTIMh such that iitibodies expressed in he engineered ccl lnes exhibi incread bseeting GleNac structureswhich irnaa increased ADCC aed vty of the antibodies See lso Ull a et (t9 Nat. ioteh 1 l Ahenatively the fcoe relies of the antibody r e cleaved off uning a ucosidase enzyme. For example. the fucosidase alhaLucn-dae removes facosv residues fom antbodies iTarentino. A, IA, m aL 1975) fiocheins 14,5516-231) 03561 Anroiher modificatiori ofthe antibodes herein iscotemplated by the invntin i' egs',laiogl An,. antibody can be pegvhaed t0, for example, cr he biogica en haf life the antibody To pegyte g n anthod. the ant body, or fgiment thereof tymcauly is heated with polyethylene g?,co PEG schaa reactive ester or adek dkeirvaive of PEG under condition in which one or more PE groups beconre attached to the antibody or anybody fagmenL Optional the pegylation icaied ot via an acyht]on rekm a , n r k al ylavia ronadn with a rec. active PEG molecule (or an analogous reacve watersoluble polyrerl. As used herein, the term polyethylene vl is ineded to encompass any of the forms of PEO that have been used to derivatne otoer proteins. such as mono (Ci C E) alkoxy- or aryloxy-polyethylene glycol or polyethyliene gliycoi-nmeimide, in certaini embodimema\ the antibsody to be peayiatedt is an) aglycosylated antibody. Methods tfo pegymatng proteins are kznown in dheard and can be applied to the antibodies accordingt- to at least some emodimtents of the invention, See for e>:ampne. EP~ 54 316 by Nahiwa et A and El " 401 384 by hhikaa et a. [0O35 M IS ODS O FN GIN FU NG AN TIWOI D [PO358] As d sened above, the ni1§RTC A uti AMX6 A-v29 A IPf:4r[ AutiM I an tibodies having. VI and VK seuee disclosed he CM he used ' create n AtiKRTCAP3. Anti FAM26F, And - M0C52498 Au FA 0A. Ain~ti lMM mantihaoda esein ntivd. by ytving e V a r V sequences, or the constant region tched thee. Thus, accord to at least some enubodients ofthe ins hdon the structural featuies of an Anti-dKRTCAPI3 And-FAM26 Ati-MGC52498 AiFAM70A, Anti-TMEM154 antibody according t 0 least ome embodint - of the invent on ar used to create stmeturah rented Anti- C~A3Anti [AM hEA-1OC4SA-d>FM7A Antt.1iEMlM 54 antibocueriztt" rezna east one cona propet t he auibodies accordmn to at leas some embodients ot the invention, such as inodN 1o human KRTCAP3. FAMN2KF MaGCS2498,PAM.7( or M 154 respected -For tample.one or more CnR c eg.inofwe RTc PAM2tF M*C52469 IwM70A. or TME&MS4 antbody or nmatons theofa can be coetubned b aem n is with known trainework region and/or other CODN to create additional, zominatlif- gineerd>.AniKRTCAP3> Ap FAM26FF At iGC524 Anti M 70A i AntM iEM54 nt bodies according to at least some embodinents f the inntion. as discussed above. Other types of modification include those described in the ionsaection >f th ina tngterfa or t cneedig method is o or more of thre I1 a na vlr \ K sequences provided herin, or one or more CIR rein there. To create the engine ed antibod t not necessrt cay piepo axres as a prote) an anbod having one ur more of the and/or VK sequence provided herein or one or imore CDR re.egions tet. Rather e information cntained in the sequences is used as the 8tarnign matena to Cirate a cond Eederon scSue0ced dtnived ftorn the original Sequences and then the second generaon" sequencers prepared and expassed as a [ N359 ioendai nohteniar biologvv {ccudiide can be aed t pareand ex9r4s 4erd hody ngence thon. le antoody encoded by "he alIered antihody seqneaie is one tOwt retains one ome Dor all of the functional Ipropertes of he Ant K RTCAPJ Anti- FAM 2 6F, Anti-MOC52498, AntiTAM7OA, Anti-TMEM154 antibodies respectvely produced by methods and with sequences povided herein, which functional propertie incud binding to KRTC AP3, FAM26F. MGC52T498, FAM70A, or T'MEM154 antigen with a specicE KD level or less and/er selectively binding to desired tagt cells such as ovarian cancer, lung cancer. breast cancer. colon cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer. melanoma and hemratological malignancies such as Multiple Myelonma, Iypoi No006iodgin 4 a lyophona n L >20 (aie "rutab ristat ldiha eukeia l tO 'l ke embona rn of the nalta 'n 'care be esnrodcd tandy or eakl Wnag A o part of an AnKRTC:AP.nt iAM 2K 052i982 A M A m An MEi 54 anbody coo!ag eqnence and sin modfed AntI KWVCAP3 AntiAM AntMGC524%, AnTAM7OA An(i-TMEM154 antbodies can he screened ros b e ng actvh and/r other desired facing properties (003631 Mutafionas nd tt have endecbdin the art, Por exavle. P(7: PubI matson W) 0.2/0927,80 by hr de esmetods cag ad seeng abody mutations usc gsataln mtaenes synthedi igaton assembly or a combinadon thereof Aternatiev PCT Pub lcation WVO 03/074679 bLeta et a.decrbes mnedhods of inibodies W0365I According to at least some embodiments of the netitnpertains to ucle a d molecule tht encode the vwdbodies according toat lease embdatn of t 92 iroVentio.t t nncleic acid: may be present in Whoe cell, in a cel lysate, or i: a pnrtall puied or substantially pure forn A nuciec acid is "isolated" or rendered stubsianuy pre" when prified away ron other cellular component or other contalninams eg. other cellular nucleic acids or proteins by standard techniques including alkaiine/SDS treatment CA bandin, column chromatography, agarose gel electrophoresis and others weIl known in the art. See, R. Acaubel, et at ed, ii 8'?) Current Protocois in Molecular Biiologyv, Greene Publishing and W-ikty Intrcience, New York, A nuecc a according to at least some embodiments oi the inventon can be. for ermpie D)NA or RNA and may or may not contamintn ic seuences In a preferred embodinment, the nucleic acid is a eDNA VOSs6I NaceteAmdsacordfint to atleas some embodirmekts 'i ll h ivxun a br obtaned using stztadd macidar biology techntiues Nor nodie espes sed by hybridommas mgo prepared from r eying m ia nonogiobulin genes as described farther below cDNhA eneodlina the light and heavy chais ofth antaibocs made b the byh~doo can be, ob 'ndby standaid PCR atpif-tc rtono eDNA clonin tece [or atibodie obtained fam n immunogioul gene 1tnrary-t~. sm epheae8\ta uchn quest) nuee ac dencodtng the ars-tibodv can be; recoveired troin th iri 00367) Once DNA tra-mrn t encoding and i agenAre obtained thee NA fragments can f further manipated by standard recomhat DNA technioes. for an le to conve thevabe region genes to full-ngth antibody chain genes. to Fab ragmnt is operatives lned to another 1A fragment encoding another protein, suchas an anybody consent egion or a flexible nker LX36$i Te ten oeiatvely linked> as used in this cott iiteded to mean i-at hl two DNA fragments gre joined suchatthe alino d queanes encoded b the two DNA fagmtents nnrin-aframe. 1016 11The is olated )NA, eucodfina th V I-i mg'~ion Can ibe concert to AkuUd lengthi hey Chain gene by erTdvey lin g I h- e.noding DNA to tere DNA molece eneode g beak- cainecoestant regi 0? (C H CH2- and C11') The segunets of human heav-v chtn constant region genes are known th Me atsee eg I,,Knbat A Sequences of ProteIns of immunokgical neres h Editon. Deparnet of Hath ane NIH Pubbation No, 9 3 242) and DNA .agenwan compasng these regions can be obtamed by standard PCR amplificaion. The heavy chain consun rnion can e am IgGl. gt2. biG> lgG4. lgA, lE, FsM or lgD consent rein, Fo a Fab figment heavy chrain gn the VH-cucuding DNA an be opertivel Uiked to another DNA moleeule encoding ony he heavky chain C i constant regrt 1003701 4The isolated DNAN encoding the N~Iv egcon can be convert 0 d at full-legth lght chain geneU we as it a an1ti chaigene) by oporatidiohatnIhin 'I aecohng iDNA to another DNA -ioleci.ercodni t. i hin nstantgi C1 T1 i nces of human vit chin Cnsnt jOgio gene Yr, knoo in he aQ (see t Kaln F! at E Ad (9)Sequences ofPrteins o.munokigica? Interestfith Ed ion, Depatnmt 01 Health aid Scrrtan ervces. NIH Publication No. 91<1242) and DNA fragnrrs enconassing these regions can be ob ned by san PCR ainrn ationthe light chn cons cant region can be a kappa or ambda constant eg on. RI037Ij To crate A SO pe theU 4'andVLeeo~n DNA froamenters 01e opera ey linked t4a)noter a, mt oking a fcenble inker e encodin the am no id sequence (Gl4ef iuch thae H and VL sequences cn be expressed as condtlgtt single%-hainprotei, with the V1 and V-rnN oined byn the exile linked Lee a e~ttr ia 1 s3Scienceae 24:43a :ossto otcnt)i~~atAad.et SA 5879585 McC ety e 1 a 99 Nator : 3:552 -54., 1003721 Producion (f AobA(RTCAP3, AnifiFAbfZ6F AxflMGC52498; Anti VAMIO70 AniME M154 Monocional Andbodies (003731 Motntocioaa anuibodies (*Ar acceding To a least soen emhrXinmets of the present mention can be produced hy a y e of teelnuque nciing convedcnal mnonoclotilantibody mtethodooy eat. dhetandard somic cel hybridizatdon techniue of Kohler andaMiiltin 1975) Natnr 256:495 Athough somatic eelnhybrnhzation pflcediine ae pafeern prdco'uiple e technques foir prodh oug n'onoctonai antibody cnn he employed e- s-i eo oncogenie transtormtaion 01 f ilm fltte [00374 A pt'lrred tan-wuasystern foreiprtrngi to-h ome i h nurine system .Hyhbridiomna production n the .nmouce iSvery weihesablivhed proced ore tmurnztatton protool s and te icqusfoir ioation of inmned splenocyte for fusion are known in the arn. Fusion partners e. gntne odoma cei atnd fusion pcednres ire also knovi ~09375 ChintedrC or han~:LZred atibodies accordh:ng to Eli .least Nome. embK dinients of' the peent ivntion can be prepared based on the euence of a nmurine monoclonal Waibody prepaed as described above. DNA encoding the heavy and light chain immnogoulns can be obtained from the maxrine hybrma of interest andI engineered to contain novnmurne (e..g- hunan n immunoglobulin equences u sing. standard molecular biology techniques, For example, to create a chimnerc antibody:, the marine variable regions can bet Ilnkd to human contant reon ustms methods known in the art (sec e.g. U.S Pat So 816.567 to CaiK y et al To create a humanized amtibodyv. the murine CDR rgijrm can be inserted ito a humnan framework using methods known in the art isee e. g. U.S Pat No, 122 53 to Winter, antd UX' Pat. Nes. 1530J 01'158i 89:1693C 2 an6J07 [0I0376] in a preferred emibodimeein (he rnibodes according tat least some (mbadimmts of' the ihnton Xre humant)) mnodonal antibodies. Suh hnna monoedonai anio sdirected against KRTCAP3. PAM2AF MOCS249S..rA.M70A o~ MMIA 54can he ganeeated using txranngrnc or tynischanosomtc rice earyine parts ofl the huina imutne system other tan the mouse ndn,1eae t'senr and U'aashinosomicdncee include melee referred to herein as the HuM~b Mo us M N and KMl Mouse RIM.. respeCC1iC 'ty anti are CdaleCine iteferredI t herein as human Ng mice." The HuiMAb Mouse TM. (Medarex. Inc.I cani hratncrmunoeubu n gene mesniloci that encode uayanaged humtin heaty ifm' and anmia) andaappa Itghi chaim imrnmnoglobulh 5Cqutee troether wih\ agte e i'ltto)5 it) xn ciat iheN dogenot and %npp chain loci (see eoz. Lonberg. et ci 9941 Natumr 3o86474n S5.56 9). Accordii the mike exhibiteduced exs ini of mouse 1gM or k a adn ittanse to uinaioti. the lntmducedi humanchat'g an Ilight chain tjngenes undego class w hn nmape mtutation to gnerate high affinity human u gGkappa nionadionadLionberg. N. eial99 supma: reejewed in Lonberz.N 1 9914 [ iadbook of Espernentai Phainacology 13 :49 101Lonberg.N and Husrar D) 1 Y95Intern Rev. hinot.. 13:659h ands UiHeeda F, and LonbergN (19$) An NA Aaad hid 6:5.36-546)The preparatimt and use 01 he uaMab Mouse itMs and the genomic mnodfoi ns earned Iby such mice, is further described inTalorP et al. (199 Nucleic Acids Rkesearch 2QA21876.2P5tCher e a. (93internatioitai hnmunolsy 5:64 556; Tunilon et ad 11993) Proc Natl. Acad. Sci U5A 9(t3237204: Cho al. 193 Nature Oenedecs 4:1 123; Cher. 3.et a, (199) EMBO) 1 .2 821.330:iu; JPa" et al, 19941 . Iramunac 152:291290 yt~% P or,. i e al, (ito 1994) tterntion al hmmunoogy 6:579- 591 an FiNshwild, D, et at. (1996) Na ture Btiotechnnoy 1: 845-851. the contents of al of which are hereby specieablC nc r td by rieeree in their entirety. See further, LoS Pat Noc 1541806: 5569825:,25126: 5,633,425; 5,79,60; 5,877,397: 5,61,016: -,814,318: 5874,299 and 5,77,429; alt to .Loberg and Kay; US Pat No, 5,545,807 to Sani at at; PCT Publication NoNT WM S 92/039 8, W) 93/2227 WO458 W 97/13852, WO) 8/24834 and WO 99/452 adl to Lonberg and Kay: and PCT Publ ication No, WO) 01/14424 to Konrman et at [0PS7I In another embodimen hun antibodies accordin to atast soine embine its of the berenti' een -ied vwgo a moase th caries huna immiuniglobunr sequences on cnane and tansdchmosomes such a a mouse that cares a human heavy chain tranaeK and a hun liglh chain transchranosome Such mnic, reftend to erein as KiWan2e ar descited in dWtet n PCF Publicattn W) 02AI478 st/I a et at [03731 Still fwrha aternauve ransgeniic annal tems axprassi t imnunoieY> ~n~sat- av I n the an' and can be wote t raise anti-RTCP PAM26 iGC52498 FAM70A or TMEMI154 atibodies accord to at leat som embodments ofth invenon. For eane an ternative tamsgedc system referred to as die anomnse Ahnailte) cam he used; suh nmik e scriaia.treapk S Pa9 NosS, 90 ,1 59,5%; I50,84 and 6,162j5 83 toKucherapa e (0,V491 morceovr raterative Syctroomcaiod sost e-(~Nr g~n Wwma minnoiobuln genes are 4v1ain the t and can b ae Ue in Aw AniRTCAP3 An-EAMAnt A Anti-M EM 5 4 anuno ds accord ue to at Ieast some stonnsof tu iunt n i - alnni.mrecynar ah-ra heavy chain toschromnsamc and a human ha't. Chn ntnch omosonn e e r io as "IC mice can. be used; Nuch maice are descried in Tocutka a t at 2000 Proc Natltad Si USA 97:722-721 Furthemor, cos crying humn heavy and lght cha-n transchomosomes have beau d cd i the ar Kriwa t al 2002) Nature Lttcnoig 2:8-4)and cr eudto raise Anti KiRTCAP3,Anti-FAM26 Anti MC5249 nt FAo&AM7OA, Anti- 3IMEM154 atbodie akcorchng to at least None embodiment of the invention [093801 ann rnonoomal antibodies accord toat least some emboamns toh inveonm can asbe rpre"wd usin ake disPlay m11-ethods fohz sni,.nng oinules ( 'are estabbsshed in the art. See for example:e U.S, Pat, Nos 5. 09: 5 40484 and 5,57) k98 to Laner t a US. Pm No. 5A27,908 and 5,87 to Duwer "t a U Pat, Nos 5,99,108 and 6,172.197 to MaM fety et t, and S S. Pat. Nas 5,885793: 6,52 L44; 6,544,3 1; 6.55313; .582915 and 6.593.081 to &riffiths ct at RtOJ Hanma msaonlt acibocdics anuc ngt o at et some cmbodinente oethe aention rm ans he repaird nsng SC1D micew Ow WCh ana m unswe huae bes .reo ntuhted such tha a huna antibody rcstanw can ben genetrated U pai uttfntite t mt at R003821 X MNAIW'OF HI MAN' IC MR IC (003831, When lnst 1g, tirec us ted to m tanas aatlejcs acrneto at loast snAe embodments of the veton. ch mc can ixnmuncd itha puied or carkhed preparation of KRTCAPS FAM26F. MGC24, FAM7OA. TMEM 54 mc n'i d/or renomb t KRTCAP3. FAM26F, MGU3252498 FAM70A\ or TMEMI 154, or arKRtCAP3, FAM26F, MGC52498 FAM170W, or4 TMEM 154 fs on pretca as eseibed by Lm erg. N. et A j 1994 Naure 3686474). &5 shwid, I. o al, 19 96) Natu e Blioteniin1y 84185 ad PCI PWbeta O 9/24884 and W( 011C 1 Prcu thi rc vdl3' be 616 meks of age tpor the Erst inftusO Ftor ac picd or i- 5.50 m of KRTCAP3 fAMT2 MFK C5249 P A 'M70A. or TIEM 154 antge can he used to :tmm the human ig mice [003841} -do' 10princ with arhu antinens by others has s' tha Ohe onenic mtrie respond when lialiy mmtuanized .irttpertontea ~ (HlP it antoen n coamplce Fcund adj oant fo>ed by every other week UP rmn nationss up to a total of 6)with antgeno nicomplete Freuncfs adjuvat Flowever adjuvantsother tha Errndar aso fond to he efintie i adth-dor who-e Cincs athe" sne"o!t~vm aefudt be, lnghiy inum ogenic I m u me ponse cart be monimored over the corse of the ttmasation rtocol t ama amptis beig obtand b :retroorbitc bleeds, The pama cap bc sheened by SA as Oesenbed below advice with sucent titer of anti- JCA' aat [AM26 anti-M0C5248, anAM70. oramt MEM A 1 inman imnnacobidin can be used for ilNs Mice can be boostcd imaenousli it antiea 3 dytet rat Mld c; c, IvnWiu s t tmdi 4- 1d1i1 f tdh o tav ncd to Le n' r-nedK e 6 arid 14 m iae tvpil\ itmm ed hr0a0h atruen suall both O Cbe and M'! cit'd i addtion both &l 4v and 1Wo12 i'gene pn h b tdo! ogeher in a single nhnte haQ% twuo ditfent human heavd chi. tira engesUC ox erndit'i or addnosal i'he KIM oNtise, RPMr soin can e used [008) GENER O OF H VtR DOM AS PRODUCING IDWAN MiONOCONAL AMIBODI E [03S61 To genetaet :bvdonzas paxducing human monocinisd antsbodies accordng h att ast some embodients of the intenttiott spnoytes nldi lyonph node cells frotm mnazed mace can be :isulated anti fused toan awproprit mmo ia Set line, sch as at mus myera cell ine lihe restulting hyhedonsas can be screened forthe production of atien epcfic suaforodies Fo ample single Cl suspensions of ee.ituphocytes >n imrunP4 mite ca fus o one sxh the number Mof Pa3X6- A853 nionsecretngs mouse .mye. om AtC, $R80 SSII wih.0% Ph ells ati plated at ittroizmwi 2N I(I-z'inl~s kttQ~''srtztr dat. oilwe bya Wo week incubator nseec e mediurn containing 20s fetal Cone Serm % 653 condoned media, 5% fogen (IEN) 4 oiM - gIh atS ImM sdha pyvatc. 5 mMk! HEPES 0b S mM 2 neicaptoethanoi, 50 untmnl pedelin 5O0 mgjn tretomfet S mg/m geniamnyen al IX HAT tSzgnra; dhe HIAT is addNed ,24 hours after the fusion. After ppmximae o aks cell can be cultaed ranmedim in whih the HAT is placed with I' Indvidual wels can thn be screened by EUSA fo;r humannolonal lgM and Wantibodies Once extensive hyhrdma oowth occurs medium can be observed usually after WliV! days. The antibod scfidng hybidona can hex reitd.scened a aad if stdl p fiiv or humn 1gG the m0onoclone antibodes can be ue'oned east twc ge ly ting dndo Tetble' cajiesdn then be endured in viro tw sm'- am"n'4 tisue cutture medlinmn for character tlor, [0031871 To p f ama m anoconal ant b d 'ies. selected hybridomas can be growr3n a 1 N 1 tl 4 3t~iti"I i f or nluniocioiait iirttbtti ouriticaboit. ) Ctpaatian be' filtttit~d -nd tonentrated before afity ematography wah protein A Sephamsr Phan.m-nacxia PiscaVwafw Nl aElatd lgG can be checked by cc) ecttophores and tgh perfrmanee 11qutd ehromantog hy to ean=e puriy The buffer Soudon can he exchanged nto PBS, and (3-cS the ccan he dete ied by DtiOa coeicen The Olnuiimml nAnzbdWe van be hutdadtodat-OercsC [UO3$$1 NRAHON F RAN$(TM A.S PRO ~ ING MONOOANAt A. koies ,con Pg to at s.yt "oe enhbUdim.ntu a the i at o oi a can be DNA dc e and gone tiureoon methods a well knon in the art Up serrison. RIIJS9ft FoY exanIPP, to ( the "IaNtioix Of antibodly frget henwaK D)NM' encoding at or f engt light &A heavy chains, can be obtained by standard mo le< oar rhnies le PCR a uificaton r cDNA elnaitaruig ag a hybAdom tht et antb ody o interest) and the DNAs can be inserted into eop;M'.sion ean suc hat the greneN area aaivel y inked to transegptianal and t anslational control seuece. n tscnet the tern;om avl hie sirne to naeao that an wnthd iCtk i gatd wot -a Vct.OU suchdlu teflsc3OO.dadtanltoa oto sequnendes willhin the vet ter serve their intended functuon of regulating the trnuscenpt on an d ansgon of the antdiboy ane The e es neeoa expreo ti sequence are chosen to be comfpat i e ith e expnessin host cel sed. Ihe antibody light chain gete and the anbocr heY Ai ee can be nsene into spaate ectOr or more typiClly, boti genes are itisested into toe sunce prenao vector The antibody genes are inserted into (lhe e e eo mehos e.g igation of carnpk'ementary restricton sites on the antibody gre fragments and vector. or blnt end ligati wo atroigon esarresentib light and hay chin vuiabe reegons of the amuadWe, desonned hemeo can be used to ma';cfluIekngt. mutoi-tidy gnes of any antibcMd }sotype b nsetg themjo expreSon vector, atlre- c ending nea v chin, consant and V'ht on on~ntreajons- of the d. wrstuoto scoet ev -l reo "'n Oraiey othekd to th CH segments witht d e the IC segnt n ert e linked to he CL can encode a signal peptide that eaib ities section of the anybody chan frn a host celi 'he anibowdy chain ee can be coned ink) the vcctor sc that the signal pepticde is inked nr to dtie ainin terINins of the ;nixodxchaineo: The gnao ptide carn ben 9 iaumogovuinign peptide or a Iioo s gnal pepti{ i e. a gna poptide from a no1'ianUflOZIbU i i proterox {O.391f In addition to the antibody chain eres Uhe recombinant expression vectors according to at least some embodiments of the inventieo carry regulatory secqueces that coool the expression of the antibody chain genes in a host cell. The term "reguldatory sequence" is intended to indude promoters, enhancers and other expression control elements te~gt polyadenylation sigrah) that control the transcription or translation of the antibody chain genes, Such regulatory seouences are described, for example, in Gloeddel {Gene Exrpress on Techaoiogs. Methods in Enzymolnrogyv 85, Academic Pies,. San Diego, Calif, 09% I wi be appreciated by those skilled dc in the art that the desivg of the ex5preson vector macdoding thie selection 0f regukhtory seouiences. duy depend on such factors as the choice of t M ost cell to be tranomwed>the ev eof expression of proteat desired etc referred regulatory sequences tor manaan hot elli exoressian inclue vial elements that direct imsh Jewels 0f protea eXp~ressiOn in. maniaaee~,usth ts prnoters urd/on enhaeenive froin (>Ofte rabif CM V Simnian VlrtsN 40 SV40R adenovtis (e g the adenov'u major tlte promoter tAd-NR and polyo ma Ahetranatwrv.y onviral regulatory sequences may be sed uch as the ubkpintn promoter or:6et tlobrin promoter Still further regulatory element composed of sequences from dh~e isonrcese such as tlhe SR alpha. m ter syse, which oanias sequensrn the $ S4)ny poote and he log mennpet of Tannadeell leakemia virstypc iakebe. . et a] 1988) Mo]. Ce] bid s'4 72) [003921 lo adlditioa to the antibody cha eacs a n atory seqences the recombinant expression vectors according to at least some embodiments of the ienion u' cary additional sequtences. such ins sequences that regulate replication of the vetor in host cels 0. oiglas of rep id and xeaetablcmarter genes. The .selectablmrk gene maentates seczn. of host cells into which the. vetor has been ntrodued see e i U Pat No 4 39%t . 634, 5 anr6 d .l 179.07. a0 x eta ee typicaly the selectable nauker ene confie resisace to drugs .. o t. as G4 hromngnt or mehotente on a host cefl into which the vector has beentirodiced Prefeed slctabL. marker genes includethe di.hydrofiate redctaset D RH gee (for tse in AT hosi celli methotexate selectioniampaiicatoanmd the no gene or 18 selection).

{OP393i Fo expressko of e Jight and Meavy ins he espression vetors encoding e hear and ueb chiit is tr'Zmsfe~Cted into a hotit ixi S tandard techUigis5 he ViiOUS lortns of thea "ter'T sfectioi ae intended to encompass aide vait ffdigues coinmonly used to the ifrodretion of exogensc NA into a prokaryotic or uavMctic host ed, eg, entroporain cr'kiu~spnate p igtion, DEANdexttam tratdection and the k Although i s n icany possib to press the amuodies according toat t soiensmodieet of the in entir in cer pnye v t ekaryc honte Mels e0qnasikrm of an odies in e3Hn al cell andmos paenby nmaain host ceIN. 4 the mt prefeed becse sucd eukaryotic cels N d s partiear namnnilian es. are moe likely tian pukryotw cehl to assenble and serete a properly folded and nm oiofgicahy acvie n "bd' 1mkwrytc exwpressicw of iifntlbody gyoes as bee reported to be inefctfe e lx prod on of high, yields of active antibody (Hoss A A, and Wood' C' R (1985(ionoke Tody 6113 [tl394i referred rn aiino ast celi f\w xressing the recomi tnt anttioa atccowki to'At least sme eibodiments a1 te n ofin inchide Chineselmster Ovary f) cl) ~inciding dh CHO ce t described i Urnmu and th ( 980) Proc Kau, A ad, Sci USA 7>4 '0 20 ed wtth a DHIseictabie marker e as described n i1 aufma id A Shrn 2 1 idiot, 5 960 - N2 m n a cells. CO0 ells ad SP2 els In particul n far mewith NS) ye onia c, another prefeerred expressio svsem is the S gne expression system disclosed i Oi 87/04462, W) I9CKI03 Bad HP 358li41 Whnz recosmaneaptrso -vexiors encoingitibady pmenes" are introduccd into man alan ast cels t he anitibodies are noduced by cii uring the hos cell fora Ptriod of ime sufficient t allow fr exression of the antibody 10 de hos e oprefierably secrenon of the antibody ito the ctre median t which ttho st es are grown. Antibodies can be recovered fro nhe culture medium sding stantdan protein purication metheas [003951 CHARACTEIOATION OF AZNIBODY BINPING TO ANTI5EGN 0039 Antibodies accoi to atlIeast somei eboditms the invendn can be ted for binding to KRTCAP3, FAM26F MC249S8FAMT,70 or TRM 4 for example standard EASA, Briwy mrcromer latest arecoatedwih pumfied KRTCAP3. 1 .26F MC5249S FAN70A. or IMEM 154 at 0P25muh i BS, and then bcked wit 5% boing e ser lbn in P5 Diutions of antihody (e, dilutions o1 plasma PBS Um o lii: .1xl hu KRTCAP3 FAM26F. MGC52498 FAM70A, or TMEM154-immunized mic)) au added to each wel and incubated for 1-2 hours at 37 degrees C The pates are washed with PBS/Tween and then iAn bated wt secondary xegemt {e.g., for humar antibodies. a goat -anti hur naB IgPc--specific polyvelonal reagernt) conjugated tO alkaiilne ph-osphawtase for 1 hour at 37 degrees C,. Aftter washing, the pates arec developed wit pNP~P substrate i - i V mgml and analyzed at OD) or 405-650,) Preferably, race which develop the highrest dter wlbe used for fusions. [097 Aun ELBA sayasderibed above can also be used to screen fo hvbridonas that show pnstve t t ty wth KRTCAP3. FAM26 0C52498 fuM70A 1,N M 154 imnains ' bratovmwacx tat bind with blah avidity toiCAP AM26 MOOS 24OS FAM17t, N - 1EM 154 re blond and farther ch.ruacterized One clone nea hyrima wh ttains the rectivy of the parent cs (by ELA An be chosen for rnk.n a 5-1 0 via eei banstored at 4 degrees C and for antihdy 1$0951 J pu~rify anti-.K.RCAP3. atnAM26PJKant-M.0C524%, nt-AM7OA. or ant-I Mh-I1.4 ntiodes seeced)rvnioms an be grown in t-Wu--iter inter-fiasks for ooloInal aattbody puifacaton. sermaa ca Ie fered and cornce'sobefore affinity dc atromagraphy svrth pritei A-sepihars Pharmacd rscawa Etted l(G can be checked by gell tropres and h h perfmraate uid chronmatography to ennue purity The lrrrffer soluinn car, be exchanged into PBS nd e concentration can be te-ned by OD280a un 43 cAs tic oemn i c7-a mlnon zlnai autsbohes cn be qhuuoted ad staed at -80 dgrees CP (O(A.911 To etnifat selcte anti) K. EA 3 . arti-EAM2F,ariMC2it ati--PAM10A, onti ^MEIM monoeoal antbodie bind to anliq ue eNpitp each antibody can he ot n a ted using commercnlly aa te ragers ieme. Rackfr. in) Conapeidnim tudie osing unlabeled :aonehani ol an d bkifnyted onoconal antibodies can be perfonned a KRTCAP3 \M FAM f MGCl2498{ FAM70,. or TME5I154 coated USA p ats a described ahov Bioiny ael nAb binding can b dietected with a strep-avid tnalkaine phosphatase probe. fOi4O01 To deermane the isotype of amre j es. HoMpe s an be pedorn-med ng regentss specific fr antiocies .ta particuar nsotype - exape t desenine the tsotyge of a ha n atonclonal anybody weds of microdeer Paes can be 112 bkocaing with % BSA. the plates ar reacted with imag /m or less of test monoclonal anti bodies or pified isotype contrahk at ambient temperature fr one to two hours The wells can then he reacted with either human IgrM or human hgM-specific alkaline phAosphtS-conijugatdf prohes, Plates are developed and analyzed as described above. 1040C KR AP3, anFAM26 artiMGC524OW ant-FAM70A, or anti TMIEM154 human igbs cm be further ested for reactlity with KRTCAP% FAM26F, MC5(:249&-FAM7Y0A or - TMEMt4 anien, rspectively- by Western blhing2. Briefly. KRTAP, AM26F MGC52498, FAM70A. or TMEM154 antigen can he prepared and subjected to sodium dodecy ullfat povcryiamide ge electrophoresis. After with 10% fetal calf srn and probed with the mnocna antibodies to be teste uman G Noing canbe detreted artiumtangG ikaline p hi sae gnd develpein BCIPNBT sbstrate tablets (Sigma CL 4 n Co_ S, LouisMo) [0002 CO JUGATES O, AM NOCONJU AES 0403 According to lest soe emboints the i rsrent invention features mntc antU.A ani PI M E r-M OC5i-MGC24 tiS FAM70'IA or atin-MEU054 tibod. or .a iragmen teet e aa ed to a thetape-uti mtoietlv.such a sa ted a dag 5% man urmmunosuppessamt ora a erdotos Pt.such coda satreie to herein as'<immnuionitnjuatesV hnrmmoconjunates tnat include one or more cvotoxin are reterrd to as 'mtrnto1ns A *rotoxin or cytotoxc agent inudes any agent that is detrimenA to eg kils c-ds Examples ncde taxoi e oaMMAs inn gmmiadin D dd bwomide. emnetne. :birtomycin etopod aosde. vincrin vinblasdne. colchivne dosorabene n c ditydtroxy antmrain dones mnitoanrtne. mihram-ir, aionsecn . sdehyamtestoste roie nrcocortikoids umocatme termtcmtie, lidoaine pr~pranolo0 anid purornycre and analogs or homoo thecreo. Therapeutic agents also I1e. fr example atmetaboln e me3Jlotrexate, 6Tmecaptopufine. -thingnni3 e - yaai -furmi dc ai alkyinting age11Snt e g. achiorethiamune. thioepa ch oanmnucil. n elphalan catuattn lSN U) a omustne CU cvdothosphamd basulfan dbromrnannio reptooto om n Ci an hr pad pL~z u DDP) ci spati n k' .g.. dacrnono en formey Ma)myci t mcan'iiwamydan, and tnummcn AMC)}a and a t t al vI asin) (004041 Other greidned e fes of therapeut cytotons t can be conjatedwt antibod;areardn to a ast some emeninlst hevtion incafe Warmyens CaifishtofNciiS, inamnes an~d imristatnes, nd dend dutve UCrO An enmWphi 0of [004051 (itoKxhs can be conjmted m bodes &ccardI to it eas sein emtbodiMeMt of the invetiounntiig iift tec hncog avaiabfe in the n. Exatopfes a1 ner typac that have bendmed to conggiate a cyto nK to an itibod include but are 'ot mindc to. hydraones, Unoethes esters, disitdes and peptiderntPaing iner A linke can be ehasen tha i for exatpnge ssepe to cleavage by nw pH within the sos olmd cornp~artua e r susceptible to cleavage by proteases. snah it pr'oteatses preterenti expresednI tunaot d sw Sh as cathepsinse. ca epsins It C' D). 0461 For s si o es cytoto s. nesnd ined Ods Ka eraai gnt toaaitboies s sA Sto e r 6, a 2003) Ad. Div Dcliv Ret 55, f09215 - Ti P. A, et A '23T Cancer 52muno rhe 32:328 3374 Payne, (2(X>-3) ancer &el 3907-21 Allan T, M, (002) Nat, It v,(acr27 73: stan ad L e R . 2002 (un Op nest Drug 3 81 09; ente P. 0. and Spirjn qn C 1 12TH' Ads .thug t v 'vl" . C5: -,247-264 [004071 Anibodies according to a least some embodiment the preset inWvetiOn also (:~ eas conjgsmted tona radioactive sotope~ to uteeate cytotov i raiophar iceunicas alo erredl to a dO mi conjtae xape of roactive isotope that can be ccnzaaed to <mtibodi " for use dfignosfielll iberapetnica~ly in"cbude, but are not lne whid, biotsnotlimited to. 1oc 1,e i diuen 3 HA yttimno 90 and lutetium 17 M etocd for preapz:na omcout avre nstadishe Zv n IEbms ofm nse'"h ncn aesnareM ora ara )ce a and sii meboa m be Cs t p oimnunuoc~rdygates using the ainfibodies according o at least some embodiments of the [0044I] The antibody conjusates Icrding to a last sonne eiboments of the ueon can be. sed to modify a ivet biologica msponse. and the mu moiety is not he consatrued as liKM to dlassiecCemiCai tecatec agett nor example, the d&g moiiety mray be a rotein or polypeptide possessing a desired: bigia ativitySc proteins mray include, for example, anri nzymat~ialy active toxn, or actine fragment. thereof, such a abrin. ricin A, pseudonmonas exotos or dwptheria toxin; a protei ch as tumor necrosisacto or inerfrnsgamma: or. bloncal response modhlers such as, for -exampke, lymnphomes, ie rle i I I RA mdekin-2t ("IL-2'), W-ineekin-6 ("iL-6") granidocyte nancroph age cakomy staimulating eo fa f ("IM -CSF't, groutocyte colonly stnaulting acir ther gAwO tactonrs 1004091 techniques fr co tIng such ttrpaew RtY 1 a nubodien are well known see. .g o e t t onocionantiodie Fr lmnoosetafn Ut Or-s Canar Ther'pv n iMonoconal Antbodis And Cuenr Tbeapy, Risfeld e ald pp 436 R a6 inc. S i it 985) iton e) al.Andibodics For Drug D CoItrm oid tmg !Nevery (2nd hd Ro-b R son at (aeds). pp. 62&33 (Niam ea ni 1987 1 Thorpe btodiy Crdv O ttoic Agent In Cancer Thenrpy A Review Monocloid Ant bodies 84: BilogiQAd And Clinicl Ar lpezaions Pincheraet al. (8sd pp 475-506 09 \nvi Resu> And Aare Pnspectiv OU The Uw 0rapene U-e Radiolieled Antibody n Cnce3r therapy n M onk A'tibodad P or Ome IltcinArs 1'k z Bald-win et a3" ppd 20X 3-16 (Acadernic Or"-';- 5 -',, ihorpe et Q Ib N eparat ion And- Cytotois i oi iie Of Antihodyc-TIon I n oszn at tmlu-iikl. Rt9,, 62; 9 19- il$i2) 004101 BISPECIFIC M ECES [004111 In another aSpect. the present in a-"d t hie e rD e mising anand- KTCAP agtTAM26Rf ati- MGC52498 anti--FAN47kA, or anti- EM:54 anhody, o r a Vfagmnentfte f, Cordig t a le 50053 CfhbdimtIof the toaention An antibody according to at least some emadines of the nveti or amtien-n portina thereCOf can be derIvafzed or inked to another functonl molede - another peptide or protein othersr anybody or Ugand for a rceptor) to genera a hspecie nioleenie'; that biruls to at( ea-st todfre bnn sesor targelt molecules The aiody accordn to at least oner danta na m n fbe de ed or linked to more than one *rherfunona molecule to rencre :nuispefic ec uls hat bhWnd to rtoct thin tvwodfrit iansie an/1'ortarttnece; chtutip-f hereT' To create a bispecifi toolecule accrrdng to as t some eMbodImnts of theA invetiot an anybody' according to at eans some embodiments of the ivention can be functitontaty liked g. by chemna coupi~ig getetic CuWion, -nonqovalers assNoi 0r £other'wise tu oneO or' more other bintdt~finmOlculeN such as another anltoady antibody fragment, pepi or bing oimetic swch tha a bispci fic mocul result s, f00412 Accortnx Ite present rnecatn tl nhde\ bispcfIC moieCrdes COnmpriing at east one fst binding Y eity for a KIRTCAP3, EAM6F, MGC524A FAM70A. o3 TI MEM 154 polypeptide and second binding specficity for a second target epitope. in a pacOlar embodiment according to at least ooe embodinents of the invention, the second target epitope is an Pc receptor, ea- human Pc gamma RI {CD64) or a .h:unan Pc alpha receptor (D89. Theefor. the inveton includes ispeibec secure capabI of bindag oth to F gamma R; ; apha R or FApzdon R cspressing cffectorcel e.g, monocytes, macropages or polvmorphonea ceds IM Ns. and to target cells epresn a KRIAP3, FAM26F, MGC52498. FAM7As or TMEME154 polypeptide, espectivly Tha bispccitsc molecules target KRTCAR FA\P16M26. MGCS2498. FAtXMMA or 'MENI 54 polypept de ',pxnsng ee to e'aetoc ce nd igger Ft receptor- diied effector c actif i ie h a phagoc:ytois of KftCAP3. FAM26, MC2498 FAM-OAoTMpOpept e e TsSU T5 l, t od' daecdenot ce itetd e totoxtct {otCe cvtokine release.O agneraion owstspemrdeanon 00O4I9i In an embodeiment accordirlg to at least some embodsments of the nventin in whic the hssia pe h c doecse is tdtrspecific, th mecule en forrher nclede a nird ind ing specifty, in addition to an aati-c binding specificity and an atnf finding speOc jlt ln one embodinent. the third binag speci sk uanti-enhancement fact )EF ou nioouk which hint to a surface protein mvolveda cytotoi activity and TWAtsY WRMSere the irnme es ons; against the torgr 50 cii [004141 The fate noent actor portion' Can bx an atibody, tlinctionalantihd trrmnent or a liand dhat binrds to a gien mroeucide g.anautugen orF a receptor, and thereby resudis rkI>aenyentofheet of the burhin deemnnsfrte, receptor r targ et t ntiger.he antieniameement factor portion can bind an fe receptor or a target ctl ianmtwe ntematv. the nenhacenent factor portion cun bind to an entity' that is rlrtfcet trom the endty to wich the first and second bings cell (mg.. via Ck D.C&uns ?. UO I M rohr mueeUta resus in acreased stmne rapon~se taaist thetfatget edit [IM*131 In one embodiment he bispecific moecUles according Us at least some embdimnts of the invetntion comprise as a binding specificity at least one antibody, or an :imhody fagment thereof. i c3dir. a.. an Fan . Fa:, Fiala 1. kv. or a kje 'ehzn Fv. The antibody may aho be a Aght chain or heavy chain dimer, or any mnimal fngment theret suih as a Fv or a ingle cHai construct as decnbed in Ladner et al. US Pat No. 4,9 778 the contents of. which is expressly incorporated by reference, [00416 The pmdtion and c'haractekanon of certin prefe adantPc gamma tuno 'dan3tibodies are dearibod by Fattgerer tO. i Ff7 PCblicaion 'W 88/000)$2 and in US Pat No. 954.017 the teachings of which am fuly rncorporie b rence herein.These antbodies bnc to an epitope of F Rt PRiyi or FokRl at b de whid is ds tintarm the i'c ndc teof thew 1irertol -. wo tus, then' rer is ot loke substantie by phystolafwa 1e010 m lgO , Speifikt anijRif IC ib des send inl this invenduon are mA b 22 mAb 32 mAb 44 n Ab 62 and mAb 197 The hybr ila procducing mAb 32 i available from the Anerican Type Culture Colection, ATCC Accession No, Ht949.Inote eboimnt.the anitey .nxtsepnr mntmbodvis J' a numlallisect l'or-r of nooclonaabd22 H122). The production and haractera on of the -122 antibdy i desetibet~etd inP. lmlet a 99) .Im5i ( l0): 49964-50f2 and oCT Puhiteion WO 94 33 The 22 anbody plodu rc ei ne isdeposited at the Armerican Type Cultre Colldection under the designation OA22CI and has the accesion 00. CFU. 11177: [004171 In stll othrd rfredxnoiets h icuo pcfct for anF .ae3&ra p ded tby an antibody hat bid o a human A eaeptot e g. an Fc alpha teceiptortF Spo..D the bindng of whih s prefer y not blocked by hmnan immtnogtbui un A (lgk) The tenn JA recppor intended to include the gene. product a one a ene (Fe ahaha 01) located om Wnontosome 19 'll Tul, k cei known tounon several atterntivey ipt-emiwntt lernorolm o ('..-5 to 10 kFla. [Lt041 FTh alpfia,1 'lSO WD9 isorsatrtutssl miA arse O fooyetmcohts a pta RI a mea pnpro$mp tboth -gA) and tgAZ Wch is increased iupou u e to cytok iines such as 5-CsF or GC1. Coton. et al. I V,2 9% Citc Rev ?ws hrtmunoog y tp3.440). Four Pa Rvsoecdic mnocona mantib e dented s2anA iih ind Fe NaOT RI ou s1RAide llrand idin& dena ae net deAsNd Re Cio a A. e 99M I hynnot. [00419] Fc alpha Rf and Fe gamma R tic perred trigger r receptors for use n the bspec itoklees accordin to at least somet emlbodimlentN of the invertioim because they Ar0 ( expressed prinaly on imneo dfetor OeM 3 e. monocyvtes, PN. mcrophages and dundritic ceis4 (2) expressed at high evels (e 3 00 t1000fK per c md f eyoku :ic aciiviies $e ADCC p c o (4) mediate enhanced antigen presentation of antigens, including~ elf-ant gent. targeted to them. [n042O] N a hle nnn - nnncim antibodbie are preteeed. other antibodies whch an be employed in the bispecifc mnlec dcccording to at iast smne embodinaits of the inton are mnii.ei neei nd huatuned nonocional antibodies. 100421 The bispencf molecul raccording to atieast sone embodiments of he present nneon can e prepued becohganut c tgit ndng pe u5 efg.. he ante FeR and anti -KRTCAP WntiAM26. .aniM(C52498 antYFAM70A, r atnto TMPM1-54 polypeptde binding spe fitciie uing method known in the at For champk each binding specific of the bispeelnc molecu can be generated sepanni and then conlated to one anote W\ he bni .pe. atzs ane rrotein or peptides a variety of copi ng <o citssinO k Aaets ran be ned fco al c(ono130gation. Esunples of cmos-iimk ing agents, include pnnteini Akcrotnd.Nweiin~dlcti~iaet (S AA, 5,d nob .d2,bennC acid) DTN * phenylenednalenide BoPDM) N uopropionate (SPDP), and *su t-uccinimidl 4N 984) apMed, 161 686 in N A et a.1985 ro N Acad cail SA 8:8-i Other methods include te decmibedinPuiUa (1985 .fBehrie Inlsn Mit No. '78 ' I18 I 32, Brea i al (1985) iene 22:1 98)3 and lennie et al, 41987) 3 kanmusol. 139, 2367 '2375. Peferred coinjugatwg agents ant SATA and sfo-SMC. both available fon Piere ChemicCoa Rnckuoni I [004221 Whe-n the binding specificitieS axn: bodie s he can be vN j vdolg ufhydryibondng of the C>emnnusbtuge regions of the two beav ca sin a purtic krl prefe:taet eniboent. the .iae region asncune~d to 0Otitxnd an od inber of Ha Vd residues preleeabiA ne ro cordt uanon 042~31 Abemnatveiy, bth binding speedies can be encoded in the same vector and expressed and asemoed in he Srne host celL Ths method is paicularl useful where the bispecific molecule is a mAbXmtAb, mA bXFab, FabXF~abi2 or ligandXUab tousiun potein. A specific oolecue according to at least some eImbodimets of the inntiorn can be a .sinle chin mokctle compriincM one nle cain antibody and a bmding det rmmnt. or a single &hain bipcii mtolecuhe comprising two bmding daetermitnants, Bispecifc mol0)ecules may compreis at leat two single chain molecues. Methods fOr preparng bispecific molecues are dcriberd for example in U t No. 22 I.S. Pat, No, 54. US, Pat, No. 48105: IT S Pat N' -5,32 4T US. Pat, No 59l,3: '.S -Pat. No. 47A ,St M; PaW. No H 50 Mi. 5,25at49No. 5 and US. Pat No. 5A2.858, .0044.1 Bindi of the bispecrfic coleculs to their speoi. targets can be confirmed by tor example. en zkeitked moarotbent assay (EUSA). raditooummoassy (RIAl A(iS annalsis, b ntssay ( .OWth in(abdon ort estem blot assa v.ach of these employing a laeedra ent(. . an antibo dy) w'" .ic t the c'ne' x 01 intuerest a exampk- e li hefi -R tiod cmples can be detectted -"ing anny ike antibody anbo tniert whIch recognizes and spediad t. as to te atdy- PeR cornpieXes Ahtrre teis tie complexes can be detected psing any of ' variety of otheYr tnimnnoassw\ y ir p a ni 0ie antdiody (:an be .idio ilw labeled and red in a raQMt3nunnoassay (RI o foe. eWxap Weintsn B Principles of Radioirnmimoa\\ay \ even t raining dottrse on Readi ohngad Assay Technigues. he adorne Society March, 1986 which in inuorpoated by reference herein. The laiokctteistortp can be detected by such means as the use of a amna. nopater or a Scntilakom dovnter or Iny atztioganphy, 104251 P ARMACE UTI CAL COMPOSITIONS [004261 In another aspec he present invention p d a compoton e a pharnnaceutcaiompositn, cotaling ore or a cominaion of mnonoelonal antibdies or antigertnddirng portions there-o according top .es some emoditte ft epsn neton forgulatea tagther wat a pharmaceotiea y acceptable canen Such crnipositon ommay rnade one or a contiaono (e g o or noe dieretan ibode or .fiuaonconggas or lu oeciisc .necules according at least sonm'.e hmodimientso hao i a plwnnaceuncal co in acorting to at lea soe embhodn-merts of the iwtution can comprie a conmdinafion of antiehdie.\ (or in ooonigte bis ulos that bindo different epopes 0n the tarett antigen orthat [004271 s discusseo atd ast som e ambdiments of the pmmsent inveAn ttI e maeditst oter moecus enc as snan orgknt rrtcle~s. enidei nniems catshsOn tN t igpein. sINes.aaeiene RNAs antItu hire whc npeiiiush and A d now a hane oni an Cntyv eihcd by wthe KRICAP FAM26F 2M "AA or MEM i 54 atlen or polypepteides resperedtvdy 'ese molecules ma iAO igalfoed by ~i knowny Wceimod&s such am bUding ns Thpicahv, hs assy wilN l be high troughput and %U scrn a re lBary of ynthesized or nautie compound n order to identity putatie drug candunic t dd KRTCAP3 FAM26FhIMGCS249. FAM70A or T MM154 rhsted activist (004281 Sped~ictdy, thw, linvitioti ech naces' the deelpen f drugs;, co,.ntaining the ectodomain of the, 'ThALM 15~4 antigen or poipet -ttora tueet' Or variant thereof or ag co Terpndin n ude i acid sermoence ecodn 104291 Tb us tho preentin Avemn non m a tiuarmut ci*nnorton 0tli'5ii theraprtutcafly effteve amount of a therapeutc agent according the present inet According to the parent invent on the theapeutc agent eculd be an yone of TM EM 54 ectodonai or ' a rngment or arn.t o a conT'aye then 0:Car a acid seq nence encoding wore' (0930J e p 'tacentcal coposiden adn o t pe nvent i rather Oonairy u'se d for the treatment of C-ancr and/or ninineo reltewd codtoo disorders', U)0-4311 llhe Otherapen ic get cgordinlg Uo at lestA soni entodi nso h sn invention can be provided tt p o Ceuic com sii on [004321 Pharmaceutca onmpositions according to at least sone nbodiments of tie vessgatton also cat be adninusterd combination therapx- combined h wit otheger mer Fiexatnpe, :the combinaaon theAnr c deRTCAP3, a AJM-26 no her .~~~~~~~~~~~~.~ unracr t o>K~~%3 ni zJ2~zat .5249 FAM70A. or ant i-TEM1 154 antibody r KRTAP FAM26F MGcj52498 FAM70A. or TMsE4M 154 modulating agent according to the present invewnion such as a soluble pedypeptide onjugate ontaiing the ectdonmaIn of he TMEM 154 polypeptd or a small molecule sTh as a peptideribozyme si RNA, or other dIng that binds a KRTCAP3 F AM26.F MGC5249 PAM M7A. or 'MEW54 polypeptide combined with at eayt one other therapeubi. or inmne moulatory agent. 04 A onmpositdon according' t atlea s embtodimtents of the geent V t en~o can he administered 1ia one or more tis of admnitation t.ing one or mnore of aief me f3thods5 known in the at. AS VNl be ilpTSCiAtted by the skilled aisan, the toute andxor mode of adninstration will vary depending uon the desired results.Preferredi rontes of adanstiraton fr antibodies according to at least sorte embodmms of toe invention tnetde inltftmenoU\ flitrandSciC int'adermna, intaporitonealsubcrttneous, spirao wr other pareneral routes of administration for example y inijection or infiutsion. h phrase parenteral adinistraton" as used hereent ean iacdes of adminisuoin other than eutetal and topical adminisration usually by inection. and include, without linavor at nOus. intrmtcular netrarderai ii t'Athecrti intracap'la, ntpaora4l~aantag mmtnderma n tap.ione srnmetede s'ubcntaneous. seticul ar. inraattinior. subcapslain sbaachnoid. iasna epidural and intrasternal juectlon and iniusion. [0(M434 As used heen 'pharnmacenticady acceptable canrri ncludes ay and all solvents, dsp r media, coatings. antibacterial and antifungal agents. oisotonic and absorption delaying agent, and the like that are physologically comnpatible ferabl the carter is sitable tar itraynnous. inramnuscar 'botautcous parenuteiral spinal3i r epideunal administratk teg by direction or infion, Depending on the route of adintnistraong the active coi-pod e anybody inmnoonnate or anolecule may be ceated in a reatial to protect the compound fio the action of acids and other naurl conditionS that inn inactivat the compound [00435. A harmaceutiea composition a coding to at leas some embodiment of the neation also may incie a pharmacentically acceptable anti oxidant. Examples of pharmaceuticailly aceptahle atiosxidnants include: ti water oluble anticxidants. such as ascrbic acid. cysteine hydrochloride sod/urn hisulfate sodium metabsitel sodum sulfite ad the like; (2) Sikohlube antdxdanIt such a scorb pAditate. butylatet tocophet and the like : and I) tal cheating agents. such as citric acid,hylenediine eracetic acid EDTAt sorbitol tartaric acid. phosporc acid, and the like, Eamples of suitable aqueous anld nonaquenus carriers that may be employed in dhe pharmaceutical tompnositions according totleast some emtxxlimentis of the invenrtm include water, ethanol. polyoh: such as gycerolp, pprylene glycol. poiyethylene. gyvol, and the ike) and stble mixte thereof, vegetable ri uch as Yie iladirgectable orardc etsters, uc s h t Proper fluidty cn be maintained, for example by the use of coating materials, -uc.h as wcithin, by the maintenance of the requSed particle size in the case of disperion end the i C au ofm net\ [004361 les 'Ctompositions a o~ containidjvnts such as oreserves ts wtin agents. e ui I jhents ant dw'ri agean Prevention of presene of rnistorganism mray he ensured both by steriliration prtocedttns supra, and by the inanusion of various intthacterkidad and pnal gents, tamxampe paahen ednotaanol phenolN ricac a and theo N R fna also be deae to include isotonic agent such as stars t sdi chloride, and th . like ; into(beccapondt not Inmo ditin. piinet borto o injectAble poamtcedcd s o) nsasy be Irought ahon by the incuon of atas which delay absorpnon sohd as alsnnui monostearate and gelatn. [00437 Ph are uticaly aceptable caale nchidat strife aqocons soiti cls ot peons and sterie owden for the Ctempo'ae-t preparation 1 sterile in etble sounor dipersion. The use of such rneda and agents fr pharnaceuticndly a iiv substances ss known rn the art cept oi; mfo ay ceninonal nuedia ar agent t icompatile wsth the jtice compound uses thref in the pharmacetient esomposiu nd accordii t at least some Cnmbadenrs of1the insvtntus contemplated, Suppeme'n'ry acti compounds can dals be itcopoatd intr the ccompositoin f043I Pherape tic compositons typicaly must be sterie and stable under the condi ons of nsanriacture and storage. l'he comnposiution can be formduated asa shutiont .miroeintson~ sapoome or oler mdrered structurietut e to high drug concentation. The carrer car he at solvent o r aperion medaun contaning for exatmple asermethanoI. pohlyoir exanmie gm;erol; propvlenme glycol, amn lud polyethylene giycol. and (he ike), and saabe niitne thereof. The proper flivdity ea he mantained tor example by the use of a coating buch as c d by the mnantemance of the reqtuird padeit ed Ntn th1 cse of dipersin and by th.We of- suft nts.i oanst cases it wil pvefrr'tl to OtnehndetttOftiC jemttfor tztnpa tiar neaknhos ruch as k t d Ohtl Or eodiaum c ide n the compouson PrrdonAed absorptin f the rtetable crposhions can be bought abot by inclin n the com o an amgen that ddays absorpon. for example. monostearate AN aNnd ehain. terile injectable sahiatons can be ptreae by (32~1 ~uhitXit~n0+ nrots (tntu itte above. asWAW rtuo.TA5UWed bystanrdwntor miacr tkratiosn Qenerah. dp>nn5 are prepared by iCaporad the acve condnun o a steriee vehc e ont abaic Edsperon mdiu and the equie< Ater ingtenient those enirnerated above, i the case of sterie powders for the preparaion feeinjectabesobinr, the prefsec eho of Wrepaanaeacun dryangard freeze-arying Lyopirtiation) that yie a powder o tt active .ngreera ptim any add io *m desed imredient from a pre visn steelfateed sadan thereo [00 4391 Sterile Inecai oluton can be prepre-d by, incrraighe ctv compound n the required urunt i an 4 pkpoiate solvent wit one ton coalition of Stedvntts etuened above, a euired flowed by stereatiof mi ration YeUce at contain n b dp o medum nthd e required other ingredients rom those enumerated abov in the case nf sterile ersfr the opa n sterile ectabe solions, the pneed methods of preparadon are vacuurm dryil land freeze drYing (hophU at On) the iefd a powder of the actve ag ent p * any ttntin [004401 The amount of ate ngedint whn can lbe comintd with a carrier material to produce a sine doserm wil vary depending upon the subj et being treated, and he partiuar moce of ardmistaition. The arnute ofacte ingredient which can be comoubinedt witth "a cr ir mern to pQd4ce a snige dosage form wil generay be th B tmitni of the compnostion whch rodu-ce\ a therapeu a effect. Genenily out of oe h udred per taenb W'o 0n1 ' ro aut recent to aix tt of active i nIre'dvntl opttubvfo about: 0, 1 pe r Cent to Aout 7( p, cznt. optionallfy -61ro n:m a to per cnt to about 3 per tr of aotice tgdiene in combinamton with a phannaceuticai iccptb carter [004411 Dosage regimes are adjsetd to provide the optiMwm desired ?epanse Ig. a theapetrerepone).Fo axrupn'a single bolus my be*Wm, ~ sec.svra ~vte dose :0ue be citniistered aert ine at the dose may be prop50.tttndll reduced 03r stressed a indicated bvfhe exigencie of th teraputic situation is especal y advantageou t o formzlate paentea com'pasktims 31n dtosage u3'it tone for ease 0 Z3miintstrtonad 30t03'iy of asase. n~ovae unita r nas med heein refe t physical iete units stated as i -dsae thre asjeci to he treated each ont COntaja ts a predetcntdned quatnttty of IWOtV copnd p aieshdeevie t produce tel dened~ eape ee ton y t W aranset ar a eton fxthe ;dosage tim t form according to at least sonm endbodjoxents a the tinro are dictad by ari Adrectly dgepndent on die unaue caracteri o th acie compound and the naricnlar therapeuticefrect to be sthieved. and tt he tStlenS sinherent in the a of compounding such an active compound for the treatment of seiitityv in indvidua Fo sdiisrin of oe ntbo the dcao t'anes froar '4 ,000c1x to 100 xng. and more unally 0W to ) plyug, of the host body eiht nr eanpe dosages can be 0. .mg k body weihdt. y gg boa weight, :3 boidy weigt n S /kg body weht or. ff3 nih/d body weight at' wliti te, orange of 140 it :ikg, An eee lr tat'me'nt (-cgi2o3lt entail a m oce p we. nce ytwo wees once every three week one ev1 ery tour vme3&s onceK a mnth onc, e very s, t noids or Once- twethtnke t;o (0 m.onths., [004421 Afteniadively, *atiftibodv can be awitittdis aLtttttst :t'eieitse fmmkniutation 4 a ae regent admintrat .s re and equency ary depending on the hal-life of the antbedy in the p3adetrit la ceiera. h.iiarum antibodies 1ow the longest half lifefalowed by humaned ntioes chimeridannbodes at nonhriuman antbad The diosae and trequeinc or adfn aon can vary dpe:dng on whether he treatment ispmphylact' oc therapetc ci ni pophylactic apphications. a relatively lw dosage i;, adm'inistere~d u-t :eaiviv irq-uenml trv over a logpriod of time. So-me pamients condti to receive treiatmetrhe est ofheir hesa ther' ett apipli aon reltiely high dosage a reltvv 'hart Otiards :ts soni tmes rwauredt until rogressio the disease s reduce or tenrnined am pmeraby until the patient hows parteal or, conptete amrteoration of symptoms of disease. Thereafet the patient cal be aAinsterd a prope Auvel s of te acve Inl i the Cmposn 3ition according to at least some embodinens of the prese inventio ma be tne so as to obtainan amot of the v nreieKnt whch i euee. to achieve the desired therapeutic repos for a particular patient comositon, and mode of administration, wtiOt ht bemg toxic to the patient The selected drwage level will depend tompfl~otions5 according to at least some mbsdiments of the present invention employed, or the ester, sat or amide fhereof the route of administration dhe ime of administration the rre of excretion of the particuhu- compound bein g employed, the duration of the treatment other drugs, compaurdi and/;or material se Oi i combinbation with the particular carmpositi nonseployed. the age, Se. weih. conition, gewoerl heih and pioar medical hiMtory of the patient being trated, and like factPrs well known o the medical arts [004441 A"thempeuticani tfeeve dosage of an anti.RTCAP, ani AM6hF anud MtiC249S and AM 70A or antNMEMiS a atibdy according to at east some emtbodetnents of the onvnton. p ufe 3 y resuts in a decrease in setvett of disease vymptomns. 'nern~e in t requency and dton of dease symptomIfree pedd an inase i spi disease rtCisiO or a pweventOaf onpaKruanneo or disability due to te disease afflitiontor xnmlefor th meament of KRTCAP3. FAM26F. MOC752498 FAM70A orTMEM I 4 polypepude pos~hx'c ve mOrW cix egovan tumls g, h breast turnm colon tumors, kidney tumor s lier tumors. pacreat tumors prosatae cancer, me lanomna and henmatolocia malignancie\ such as Multip t e Mxeloma. ilypih Nonliodgki lylnphorna. ani CD20 (in t iwvmab) resistant lyarphoma leukernia' cMItuema a tlmet elicffcoel' dosage" coattriwliy WbAS cru gtowth or tiior growth by at least diAbout' %, 40%q 60%,f% rtve 'Vk toIR unOfe uics.teat t'0 a poudtonfabitm growth nt be evaluated in an a inai modelsystem predictive of niccyni h~ttmiai tmoh attematelyj ds p3rpety of a comnposition can be evaluated by examwinig t'a bity of the compound to i nhin, such inhiitiono i t by assa known to the skdled practitioe [00445] eAd ce o addionally a the"pentiaily eecti ye dlosag" iden'y esul i at last sabie dsease, prefe aby partial response lme 1eerably -omplete response as assersed by the WHO0 or RECIST csteia for tumor response (Nat Cancir Int 1004461 A therapeutay effective amount of a therapeutic cnomood cant decrease tumor s. (3r *etherwtse amre1oratte symptmm in a suhject or otherwise Sppdon pirtiitlor complete staK disease und/o pertid 0r complete response as determieed above, O~e o oronarv kW n tarut oud he ane to deteene 4ua amouns based on suc actor' as the sutbjcde. the seneity of teA object .svnSptorm an! the particular enmposton Or route ad tmi nistation selected, R1447 fheapeutic eccaiosidns a he xtrnntdered with madiua device known n, the artrred fo ta therapenc conpw t ma at leat omeemodna Meh tWation can he admniserd wtII a vndlyp"ode'i irtjcction deiesc , . eie icoe in VAT INat . .... .. 631 5.3S3.4l inpian.and niodd~e\s ae in the present jnerd inmche . Pm..No. 4.487.0 Sdiscses an tie icewsi pump.dse meicaon aa contrleed tate: ,, RS at No 4834, s hich disckoses a therapeutic device for adminmstere rmediceins (hruggh (he skin; U.S Pat No 4447<23 wich didoses a medication isio pn mfi o delivAmg mediaton at a precse inusn rake" Patio 4.44-7224. whia (sseoss a vaale How :Oiamtse. iutnsh prasf ontidnnus dug delive SP Pt No. 44W9% 9 'Which diseses auosmotic drug de:ivety s nysttn aong tnulchamnber comprtmenta and U t No 4V7r6 wch diao los an symot e druzg delivry system.hee patient areicor ked hevoen by reference M"any other , sic-h implantsierer n odules re known to, those skilled in the art [00448] In certain h a or o(her KRIVAP3 .AM6 AIGC5bodients theOA aatuld txlit VI "(' 2 93f M"0 TN.EJII4 einted dRies cntnn toat east me2O emodents ofth a be irulet ensure prope d a io vivo, Feanehe blood-bramn harder (1h exI eszm\n highly hydroph compot To nsIre dtt the therapeutic compound ccrtii to at lk"'st Sonme embodinmns ofthineiocos(e BB (desired) they can be fimuwuted for eapige a iposames Fo ethods of n t peg- c' b Pat, 45,1 5 374,548& and 53993 31 The ipoSome-s !115 a i pWse *emie o i% tS hh se eett ye tfatsporten tnb peac cos oran tus enhance targeted drug eers g Ranade 9 21. (din. Pharmonacol. -9,685), Lan~mpbtay tarefrt iitesicuelve of biotin seea. U.S. PA. No. 541616 to io et ai :mmaosides e a, 0988) Biochem. Biopbys R4es. Jonn $3: 11238); nibde (P. , G, t.w~iC al. [99>) PU-BS .ct 47' . Owais et at (1995) Antuicrob, Agents Cheiother 39: 180). surftac.tant protein A recpo (moe et AL. 19951) Am. J1 Physo. .233 134) p120 (Sch0eem e a 9940 . 3 M i (Ch 2(s9:9090: c o K e tan N. L akkancn 1994) FL1B S~t, 34(I. 23:.1 Kluiont e.A fi (9940 rumnomethods4:273 [O04491 Given the specific tinctng of Vte antdiesk) accordingly to at leaXst some mbodimeNts of mthe iAnvention fr RTCAP3 FAM26F, MGCS2498, PAM'AlA or TMEM154 plypeptides, the antibodies cart be ued to speccaly detect KRTCAP3, FAM 26F, MGC5C2498, FA M70A or TME~M154 expression on the surface of cells ruid, er, can he used to purify KRTCAP3, FAM26R MGC52493 FAM70A r TMEM54 antigen va immunoaffinity purification. [004501 athermore nhe e)pression of KrCAP3 FAM26E 05249 FAINIVAU \ orfI M EM54 powypeptides n vawats tuor ( r de human abnodt ''ttibotd dompotS idof antd Thnhot acerdng to at east so0ie en bod nnt of the preent irrventdou can bie used t? toeat a atijec wth a nrnonenic disordert e adisorder characied by the prfsetne of ells expesing KRTCAP3, FAMi26F. MOC5248 FAM70A or TMFEM 154 anwi"enach a oyarin cancer colon Cant.ing cancer.reast camer, khmev caner lier cancer, pancreatic Cacer. Prostate cancer mela t guizs h as Mitee Mrrnphoma Non i lymphoma, ani CD20 (e .R ituximanb) resistan hmrzpho.nrau etmia T cell kiekernia, as nent onedo PC snetc umlCuls ad comoo0 no CC ~)cwng totes some ebodnnuents of th inyedon can be used Vo detect ves ot a CKRT ' 6P3 . MFCK 2 . PAM7A or IMEM 1>4 polypeptide or levels of celts which contaila KRTC APS PAM26PF MW3C5248& FAM70A o TME5M 154 polyped pectielyon their membraneesurfic wc leels can then he b t? certan dnasense ptoms Atemratvely, the anhbole can be ed to ht or bitoek faictoning of KR AP. FAM2& M MC52498., FANM7A of- M 4 polypeptils wh ch, nrn can be I iked toteWSy a~ti r "'lorton of certainc" disese-t symptoms. therby lnp Icatlrtt KRTCAP3, FAM26F. M0C52498 FANDA or TMEM154 polypeptide rese eas .metdianor of the disease. This car.he achieved by contacting a sample and a control sample wtthe-an KKTdAPS ant>PAM26Fanl OO52498;antiPAM70A or an& VNEM 154 autibo under conditions dhat aldoiw for the forruation of a cornplex between tbe consponding antibody and KRTCAP3. PAM26F. MGC52498 FAMOA or VMEM 154

III,

ptlypeptides .respeeuid eNAny conapexes lonned bet wen the antibody umd RT'P3 EAM26F.NRMcK52498 FA M7O o 1'E15f2 s eclpeptides ar detected and compared in the sample ta dhe Cofntr oi [M04510 inanodier emodiunsent the nobodes e..han tatibodies. tdspecific and hispecific ? etcues andco mnons acconie n ateastame emnodieat of the ifentoon can be intaily tested for bindin an ty a socirat wrh therapeutic or diiagnostic use in itro [or example complaitons accordc na ti at last xom~e emnbod isnents o~f the ienitionti e tested 1.1W' oo die'trtrne asa 04 2 A pi' ous descnbed hm ant K CAP3. a Mi4FAM26 F si MGC52498 nt FAM70A ri an-TMMI54 antibodies according to at least sme emodnments of the invention can be en uansteied t one or ter :ore therapeutic Agents e. an cytotxicagent a radiotoxto agent or an nnnosuppressive agent the antibody can be linkd to the anenttas an iramenocouplex) oran be admistred separate before. ater or vckuent i e agent or can be co atneisterea ther known tieraps ei an anducancer therapy. e dg,irtdationt Suchdhleapeutie agents incde among other. anteCopit agents such as doxonienadiaman) cisplatin hlerncmen stihae>e.rrus~n. hiriftwel.and cycophDsxtM te ymanrn hih by y effeve at leveh whch are taxt. or sutoxeo a pt CIP intravenously administered as a 100 mag/dose once eve xty f weeks and addamci is intivencuv admirnsterd as a 605 ingi d e once ev 21 days, Coradrnnsraton on the hum ant, KRTCAP3 nFAM26 antiMG3CS2498, arti4-MF A ora MM1$4 antibodies or antigen binding fagnients thereofK according to at least sce enbodiiments of the present sntention with chemntherpeutic agents pnvides two antfi cancer agnata which omcatvi diltfcretecharnsms which yield a eytotoxicesfeot to hinna ur den' cele. Sc a c;atrienaioon en soLve problems aned t ievdolpment 0f stance to drag og r a chage te angenicity ofne [mor cells 1h1c would naer tlhef:i aunreacti e woatihe antibody [004311 Also wOh ine .cope according toat least sonm ben ts of the present wenion are kits Compt a ng the KRTCAPI FAM26F MGC,5 2z498, fAM o0A r TMfHP.M 154 pvretieor antibody criipositdoos acmadine u's mt least \v1)0ozIbotvtt of the ~l'~t~Ot~. hnnnatbde. iteifco ndsnictoeue.o imneoconjate and Iticto for ue. The kt can further contain one ore re adkiuonai reaents >ach as an urnunosuppressive reagent. a cytoto>ic agent or a raldiOtoxic agt~t3, or' one or mPon addiction human antibodhes according to at least NomeI embhodiments of the invention te giha hman ntibodvy aing a complementary activity which binds to an epitope i the KRTCAPI FAM26F M4C5249& FANYDA or TMEM 154 an igen dtinct mur r f firsth n mtibtdyx 0455 n ot dimemm da. Nhct c-an e aoddid malwed int an a-eat that dates, e enhances or nhb the epressin o te f cybo re eopors by (cr example treatng th ubj with a crokini Ieten ed ctohne for admirzain drnteentU Weid- the mUhisnecifiC nl'e '-ie of& granuIDote Colontn0 lainu fato SOC' arannilcyte niziciphage ctNU aNltidtd a factor {GM-CSh after(3n FN gammi and mo feie factorhTNr [004551 The coirnp'ostons jeg. human antabodies notispecit f a bisectific mtoiectdS) accorinig to at least some embodiments (4 the inention Cii 55 M be used to target cells expressing e amma Ii or NRA dAP FAMZ6P, M02529% ~'lAM0 or lked to o moecode tat can be detected. Thos the invention povcdes methods ci ci o n vitro ceal ersrag Bc reeptos a as cana or can bed , a raiosotope scent compoI d an enaveox or an enz xme Co- factor DIAGNOSTIC USES OIF -KRTCA P3, FAMOKW MCC$2498, FI)A, .11 ME~ 154 POINPEPfIWE POLNOC Fil TDES ANID A NTUIODIES in ceain enbodiment the poYpetpdes and/or polynuieodes accord to at east some enibodinents of the prest invention are used as markers R)r diag.nss os eases wherein KR'WAP3. FAM Nt0C524% FAMThDA. OR "[MEMl154 pol y peptide and/or poiyni c~CoUdes arc (1& fential v present. According to at least somei embodints the di ,eases aresice frm but not limitd to caner. and imn eae odtosa defined herein 4 Aceord~~~~~~~~~~~~nu~t aotite iioii~i5mthr (cldn 0it least omenictns of the pmrn n ventiOt aight optklnally be used alone or n combanato e r or' 119 her~n. ndor in Combinat ion With kncrWn ma rkers Ear bang caUCer, A!udin butt not hsited to ClA. CA5 -3. Beta2.-n crogkouhn. CA 19-9. TEA mor in ccmbination wiTh the known proteins for the variant marker aks described herein. According to DIrTher embody me so markers according wat least some emnboinments of the resent invenon m ight optionally be used aone or in conination with one or more other compounds diescrid herin and/or in combination known markers for oarian cancer, &Kinldinu not imited to GiliA, CA 125 (Mucin 16hk CA74T AG, CA-O, CA 54. 0' A. 195 and CA 19.9 in cominatin wth CA 125. andio in combinat WiNh the kown proton forhe varin marer as deaid hrein. According to fiuther srbodiments arkerarding to at lest sortie eubodinetas of the present invention might opionafhg he used lone or in cominaton wth one or more' othercompoundescribed ein. and/or ini conbinatoon wih known arkerfor breas cancer, including beott e to Caicito:ni CA15-3 ( cin CA2729, TPA a combiantion of CA 153 and CEA. CA 27,29Kmonoo antibody directed against U i Estnoaen 2 (eta) ER (cerbi2 and/or .mbhinaonwith the knAo proteIns for the variant marker as described herein. Acordinig to furthe ernboadients mnarkers according to at leat some ernboodnsnts of the pr iint invention might optionally be used aone or in combination ith> ne or more wher compounds described heriv amd/onomhnatn with known'narker for renal cancer, including but not liunaed to rinary protein, creafnine or creatinine cleranc. andbit matN uke or the iagwno or asesmnt of prognosis of renal Canwt\ peeicaik'lly . including but not i nted to nsedaro endothe A growda factor, nterletikin' 12. e solubleninierleani receptor nterceelular adhesion molecule~ hunwan chorionic gonadotropin beT ins he growth facn receptor. tarbotc anhydrase 9 (CA 9)endostati. Thymidine phosphorylae ndor in einniaon wih the known protens tor r.1 naant marker ns desCribed herein. According to farther embodiments Markers according t at leastone embodiment of the pretsenk ventan might opOnalv be used aone or in cominattwih one or mo oher compounds described herein.alto in combation with known markers tar Ever cancer.ncludig ht not atoted to Alpha toproteln (A ? desgamm carboprothromabin TDCP) natqu anise carcinoma antgen SCCA nmwnoglobndir M fM) sA P A . or fucosylated AFP 0P73 (a golg protein narker)nd fcos d Io {TC(F( en IP S-t GT. free insiilike growth fador (IClG I.PI Acordi to further embodiments niarkers aCCording to at least some ebodiments of the present in on mighr opioall be sed alone or in combmtion with one or more other com~ipotunds described. herein. and/ar in combination with known maiters for mnelanonm cancer, incung but noite to S100-bet, mloma inhibitory activity ~~iiA), lactate dhydrogenase (LD 93) tyrosinase, 5-S~Csteinykopa, L-Dopa/L-tyosine. VE S, bGF . IL-8, I -1 MMPs1L. l6 L 10. sL-fR 'soue Antere receptort sHLA DR soluble H L R' dHLA-ciawl (soluble iL tss H. TuM2-PK, hnICD9 NI-LA -elassa1 tsolublIL A-class 1, Albumin, TuM2-PK (Tamour pyriavate kinase type M2.M sFas/CD95 YKL.4. CYT-MIA cytopla>mic me nomaassocated antigen IV MW MA Abhigh-mleculrweight moe lanoma-asociated antigenA STAT3. STAT l ap100/HMB345, p6 .INK4A, PEN, pRb tretinobiastoma protein). EGER, p-Akt, cKit a m e AP 2 DM bcl6. KI67 (detected by% b' Cycin B D E p21CIP! Gemninn PCNA Iif cai l ee cieamr :tigen) b-I2 ba bak APAF I LA 'V E I (ymphatic aeolar endh hy n m receptor) PTN P ( nenn 'o n t ta tenin, begins beta and beta MMPs :mathx netafopotenases Djsa'hri"" EACAMI e cnnoebrvyoninti'gnmeaed cellchesian m del I, Oteonecdin TA Melastatin ALAMUCD166 (cvated rkocyve cell adhesion moeule). CXCR4,Metalothioen A\ceording otohes embodiments marke according to atleastsne emnbodimit of the present invention noght optitmybe used alone onr 1ombinaton vt one or more (3t~~~ oee bed henti n andior in combinan ihDnWn markers for pro state cane 3no but not ime to PSA, PAP postatic acid pWosphatasex CPK- BB PSIA. PCLAI.3J ndorin hiato withthekonplers for the.vrin mnaicer as described herein Accoring 1 to rther erbbd ments markers according to at least some emrnents of the present inwention irnight optionally be used alone r wi combtaationwith one ori itlcr ther compounds describend hemn and/or in combine on ythkown rarkers or pancreatic cancer, including but not hened to CA 14and/or n combiaion with the known protein(s) for dhe variant marker as described herein. According to further mbOdnents markers according t least somenebodiments of the present uwenton ight optoynitiy beused alone or in onation a one or nore other compounds described herein; andc/or in comonton with known nunters to hematologicacnce including but not limited to soluble forsofitunor makers like P Select CD-22 inteden cytoknes, and/or in conibiahion with the known poteis) for the a-iat marker as described imren accord rg to further embodinents nmadiers acaording to at east sonmc ebodimnts of the present i nion Nikt po na!v b sed Wotne (a in bidanini with one or more other ponds de bed her action com un with known m s for colon Cancer, jud" bNt =no a lUZd to 100 CAW T-9 CA . adortcrbrttonwthte knwvn prt Mshrte varltmr zW~~1Nenited voteasyi PC Awned i a ete o a sample obtained fron a s ectt Accorie o ng enb create sampol.taen frome rsbect tio rni a e WOn. Wine, O ina prostate flid, spinal fliud.sen the externin criPCI nS Of the siin. io es an gentoinary tract tears, cereiopi'l f sutn saliva m pertnel fnd pinaI fluid cyst fluid secretnns of the breast ductal system jandior ag berek naho aeolar lavrage. aae of the geddie sstem aud lag of any other part of the body or systean the body; samples of any oa inclugir >isoated eiis or tissues herein he cel or tissue can be obtained oro an ganseleced from, bt not mited tolung. colon kidney pancreas, ovary prostate bone miurow> lymph110Cde breasr. and/or blood tissu sto or a tissue sample or ans' emnbtnation thereof. Pior tO be sbjted' be the d1gnost e Ssay the sampl an optionally he djted with a tsuitabl eI cuet In certain n eboCdents c obtainedfronm. 1 Are u i vito Prior to Pet i e diagnostic a N rs Welknow ts or flidd colecn methods can be utled to cCect th biological wIne from a suect in order toteterme the lee of nucli id and/or poiypeptide ofthe I mer of interest in the'sbJect. Examples include, but are no limited to ine needle biopsy needle biopsy core needle biopsy anvia ise. g., brzin biopsy end lavage. Regardless of thme procede emploxen on a opweaip i obnaoed tesl of the minter can he detesrnoned and a dianosis can thiu be made. 1 it least some embodiets the present .nention provide variant proteins, which ma optional be used as diagnostic marketsoptionall as markers fara vtvo nagig Ac\oag to at let som~e O: odmemfit the present inyedion therefore overcomes the ns deficiencies of the backgrou art a th reard to the need to obtain issue samples and ubjective interpretation of rantAs. As Wo ag marers, the na kers according to at least onceodmnsof ,theofiet iarel-tioil 1so proviedrfrtn ado bette meuurmet at es fo",Il.r. ais oueases ano pa-oolca Coto n.V' '"0iav InUo 't- 1k2 0 Ugg\l these ars c bperfA:Mod 01njimetCou vt StN Ovagin 3dahtsaseCf nd nRIalidc ptae odi a nyndoerap PitaOe i mrke: r disrrsuticn. hi at eatrie ei mbodiments te present invention finer relats to digei ny for detecthmg dtease. partcuhrly- in a samprle taken froa suject (padeit optional a bdsanle a bodysere se. In a eme peptesent reonance rniagheg <M 1 H a Sund. Optical clinging. Comtpuite lromaph~v rnato nmunnaassagy i P \ SA A.slot blot, compoetitive bindig assays. f nocimetri imagine assay. \-esem lt, e tAhe lke tcceorng to another embodients.the diagnostet assays ar- NAT .nucldese id "amplioatin echnaoay based assays. inliing or eCanmlpIeuce ae aa Chbridsatoin assas NC R orardnt. there e ea mI PCR

T

he diagnostcassags can be quaitoae ar quaMtatve in some embodients, the phrase difental pvsent refers to i erences the qvrarmiy a a aru-ker- pnen it) (), 55flnvie U4lan tro snbA ixt bav..inkg one of the berin cesabed diseases$ O conditions$ as om pad to a omabanpie ten oam subjects who do not have one of the .herein-described diseases or cnoitton For exanpie a nucei acid fragment may optionally he differentiaily present betWeen the two samplefsif the a oft tf the ndc id fraginef in one samgle 0s wiicanll diff erent .rx.

amonont of the nuceic acid fragment i he other sample far mple as mrsured by Zk-iron ans/or N asked Rassas A poypeptide s different present between the two samples i the am orf the pclpeptae i ne sample iign is d differem awrnn detectable in one satale and not ttcta en the othe thien such a marker can be considered to be d iffre pea Optiona, a relavely ow amount of up-regulation nt.zv s erve as th Iahr as <kescribe'd hr In Oe Of onns'skill in the art co uld easily. detemin rOe caire levels of thematers farhe ldac is rproied inl the ecoto ne ten- araker" in the context of the present torefers tO a a ad ent. a pepd or a po lpepide whih differeniall resent a sample taken fii subicets , D aviiioe teethi -f,- 'ucae' o adifions. acoprdto a cnettrabe saxore aken tIM subjets h Ao noi ave one , e ove senhed disases Accordipgy W) a$lt s; Optt ifk dmnt f pflik-tYseot rvelio a ;go toIV: a ssy can QrOviit quolative or qWGixmtItai on t'he te ftemrer ntesit home embodinents te phrase qcjaluative when i n erne to aitenee n pe s.on le sof a autcede o oypeptde aI deenbed hren r efers to the preee eversus abtrence Nexpressin, ort somse embodimntus the temporal evutin o reseion, or in some emnoo the ts tg of eprssion. o in some embod imnent s. ayA s tona nodiiication at the ex A icdewn ad ohr a he ztpttacted by oskw k M wte ar4. In$ some e hotme Its the Pi~ q~~ttv we in reerenceto diffnd ences n express onee f a po y ide or polvpentide as cecibdhe rein. reest absolut dffrece in' ciwtity of Cxjsression:, as determined. by anmans known in the aa. or inote emodmnt,0eatv diffrence. whien .ta e statitdy signibcant.o ifl some embodimens. when viewed as whole or erC a ponged period of tme etc indicate a tend in terms of diferencesin expresin The tet level" rers to expressIon levls of nuclec acids e g RN A ador potpep ofe ci he are acrd to a bueast some ertibo et of 01crsei nvnin hi Cisitain Otsobijnswtedansi nekr Scri~ to at essnc eodiments of the venon areoeaed to a con on or th mee n esc or absence in other embodiments, threshold levels of the dianost markers can be tabishedathe leeof teaiterS in a paien spe can ec conpareto the threho IC levels In some embodiments the tern "testamouno a marer refers t an amount of a marker in a ubjevCs s ampe that i con s nw ith a dia gnsis ofapartcular disease or condiwioo. A test ntomnt c~an eeihrin aboeatno'ont ory, tncori~n)0 ate am'outnt e relative intensity of sgnals. In some embodinents. the emi control amount" of a marker can be any amount or a ange of mmmontsto be compare d against a test amount of a marker.or example a conro amont of a markernan he the amount of a u patienwih a tiaa dsease or coiidit~~~~ot}~ rr 0 Aesnwhu uhadsaeo condto. otrol aunt: ca,"n 001fithe in Oablts amount (e'g. mirIoilr *o3 a re J atjv amoun izi I ft (e r relati.v e it enst ot signals [b no011 embt~direns. the feri "det'ct, refers to idetatin ' th reecebsencet, or amont of the object to bee det.ed I 24 in ne e odients. the term "lai ideN any uoiety or :tem detectable b eneosopte paw eenical Pnchemical. it nnocrhen~idorchernical means For e ampe u le include 32P. 45S Iuoresacera dyes, Metron -dene reagent, en:ymw acon used in an EiSAl botinstreptavadn dioigens hapte and pote for wich n{isera or monoclonal antibodes are avaiable or uce acdolecules with a sequence corplemenay to a gethe label f en generates a nsrable Signal. such a radcacue, ci mocnge 0; 1 or escen am that c to mt1ft the amount of bound e aY ampe he awe can be acorpoat'd ior e tapmer raproe either covalee or thzrougand crcan de Waais r hvdrwge.: bads gam icorporaion c r ai euciecsides e' b-rinhaed Q dWe n1ides theatre ecognred by streptaadi The labei may be directive or idne xty detectabe.ndiret detection can ivo ve he biding of a seond lbe to the first label, ditly rn dnrect l'or eample, the label can be the brand of a binding paune such as biwin - is a bina g partner for streptavadin, or a nucle&(fjegnacCswhich is thend partner fr a compemeentrysegncee to whih itcan specifically hybridize.. e Indhg partnr max tef e directly delectable. icr rampe, an antibody may be itseliabeed vh a fluorescent molecule. The binding aitner so may' be miirtly detectableor erp! nucleic acid having a compiemenary nacir-otgide n selietce can be a pa of a raneO DNA oece that s in tndecna tmug 4 hybrization ti oh:rlabeled nuceic acid molecules e& T 11ahrader and A.. ainusner. lo hnWobgy & (1 Quantitation of the sga h achieved by scnillation county dendnetry orflow tometry leveinaan:mklttibk' s~s. ptinais' or ue wb i~nuov~'y~inldce butar peroxke ne >pdhhtu mid others commonly used in an - SA), and cakwmetk labe ws suhascloxc old 01 wkloreo glass: or jiastic , hed ienaiev he 4irk.1 the sanIple can be detected using andirect may where-i for exanpteasecond eed antibody is used wo detec bound markerspecific antibody and-rn a competitiontor nhibition assay whereirf or example, a mnnoclnal antibody which bind to a dcistinct epitome of he mA ket aie incubated -sinaaneorl withthe iue 'Teh s. ~-c<il~ah (or selecnve-v 7bxnids u't an atiibody o Ot'N.specitteallys (a seleeivelyi mnuneacte enh. or tpeci nteracts or ind wvhen neerring to a protein or peptide tor othe eitope refersin some enodiments to a bindsng reaction that ts deermnative of the presence of the protein in a heterceneous populaton of proteinwend other bitoies. us. under designated mmunoassay conditions the speed antiboces I ik b in t a p a rin at east two gt reatethan the ckro ispeiic aigna) and do not subtanay bhd in a significant arnotin othr poteis pesent1he samiple.speeCi binding to 1 an tbody ider 5uch co1d t ions aegnvre an antibody that i seated or' its specifnitf a partly uApteri. or' exampte polyconal antbodies taisedo seminal badc pronein frat specific pecks suoh as at ouse. o huan can be seleced to oainlOnlY those peolydalIt tbodies Ihl jpd repedcniautnoru iicted. th SemlN basic protein and not with other pren excep for poimorphicaiants and soewf semnna ibnot proion 1 election nay be acheved by staying our antibodies that crosseact with spinal basic poten nmolecides from other species. A ariety ot nnnoassav formas nty be used to seect anbode-speficaly umn noreactive with a paicularprten or e nmpie, sod-phase .ASA inumanassays ai ro tmely used "o select antibodies specilicai.y inmunoreactive with a protein (see. e. d. [arC & Lane. Antibodies. A Laboratory anu 8 for. desc ice of ununm aNy fsomas and condion ttabetto dtegr4ne pecitc miiiaoreacti ty II picalig a specific or selective creation will be at least wide bcyround signalor noise and nte ticlly nom than 1 to 1)00 times backgoundtintostic assays. accordclig to at least some emibodiments of the present inirtaton indladet bare not imtuted to uniomaiassays and nuclec acid baed assays. Immunoass'a y' is an assay that uses an antibody to specificaly binda atien Ie iunoassavs characterized by the Zn of specific binding properties of a paraar antUbody to iaw. target, ando r uantif the agen Accrding tO ia leaSt l Ie nbdimenthde present mvention poides a method for deeig wphe polypepides accorntg to at least some emodimrnentfhe invetton in a biologic ample, compriIn : contacting a boloIc tampl an hawibody ' fic eogn ig a polypeptide xordin to at1g. some embodinents of die present inenio and detecting ad inkirtltwherenthe presence or an inmeraction correlates wit the presence of a pofypeptidwin h biological sample, Ac id n wt at least some mboimets the pr-esenrnvet nusie airmetihod for detecting a polyncentide according to ai least some embodiments of the inven a biological sample sing NA'I' based assays, compising: hybridizing the tsnited nudeve acid nmolecues or &ligonucieotde fragments of at least about a nlnimin length to a nucle acid material of a biloital sample and detecting a hybrIdiaon omples wherein the presence of a hyidliration compiecoetes wth the pieseice of the pOlvmaleotde in the bioiogicalnsmple Now Ynitin a nampks of methods or assans are decried hot The prsnoetoias eae okt ae pon su"ch igoscetoso MM NOA.S$AYS hrno og ed hihng a, m ndede tos ear p e a eryrnnune as E ch as en ed inimmsorbeti assa ESA a ad jo oAmune away t Rl A a Weern bbh as. oa so Not asay ee U PatwS . No MM:2414376A 1 45311 Soinrde 4A7 8(P ienerailv. a snbject ora npe obtained (onea bject i contactedwiara tibody that seerfiaiInds a polypeptide according to at least soa emnbodinnts of the Invention, or afgmen:hereof Opionaly the antibody can be fixed to a solid support pror to contactng the anybody with a sap Example' of solidsupports include buae antimted to g .as or tiast in the Len e oreg.anairter plate, a stick, a bead. or a oUcmobead Aftetr nctbating the Sampk~t with antibOdOes the sniture is washed a the satibod mar complex formedS can be detected hi can be accomnpshel b incubatinge hashed .,nbi e . wi.. i a detection reagent Atrnatvey the marker ine the' sanpk Can be detected using ant ifreCt 205s . wherebn for ex EnNAO -d labeled alt jbov is us"edl to otohond ualerpecic wluithod, Throucghton't Ole -iSan v,. incuation: anchor wasing, tens lay e dh9eired ae each coination of reageit nuatiaon steps can vary frn about a seconds to several hours preferably nrom abot nuanutes to about 24 hours However, the iunbatieon tie will dependi upson the assay fomrt. niadzeryolume cocentratn and the ike. Usuaty the 'as 5Say ll w!be cOwn6ed oni at anbien temper aalough they can be conducted over a san ogf teperature, suc s 0 V: to 40 '. The trtOtlit Of an anibodymarker compl n can optional be detemorined by opnang to a standard or to a control anmont and/or sinra R adio nitmmoassay 11: According to one embodientntis method invokes contacttng the biology cal sample with a specific antibody (Wowed by a diolaheled secondary antibody or antibody binding proteite protein Airbe ed with 1125) prucirated pael s rrot oa o the aon o" the nawrler poivpeptate in the satnplte.. Ennyme ed nnrunosorbent assay ESAY ThS method nv es f atioo a sample d i e target polypeptide to a sresven a a We of a noertiter plate. A subhstrate spJnc amtibody couled toan enymeis appi ed and aowed to bind to the target

WIT

potWypep do.Firstnc ofthe astody is tea Oted a Jmimaled bt a in meactm Oro pio, mg ItanI)e einsYOMi oo d Ol aortati nk din twi mehod ainmde to seAdih lpf05~dcse and kinptsnta .hemct senate tpi the an s ofoh produced A a men&i~at m ceMIpt etosn rac uan Xecesett:III *nti d ves ep raineaageutincottntn th oare binding reagent: mn be. for caanolpt enA ur seconddry anodie.Anibodiy Pinndin rear may ben aoabeled or enzym in sed A d hereinabove Detectiom ray he by~ aead;titgmphy flco*lortilnti.eaclana or cet amaescente. his method ahows both uatitenav ryis tof Me amonf of targetpoiyp d zne Id iliUOn of is MAetv by a reActNx no~snn on3 the tumhram whicth idicanc f *grtii Shiito in- the t fttin d durinsr n: rlcrphoreasx Iinu m hi nochernicai mialy ais Ti mi eehod invest deecdon ot a ubstrate -a satu i id ces by a anabodies. Thei atiboosd en e >enyme lnked or lnked ant ihojs M empfl ,Joyed, a cctari 1ilettic ractiono Iay icwm renrd. Fluorescencet actvated cel sertine tF is method in mvtV detection 01 a ueide in cell by iabod eThetiboes eedtO Ibooohres L~tecionis by aman ofa dlorting mact" ine -which; reachl th wveenrt of ih etted fon each t aS it passes through a .ight bea n, Tii method may enpy o or more a dbices it taneousv .NttIICACI 'IXTNOLGY(NAT) HASED3 ASSAYS: Acdording to at least somae enbodime the rrvendon also contemplate ne cids whih selectively hybridize with the potgyacieotides acco ng to at least somame e~tod'nsof h din venukon. Teolowin k a ~ are noo tiinfeamlsaNuc Acid mac~r IK ' L~stanedSYnttic Reactionj -Q.B - Cetycling> . m probe reati on Rranched DNA. RFY a sDGGETiGE, Snerand t araton and Comoarative eteenic N> o cid of toes 4n a hbcdogoceal sample roy be etlfected by asays which 1vo5 nachnc acid amplcfatain kcedmoog. Ar~Mtfcationl 0f target uckeic acdd sequence belVO caard 0 bhy a aurober of nae k etoAk kan it;he art NOnK irtt eamp e no ephCAidn bechnqieS include pimer based- C P M, stand displacement a m at Aon (DA . tancription based aniphea ,tone Qp iucase 4s nten I an \ Rx oh a v9 roc Acadci USA 6 7 ardi et 8 1 o ed oy I a202 KNhkt ak 99.Mehd MlBc 5YGTi art rrbroo.t m 9. supia) As used he~At i to 0 11Cg tade Which e tah,' e: ichmean t inrid a with) a AT sequence. thereby cean a dWuye stranded regon wh c caNerv s 'in rIntrmon norit for DDIA tes under suitabLcnros htr'noo Wpification pair " r "p er pait )refers herein to a pa:r ogf onucletides (oigs hah are selected to be used together in ampyn a selected nucleic ad sequence by ere of a ilumbtt of ('pesyg fatnrndfcation uroeaaes preff a polynerase ham tracion (>oonckohdn ~ ~ k an~f.0S~-fw t lat > s'- m N mfjcbodunts of tMe pten inenion niay be of anys ontab'te eng itdepenoing m the particular assa fomiat and the particular needs n a rgeed geno mes enployed Otkioaly dO gonucdetide primers uat Eleast12 ncdeotides in length prferably between 15 mnd 24 andeeideand they ma be p t e da tonnueic c As conrno lo pnw u' the mat the 0 oigon'ucletide P. Prs can be deuone, d hi alin intuo S rok e a 19 9 Mlecar Gmoen - Laborat 2u d Edi6in CSH Lahcramr Ae'\\ub'nr t at, I 98) in ( arent. protocols in1 Molcetir, B 'oh; Whes' & Somrtin N\ C RADK0V MAGING MECPH-ODS These eth h ianclde b-re not l o ostron emission n p y and single photon emision computed tomography (SPEC) Bt of ese tehniques ar non mvaste and can be used to detect andor measure a wide variety of tissue events andOr uncion. sch ts etetui cacerus ell ba errnle. UnAike PET. SPEC? cu, optnaY hens-ewith two sbel s -n SPEPCoEs as wee, ror c ample vith ivtgard to cost and the types Iiabes that can be used. For example. US Patem Nu 6,696466 describes the use of SPITC for detection o(f bnra cancer. Accodin to at least some embodients the present iteon atso relaesto kis based upon such dhagmostic methods or assayn THE~RANOSi1CS Accoxrdg to at lessome emodiments the present ienveni alo rate to the uo of markers nd WAnibodies according to at least some embodiments of theenlonfor t0eanses.r. the termm teran cS e tcrih the une ot dsaotC test ing o diagnose the dianse. chos the cnreot (titv en~t r4C. aCordin to 1 Ni$4tAutS O dtagneste testing fa wa itOtatespe:era ceod to th. res\ o dnnostc test benea.tic tests optiO" o I 1ng 'eue t o0 L sele tit f orfl-ft: reatments dia a prticarig .ikel 4 to benefit thorn and ur~dy10 t produce sidesetffects. They can aso tovde an eaNd and ohdective indition of trattnent efficacin individual patients so tha 11ncessary the treatments' can he altered wtt a minimum of delay9 For exampleO AKO and elnntc tc1 Oethef created .lercep'test and frcef' u~r~'zxmnah frte creatmnen er Irat Ca(ncer' m the tWftOse e test approved s sevusagwih new tetapeutic davo gn adding to Herceptes (Whfi i5 an enmtimoh strchemical esl. ther thernde test are in development which use tradi md' "tna c 'mis t ioi n ssty celitasecd tchaogine ad nucdec c id tests. Ptas recently launched T1%T thiopurn n Ao Nova Iolecuhu pioneered SNP genotyping of the apoxpopr'oteln E. gene o predict Aheines disease patients responses to chonomaimetic therapies and it is now waeN used clinical tia of few dwg ftim:i nd dct husi the fld oftheranrattes prevents the inte section of di gnostic trtng infornationtt predicts the. response oft , ort SURRX MARK IRSE '\vconirlinag to at least somue emoimns h present invetion a~orltsto the tie, of aer a anant e aceodmnz -oat least sone e.nodi.ments f the in ventton as Stutogate smrkers A surrogate maker is a marker that is detectable in aaborary and/or accogrdogn tw a e hsica sign or Sympm on thatentad th sed ' theaectt as a substtute for a chneal meaning endpoit The surrogate marker i a crect measure of how a patient funct ons or series Whch is expected to predict te effect of the thernpy. The need for ogae maArkers maly lse .en such moarsers can be measured carne"ngre convenientl ormore fre nt than the endpoints of 3nte rest in nw nk othe tf treatment on a patent, ch ar referrer to as Ot a edpointOs hdeallv. se'agate marker vid he blofogicabs platustble, predihttv of disease pmgression swk'arae :0 stan atrdold assos ionswudhhunt nietoraiialcii anemist a mnnmoassay c edbasei tech olog esbm ic acid tes and Mag Su t u endpoints wee d fit nanly In the carovascuar. For eane. .atihypertern e ti gas nee approvedi based on their effeeni ess nt loweruingblood pressure. Sin ~ d ad W tepast cfli~nioWtrantr avetshvebenaprve Itudo their UNy to decrease caoester nnedrt evidence that the dccease aOK'tit' unt am theroerotica heart disease. The easnent ofchoidesterol levedA is now an accepted c sunrogate maarter ot atneroscurrosii In addition, currently two comnotnsy used sugten '~ ma kers in Hin studies are DI4± T cel counts and quantitative plasma {I.RNA In so'ae 01C thk' .'nvlin te ~k 0v m pattePO My sene as S e rler o t a diieasas wI he appreciated s one siled in the art SMALL INT'ERER NA NUCLEIC ACIDS AND ANTISENSE MOLECULES Accosting lo at least some efflbodhitlctit zh present soven1ton trie 'tt~ osa interferin g nucleic acids. in pamiuhar siNA compsing conmplementar sequences capable of spec an haizi.ng w.b the polyudleotdes according' to teas some embodinseras o1 the iflventiot (i'e, with pvoon of 114 7 75 and F04 IR715) and specfiahx slenenig these gnee According toat least some emiodnenm the presem invention relates to sqtuences and constructs enonair such nucic ac and to ew ues of suc cii cidsR taronstruts to aodfv FM PS 1 5 or [041 7' gene espresion paxiclars'to reckicef or inht: gemzy> prsmn. CJertal single stranded nueic acid molecauea able to for a self complementa doutestrande rgion whel part of the nucleotide sequence is able to interact with another pat of the sequence by WatsoaCrick. base paying between in vested repeats of the douestrded regions mayonn o m eta es known as hairpin stintnras 'e hairio structure farms wih an unpaired "loop a nacioodes at one end of the hairpin structure, wtththe itnvetd epeaseqence anneedEe loop may o faciitate te folding of die i.cleic acid chainI 131 tchnologies. S techniques ar describede for exampe in US Ptent no, 6373,099 and in Grimrn f) (Ad. Ora Dcliv, Rev, 2099 6 9): 6 703) Accnrding to at least some emboiments the pb sent invention further conempateN iantisene RNA molecules complementary to the polynucleoiides according to at least some embodiments of the itnntkm or to any frapxent thereof. Antikense RNA mayix be introduced into a ceul to irhibit inal atiun of the conmpementary mRNA by hybodizing with the polymxuleotides o the according~ to Matleast some embodiments of the invention and abstructing the translatkun machiner's siNA or antiense 'noiccidex cois to at least soine etaban of the invention may abused as a therpeuntictool to inibt P041.5 ' and 1 5, > gene expression it vivo, 'e Ibiag esrte e offerd for ~Jorti poses OnnadauWi not inewnded to lW1 te scope dhe prevent invento n any Way" Allpatent and ilanrrere cctd in thie present specification' am hereby EXAMPLES LXAMPEE I IfIMDS USEDWf TO ANAOYZfE ITH XRESO Of THEWsk [004561 The tarets. accord n a to at leas some embodiments of the pkrsent itrnotezaflo were tes ed t regard to theaseir expression in Vaotis nceo anoocancero tiue sarIples wandor with reg ar to as expr ssion in a wide panlof hutnart salmplsk vch contis vious types ofimmune ells, and hensatogte agaes sampe and cel eas vw. as sevel samp of nora tdescipn of tm anpIes used in e non and canerous tu nels use atd in i " tprese IFteid a i Ts provided in Table L The, lst of the blood specffi RNA s'angles used fito e PCR 0he blood panel described i 'Tb e a pnnv d a e descrption cc the svnpes ed ithe normal iu panels are provided in A descapti oro ampes usea inw teo-var'sane testing panel iN provded in Table 4 blw'The, ke's for the table 4 I's Table. Sample W Name Quandt a Well Name Quant N Iesus Ai Al 3 4 58 8 100 1 {#27) 32 IS 4 8 N Tch A2 28.5 100 0 94 {#64) 32.909 7343 Larya A 8 2 4 48 o 3 4 #4J2) 3 Gm 87 5., t~t Head/Ne A1 3n4067 100 108 0 30502 1 A 2,79,41 1000 14 9 4051 3A5 2 m 18 S~n\ AL 3 10543 1 99S V17 20 0 IC O I I 7 91 .3%1 In N. N lA it m T anT S&NSC. 316 (1 3498086 9,5247 I~ NO, j9 71 8 ' 9N? aN 1 37 (425) 341.s53689 9 1N 0 190 3214(28 6 T+ Ni ph 020) 3 .2578 9123 28 135 #2 31 2 38298 NCol omp N (TrvpI~ ph 40 ] (#2611,) 3~ .063 2 f 1,26 t9 In # 0 (061 N~iin~y 1 vmho (#30" 3 k375 18743 3- -(#289 29 14, 48 6 011 ( 34 .6,.99$ 12639 4 38 #2 6 43U 7 * 4 N Kdo I h 'ae m mpb 5.S__ (vt '3 5J 9 W .1 (#204)__ 28_____N 95__ * <P 6,,! 34 Sta [1 59?63?65 134* 4 )1~943y 134. N t ~dn L t~nh x$f- N !ay, "' 3j2>~4 199 22843 146 W K) 301,7 2M9 '256 N 1v1 'm N yn S2075 7243305 47 00 307 r NPdd N Stu M4NV 14 802 * ON> 3337~9852 2638203 32A55~]13 4991_ 1 ~ 021r~ '77ct3 4170353 1 '"s19 & 235 508,C T Maw N flco-A tNki ma S21( A19 331943 19121 16-A ASS 30332 14-,$9 ------ -- " ' (SI '0 al ~ , - N. . T 0 IW4 127h 4K212 16 (#37M) 33'537 21422 N2W. 3t3 0 U3,M1 4 N~ ~~~~~~~! H, 38Q)_ ~h 3 124 2 ~- s sI T. b c I i le nV.. "I ~ ~ MCSP13 1 Xb 1 tat-- N \4 3---------------- ---------- -------- t 7 'I "" "" "" ---------------------- N 4- ---- iI -- ------ 1 ---- --- ------- ------- ------- ----- 4Jw B 33W1b(7 kx KUYs 31 B ce f 13a~_ actI ~~ '4tl'v'}rs. ood-e v"-'czi I. .................... ....... 1 ---- I T- -- -- - -- --- --- --- --- - -- ----- ------- -- -- --- -\--- -- -- -- -- ----- ----- --- 14~~~~~~~ I~ 4" ~vAccl _____ I U ('0 bloc4(dN hk;ed 4W ce~l 3CD4 w ..... . . .Tl ...... ....... 4 ------------------ ;----I I? '04N 0? ('1) c-ad ls~ ' blood-dent ~~ ______ 10 CD\ \1548 CD -4vtCBM 1:548 04 4r V dv I s NIN croI~ cet ftrddcs"4 ............ N......e bid~env d JI '2F ('am~o B UI -ar ~ o-en' -I -_ -- _ _ - - ---------- Or~an/ tThIi ype iims~tr par~e[ san 1 L _________ __________ N i fN~ s r~t CK D(:3 in atwe (2K biuod~derivtsd tk PN ± ~ I OCs&I' DC~ ±T c.di~ bh~itdtived ~j;~ 4' 1 "ni 139&7A1 _________ I v'v>phNcide. I ~ niphema I Iduscie I sm (k54t~l3A1 I '"tit; I N ~ lp'~ Pfl' ~ '\~'P vxix3 ?SS'91Ai ~ ________________________ I ~ II P N rlt d SCtvin 113325A I dvv~mh N xie Nnn ii H 'NIL ~ I 1 v'~phNnde I olhcn!a~ CNL;4K.ARdNA~~ (II) NUT I Fo~k~~dzn C 1\ N a ~d ~ I ' m Vol. (41.1 c4lii3C8A\ w"e ( di I 1&culnr ti~~k (H ~ I st TiM__0111 uILok'xli ' ( U) N UT.. Y N IdI yrn2ThiQ2A1 I t.. Ncsie + I ~e Ccli' N IL fliUuse Lanze 13 I tin D1fB(:di I ON 2 {VI)IN\ k I ~. p N IL I } sroe 13* ~ 'jNl fNjff3( . CN34P&14S7AVs __________________ ___________ + Larni-~ 13 ______ CN*9jHP:0D0xP~ ________________ t' m I ML IIMOe t~t j~Np~jv~yn}j~ 77.322 Al (5 tttc~ 0 Ofl j(~C ............... ~~~r~a ........... ..................

t p M ............... -_ _ _ _ _ _ _ ----- .......----------- 1 his. - - -- - - - - -- -- - - -- -- -- - - -- -- -- -- -- - -- --- -- -- -U \ ~ Y~l4 7~6wl .. ... .. . . .. - - - - - - - -- -- -- -- -- -- --. .. .. .. --- - -- - -- -- - .. .. .. U l .... ...... ISo Table 11, ----------- - ----------- Y M P~atd2.--------------------------------___ --------------- ............ ----------------------------- pi yIan: S e1b tyutl 1d 4ye -e e -a t -- -- --- --- -- --- --- ---- __ _ _ -- --- --- --- --- ---- --- --- --- - ...... ...... ... i ... --- --- --- --- --- ... ... .. .. -h -- --- -- ........ . --- \f, t MG ueAR MCr 9 61\ t:Jpf '14' ............ 30 I-P-:i22 I B y a s 2 .1 -- ---- -- -- --- -- -- - --- --- --- -- -- -- -- -- -- --- -- -- -- -- -- --- -- -- - .. ...... ..... i--k -- ----- --- $--- ------- > ~ t --- -- -- -l-- ---- ------ ------ ---- 64-(\ N2, kveb> I Wt~ ~ c~hbr ' m ............. .... t ............ .... stV\hwfN Sto(VI &h n"orrmA ---- r' - n ------ ..... 7 brnn T i IIN '7 heartsn& Nfl- la , ntinO , bka rt-zI mte ll'N 'in oouN brai 00Pfl: I ----------------- fl' - ~ ~ ~ ------- ---------------- rn~ hal''o]10 1" 4l k. N- iur nb MVyln -apt deonuk 1 39 lie zk tw ...... ....... P ........ 4 , .l t 1 ........ ___-_-_-------__-_----- t-A ------------- P~ dw - - --- -~~~ ------- ------ i U _ __ ll4 ,nw .,w ... .. . .. . . .. . . . TA 'N i&- ~ ~ ~ 5 'K k~3f ( 9 ra OlinR " i 'wD \mb \mAB W A- WINcM -UVCC ---. -- --4 --- I I - :5 1 a \Zf \ vble nrw 1l 109)' , N 4 W<. (IMP 6. t \ tN4< I p ------------- -- --------

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z~ n ros H I~~ v ~ tIrk -fli C"1om ~ 4.T.A.,.4, 1' 4 ~ J~ ) > ----------------------- ~ - -i .- ----- 1A MtJN2 J:a Hi 1 V Ti'WdQM H'. O"If S 27k4d J ~~K llc ( Q ' X1st'n~ XuV Sl II M h A Mu±nes1u tm AM \l A A IA Mnou:ardlm .44 Be n ~ igcn a3'Y~n tandrus> us 'Li untu8 \ 1 leOt a N \ uxtu;MN'r n 4Ntd 44 .\..... - - -- J\.d \ VmutnmuS4r4V 47 G~4 G gn med 'Nor RQ NN, SN 44 kI N I * .............. ix,3 t .tCNi PN, N Yr3ml j 6~ CNPS "N~orvnwd1 eN AR J N1X 45 ~ ~ s.n 6' 4 C-N P 7P44PYW-N N w S 4 ~ - MqatCeinand EHpedmen Pol roccdne5 Ited ioObtmn E bresso Data [(0457] RN A pmparatioa WO4S R RNA wv btiedfo ABS {Wlm i DR 934 . SA http/ ObAbloreagointotha hbs nn ainkwad. CA 445 USA etwv . Cyneclg ncology Gu sA ue Ban" C hikred oapaa] of Columeb wWWenftfltchfon. ambU5n .V d x TX7R44 UA hattpfwww amobion com Atroad etroit.is 48202 3420, SA waserandsxm ARMCes LO Emervile, CA 94608 USA.vww eisc MBCR- institke ar Myeloma and Bone chance tewarch MWet KiAywood CA 90069 USA, wwwamnbcriorg :nd tmm Gnomes Co borag laea Di of Seacare (Cambdge MA 0239 wwgeoncrm Aifternvel. RNA was generated from ood cell ccl uno o tesue samples siniR Reageni Molcuar ReMsWaeCenar&.) 0cOnding ( ti M anuate aStCUctins To01e ando RNA samphwane obtndhe' OEl hr ents or from postmo mMost ttal RNA aples wre treagted with D \ neAmbiot, 10459i RI OCR R '4r 'edRNA (2 4) ns uec vt 30041500 ng random eesamer prtitg ud500 pNI dN in ato u oi 3.2 to 156 l- e mn~tre s:icetefo eR at 6SCund then u ickly called 0n iC wee. t100 olX SupctU firt stand buff (vitlroge, 4. to24 D I1nd 00 te jaa Promyega) wer addec, and the Ttutre w55 } th~eu for ( 0 1? >1 'at units~vux fba. W. .. il . l 2' followed by further incubation at 42 C fons n, l'hean. 210 YJ (402000 rOuni o supersnpur (Invitrogen was 'd and the reaction (final voirme of 50--04)was incuated for 50 ad at 42 C and then 7n)c'-(d'0 C fr .mie rhg NA was dkted I 20 ia TE buffr 0 lM Iris p :.i M EDTA pH S [00$4601 Weal-ime RT PP analysis camied out as described below cDNA prepared sides\ abed abo-s sed Aa w.mphite RPCR reactions ( 4 'jad popm; of 20 pU s i-g e SYBR (reen [asa (PE AnE ed Biossem) writh speaets pnrners and N Etzyme (rognech or mA - or Roche) The apUfiaation was efcfed as follow"', .50 'V fot .2n ada 95 fo~r 0 i d the4 0 cyclesf 95 C for 15 foiked h 60 P fl' I un. o~tt .a s'5dssocatio step. Detection was perftormed 1y usmsn the PE Applied Biosysem SDS 700. Te cylek m wheh the reactions achieved a should level of fluoescence &Y= hreshold Cycde, described in detail below) was rgierd and was used to cakulat the r ipantity in the RT reactions The relative quantity was ca elated using the equaion Qefciency t Ct The efficiency of the PCR reacton wa:; calcuated frm a "mndaud curvee created by ausing. different dlut ions of several reverse trariscription (R'T) reions To minnrmze inherent differences in ste RT reacting the resulting relative~ quantiti were normab red using a normialiation factor cakculaied in the 1o0owing wy:r" ['04611 he expresio of everaghomekeepig OK nenes wa checked ogn every panel e he' ae psanut of each kepg gee in each g calculated as deskibid above; w 0s dide bthe ttodian grmnYffis genet itn al paine m les to aotndin the 'reaive Q refto Mi . lhea flr each samNe the median of the trelative Q re ko MtED of te wiected housekeeping geres wascalculated and served as :noraliation faictor of thi Nana for flther caltions. It should be eted that tlhs type of and iss provides reste quaniflcnfion [04621 1 or each RI sample, the e.pressio of the specdc amplicn wa norma'Czed to the norrmaiiztioni factor caicuheed fron the Cxess3Od ot iffferent ose hieptin gnes As dete ed inect on above, [,0431&3 These lhose keeping genes are different dor each panel [004641 P snueee f~cster and amhosof th stokepigN s'o in a) the oar cne exmpes areIP. RT 1 S1A and (6PD [OiM55 SDHA (Genank cessn NoNivL04k6 tSEQ 1D NO: 136); amplikon SDRiAamplicon tSOFQ R NOSS) SA Paml prme-rEQ I, N3:A SDA Reverse prueer SEQ ID NO s4): [004661 RPRTI enank Acce In No NkM 009 EQ ID : 1NO ampcor PTWP mpho n (SKQ 1A NOQW:St;3 PRI larward pri)er $0P T NO:S4 H Reverse primer (SE I. N0:S i [00467 G'DGnat a o o 042S Ol 3pB D" N 0 9[' P (O0469 CSDA (Oen0a2t Accession No. N 46 (SQ DL NO: 13);unpo SDHSlic o (SEQ 3D9) NO5 :eard me (SEQ DN8 ND R eversee r mer SEQ I! NO11 Uniqu68 Ih peut s Qi th oNs'ekrgcing ecorecsurd gne a$lQ Dh e 0nisc [00471 box Gifank Acceson No M1009 (SEQ 10 NO1 ); a A Umphcon SEQ 1D) NO-7 A: ))A bIx Fakod prarndr 'SEQ I) N0:7) TA O Rersenpners Ie(SEQ ID NO:8) 10047 The wnces of the housekeeYnpg genes re nured int a he eampls of blood ae were a fo s [004731 I-IS AW LJT AN (Accession No, Q9Y450 SEQ ID NO:1411 T15333eg30, 34.F orwad eitwr SEQ D NO168 0i :n30 R ese p !'er SEQ M NO:69V T05337 .eg30- 34Ampl eon SEQ ID NO:YfU. [(AC-741 DFISA.\ I WMAN (AcsinNo P3:1040 ISEQ ID 'NO: 142), N178 1:ten5 48F Forward pnl (SEQ ID NOQ71), M78 245$R)Reverse pimer (SEQ ID NO:2 1. 75.7 se&S4 samoLuo su)ID NO:) [00475 SLC25A3 iAccesn No Q7ZN 0NSEQ ID NO:44 SSMPCPsed2 st No o SSc ee pal e NO:. SSMreCePe& rnp SEQ D N{o} [00476] SFR 4_Mi M SP75A (Acesson NO Q 8170 (I.Q U) NO.43< HUMSRP75AeC33FF d prim, ner ISEQ ID NO65 SRP75Aseg-33. R I Reverse somer SEQ ID NO:OO).. ASEQ ID NO:67) 004771 ii Acen N 04 SEQ ij NO:37 $1 IB u PW R o5 - MHPRTCseg p n SEQ ) NO: 26) f00.78.,, AATAh Box idAT prnte A NO P222 S Q NO 4 r SEQ ID NO 1291 iST iIDXseg7-9 Amp lon SkE ID N)O3 i9047E l Anaother- oxtedfp fled Rmpedcwteerrsio atem h accorn og to at leat oe enbdmems othe wa onwsME) dis nt~ en a~st~i~tn nd ~etomane. t ~ insquem6es, [s s ionata tron lit mot ,dlyte A aetri~x un~rar is &wnloaded &ro 0the Gene prenson Ornibk GE) \yyWfchflos4ligeWGEO\ DataIn i miic ating normalized by settrw ghe 9)5 pereenle to a con4stan( vawe tflrnau ed I pra tson~.00x and noise is tiltered hy \etding the kwer 30% to O xperments am a ted uist automatialky and then manua' to identify tissue and condio.n and chips a' eruped acconiang to thPN amiowtaion and cws Yeifca ni of dTh gaping by eonpar ; he ove1 expressioni pattern of the gen ech clap to fne ovem'1 'xv"erage.Kporsion pattem of idegesid gmp ahpobe in each group w i gned an expresson vaine whichsme median of the expressions of Ft ptbie~ i ad(hi" ncnedin thie gronp. The vecor to exiesl of a.l11 hst wt~ a certain groop the wWad chip of that gropand uhe collehivn of all such htwI chips is a vrulpnl The panel (or suis-iawel) can be qzjerie.,d to identify probese ,ts wi"th a etured behavior specific expression in a sbse of tsse or ditlerentnl expri betwen disease and healthy tisses These prbesets are linked E UEADS contigs and to Relbeqs (htto/hwwwswt hmtih~got'efiSeqi) by9 prob4edevei imappinn fort .the .anaiv is [00481 he Affyetrix platfons that are down. aded"am GU95A and the HGU133 fam {A A2O and US '2( ThaI tue via panes weu created U95 and U 33 Pius 20 based on the cormsponding adorms and 133 wh ch uses the set of common probesets for 0t3133A 2U 0 adim G 133 PLUS 20+., 004S21 The results of the MIED (sovery einne are; preented n', scir 1ot's, 14 satterp 1 4i0C Is a cold(rpresentatia of a gjwen.ii eje (o of gap;) The YONsi is eup, the redan p 55Won IN tpon nes d h a sobd marker. mnd the expreossin vuues of Ihe de ce gpRett inpuy oa c .S'Ilt srg ll by ~ he ('-MA The jrwxpare. odcerel ai nalld sf %inwst-olloueru teTl'"gltla( o 00git :fott-nancer disetas, e'c. W t a ittike Tr'etad cls with s sou.Ru Nrnudlwt) s Malthed wiph crss, and (PQxVCe with a duno.n The rumabeu of chu m each pop i SO wctn uceet to ts [04831 EXAMPLE I KRT(nAP3 POIXPEPIThAS N POlYNUCEOThDES ANO USES THEREOF AS A DRUG TARGET FOR EROD)UCINC DRUGS AND PIOLOGW$ P ) [ESCIN N R CUTN W9Y 9 s W93^43 1U ea ID 7J24 5829 Ceatures 6 incedpts and of iore the names for which are gva T) , T5he scored pror hardants are g4vin table 6 TO E'Q '-D NO W93943 SEQ D N:) -93943 N SEQ 0 NO0:) 3 [7EQ It NOf W9394 4(SEQ U)NOt)6 W93941,P SEMrQ US N u W9394 f S : D NO 5 W93943 p SEQ ID NOn WV93943A ThSE0 F)0 O 9W943 l ($N N~ES NO-I2' .54'. 3SE , N W994 VP18 (SEw MN W9394i T ( Q FD NO6 5 ese steuecesaev(n tee known protean Katec assodat> ~c ned pltre ei SsPrt accessionideifierKC HUMANSEQD N ) knownl aks accca.r to thQynonyms KCP KRTCAPJ.*I KRTCAP3 (kentiinocyte associated potint iden d a) severa in large Seak studies, ch as the ientificadon of secured and uenrane protein in keratnoytse ( 2nkoba0a et Re 203 I Der0l. 148(41n54-64 1de f roteinm2ad a ir a, 2(003, eoss RearchIQ 130 01 Z',25-7Q), aanotation ochn soe'2 anti 4 OR$1 Ry~jpjrz at 2 . NaturzA4 73 223 nd febkngth cN roecs adet B 2004 (enome Res 140Mr 2121 Soeusber et 2002 PNAS 99(26 1689940 Hawem no IpecAf tforetn wasplised aoxt KRTCAP> sequence depicted in W9394 % P 7 (SEQ frI~NO: 12 encoded by the c.Orre.Npiing W93937 1&Q ID NOiSas reported in W:000 enong coker hiian proteis aing ydrooc knasI YheWO2000000K06 patent applianon doe aot to;h. Kow Vol. tha 4equence c~okvs lag" i>WB)3_1 EQ1)N:1)0 W93943 3 SEQ i) NO5) are di naia e pressed m ora cancer l can or inanohe aav Alo heei o edig n\ 00000506 apglw in ta QID NO:2 or 93013SEQ If NM:51 can. be used as n tar et tor treant caner and nmne eted con n or aan s there A s there s no eacang n W02000N0) 06 application that antibodies specific W9343 17 {SEQ ID NO: 12) its solkble ectodomain, and/or :hanti thereofcan be used as Sequnce epice ' W939 P "fS~g NO. .as reored in several paen apvicatdnas For exanpe 52c{0065888 " r ts >4 2. SEQ USM NO:7 among vey huenmber X6r88enes 2o70c6588 pasort to discros methods and agemis Inding antbodies Specific to ns tor ntg for evaluating cancer .p osisand for use in therap-es. eS US007006588 pet application does not teach. however that eapresoon orthe sequence c.rrespon14Zg to WP 2 SEQ 10 o the use of antibodies thereto is eoreisted specificaIyto the treatenico diagnos ot canc ' o bre~ast, cOnor oirnn cc :oor iflftllCrmre cndtins W 029 0304rport-s W993 P2 (SEQ In NO:) s uqence among very large nurMber of oher genes W0200 9004 purports to disclose koaed nuclei acid mote encodig novel polypepbdes and antibodies that bind to these polyptnipde\ The, aphari'on Birt r ponedl vrlxy to anosi an heaeui mtOds ' osel for danoa wa n prepeincd nd/or prognosing disorders related to these novel polspeptdes and to screening metnod tor identfying agonists and ntagonists of these. p \ no leotdes and pTpde heplct to provide methods and/or compositions for snhtu Owl cnacr;tro Y iction an~d Bnio ftetrvpON'tiees incibdig an.ibod based therapes However he o20090304 paent appiiaion does not provide arr> specc teaching or incentive thatwould direct a skilled arisa to use antibodies specific to the polype ptde.encoded by the seagnee corresponding to KRTCAP3 far the treatment or diagnosin of cancer urpecide oaria llngabreast or colon cancer and/or Uflrttid i toi, oneeawonsu W o241s Wepor KRTCAP3 among ery large number of otner gene. Th appn a0ion oecl Oranty relwe tocoostssadmetd psoreo f ading i the dannoses sf the 1A nodsen aon Of a ung and methods of screNWg Sfolereh Ihpete agent for the eversance -eaneopni cbditonso degedwo s p027ded ae peteipiana methodsto nh the gnt dof nn e w to treatsuects hmg neisi un "s.iThe W n u9se p natent p4cafinde eac h, heseowrat geence.correpondicg toKRCAP t e enta oe nepesed pn ovan cancer or breast cancer or hon caner o- nune specfic to KRTCAP its soluble ectodomnain andora y ents thereof can be tsed as eiagenuu oianost agents for treatment of cancer.eseeial oaranandor breto ant ~kd~cln can acerad/olr immne.e'inuted cond~tons, U0O3i 0.2 patnt appicaon md it rselated coMt erparts datscose PRO98% ieranocyteg asoated protein 3) and ptc h the prou cion and tse of antibod es oe Ohn othern co tebinatin o gen wh h candersA 0oee 053 aco puriot to dea ie teh r ods for caing andignostif fopaanned Aopo ,tu -tethe eachssion 0qf U nr o2 o or7 any coton tah a en o goes nil to KoI., ine podoctin. ;1ct r If'sentn tereo an h co mudi n Ohe pev oria0 pnosuctr agents anagOment amd 1 mioaton pf caincen pp 1ps t o deat ir.uhd fo adhe thei ad = i n a ini of att efft ni pron caner bk dteIt"rs, Pe ices ng al expedin ota modl the oren andtor acofvity of's or incaeet Cget di d I0alsohe tdlin ,na W( r,1 10593 anpton hat anbofsup ecKifCAP3 its schble anamen and/ aeftat tn of aner hea dagcati o n an t s ued h (harpeau codQ~ist 4' ag7nsf~eent n o ovaan 1) oasi,' c o ox hntg cane andoro Th and hmcd seqene of XVY4 0P SEQ 111 NO, iD) anid W93943: -'141(SiQ MNOJIvrepreviul d sed b t aican o the N trent applMaOUS 1; W Iie a pe n No: 63 he~ica 53 patentMTH Aolcto No V !3ANO wever I ere D s notecin in C! I U/i Trp CnoT O iw!t0lh re c n cAe a n rede nd ton in payola. at 0tAs soni en~tonwnhs o th reen :iino t oth eo nove KI AP3 vrant and discrete prtons reofa adug target fo p thexatic nai maickS. peptdes antbodies.aisen RNAsiRNAs ribozymes and the like, Me parnuri the nventioneates to dCagnosc nod therapeIc olclona and m ociona antibodies and lamentss themof thaitind KRTCAP3 varants, and poxns and variats thereofcut ati o~feo~ct according to at leI oonf Owiolnns 1(e'sn inv on to use atibodies and anybody fiagmients agn K1CAP3 antigen\ t\ \e rted Ssok ton ukate or fnernents thereofft:r wteasa and diagnsing ok a -n cance and/or beas 6aene and/o oloncancer andl untrtned conditon X ni0 Otgen o differcnnfy eprpessed known poiymorp sm to at posttvn 79G R at position 14- an at positin 114 of' KTCAP3 proteini 1S.Q ID NO:)ee previously reported d. &ertincyts-ssotaedpotein 3 (EQ MD N0,7i1 hhvdtob tnips As noted above, W9304, , \ fet ur rcp whih e sted inT' i above, These transcripts encode for poteans which axe tarins o proton keranocvtes aso iatdproein 3 (SEC! IDl NO C-' -lt A descripti of ch v nt tn cordi least $o0we. odtebso the tlttiot\ 0 IOW proved Prtin\99: 2(SQ IU NO:?) Jis, encoded. by .~i oRVRint: tra~ncnp' v349 0 n ) DP) I .tt codinp potion of transcript W0943T)(E D0: st potn 7and ends at pto on .Te trncr, also has the foihateino SNPs at listed in ThiW; (ves accordir toen pon n t UCnhe i wn the SOOernav na acid ted). 7'ahf 7 ANudev t NI!SVt & N ian ptei W93943 P13 SEQ ID NO 10N acc ing o at eAk snaw embodiments of thnentun a an anino acid ence ended by imrpt WO9435 (EQ hDNO3 A descition of he renanip of the aiantroten according t0 at leasernel etboidtnts of te toention to known proteins isn asfolkows Comparison repot between V93943 13(SE HD NO: 10) and known poteins KtP RU MAN SEQ ID N: AA inwe&.ted c p D"yeptd pt ut I 5 } dq at least 90% Iomoloous to MRRCSIAPDAAROPRR EMPt GLALIV fVNLLLGAVIIGTVLRIIANPRGA 1PE~YTVAlsiiSVG.SGiL[ con spending toamino acds 71 of knowaprotein KCP3 OiCMAN (SEQ IDN:? which also corresponds to anmino acids .L 7 of W93943 M3(SEQ ID NO:10 a second anino ace dnqusenc-e heng at least Uptio Y least 80% p.ndAly at least 85: ooerefer-abi at least 9(% and most preferaby at les 95% hont to a yovi$epue hedng the sequence VSA AGDPOGSRPiKALCJ>Q t$S (D F) NO: 146) cnsponding to anon ac s 9 7 7 of W93943P SQ) ID NO: 10 and ai inn amino da ~ sequence being alea 90% honmologous t V VANLASRNL PPIWVLLA1AVNL LSVACSLKILLAVSLTANGGOR1 IJAOCHPCO DPeVi lPt 'e n P~DCPFDP'I.OYTALI~AV SLLNISAGEAAiSOYd CV AA L ROW"P, e LQQLEMTELESPKCKnPNEQi.QNQEiRASQRSW 11 crespodig to antno adds 72 - 240 of known protein KCPSA3-HITUMAN (SEQ ID NI>,which also corresponds to ando acids 9$ 6 26 of i93943P 1SEQ ID NO.0dO), \vbem n id first amno acid sequence, second amino acid sequence and third amino acid sequence are conti6uous and in a sequential order B tiolated oypeptdd corresponding to an edge porod of W93943 P13 (SEQ ID N:1 coiisingan anlne acid sequence being at least. optionall a tbot sWo. preferahsy atl east about 85% more prefeuably at least about 907a and most preferable at ai about 5)honaoous to t D sq n D (SEQ ID NO: 14a-) oftWN.,93943_Pl3 (SEQ, O)NO:10rY)

IN

2 ('omptaristt' ep between 1943_lP13 (NEQ 11) NO:0 and known p meK N 76257SEQ Df NOd A, Ant isolatd chisxwci plypide.s, iieals 4POai ejec bein-g:at IE TVA N SV ;SGLLU coep don o airo o i, ds i 7 o ako apin NP TC A S. vK& N w amto e ipuncis o Znino 160 a 71 of W 903 13 (SEQ ~ ~ ~ ~ ~~& If t>I(i.asmocaroi ai 02 s beitti at Last 711, (Yptov k i peayt 9017 pora lat 8 no prefealy at east 90% and most pefeably 95% hoarrilogos o polsppep1de MAin dhe ?.eglr'c VSAADi GGGR APO SRPK QAI.:Pr (SEQ ID Nt> 1 46) corresponding to amio acids 72 97 of WO P94,1-3 (SEQ .i0 NO: .i X a thin amino cidd seqtience beinti at least 90% hoinologous to WSS9LV cormsp oding to ai acids 72 -7 of knownprotein U-)~y:~ aO'ctd,) 985- 104o NPe776252 (E 0D NO:Si wich ao oresponto o ac 04 of W939A3.P SE4Q ID Ntk 1 o a brdiing amino acid A conespondns, amino a .a of V03, 13 CS E Q1Df NO.: .10> and afourth, amo acic uenc benga es V .EP 1DCR YDTAI S 1M45AAALS YCCV AAQ GVOPCRKDOLQOQ EE~JSP.KC.KRQENEQ.LDQNQE3RAS QRSW c o-o2r NPi776252 (SEQ ID NO 8, wherein said first amnoaid sequence, second anino acAc equence. (i rd amino acid sequence , bridging amino acid ad fourth amoo acigdequence ar ongsotsa in a SAn listed polypepit rr n go edge. prtions of WS93 3 (Sf1 5 F ID N:10comprn an ano acid sequence being at least 70% opdonauly a last about 0.,preferab at nast about rusore preferably at east abot 90% and :n0t prefeniN at least abort 95% homolgouso the sequence VAAODPOGGRA PGEPPALCLPQ (SE Q IL O." 14 , + i) ' W3421SQI)NT1) The Iocalszatics of the variant prote was det erined according to resulhsfon a nun of different software pror as and nal es iuding o Si nalP and r-e car'd to the cell:' nienthrane n praiCO V3940 3_ S) ( ID RNO> en ko hasb ftoiowm a die *Ss SPomoria isted in lawb 8 adcoing t thou YoitoDtf era OenA. wn h emte arino acidt h ed F4Q ) '> " Theo Oig~ po n nei catf 493 53 (S DNOR posno sun a AM! ito7Te p1 5a7?ase 1h: iina. SNP s Pa WM sed inable 9 Mvcn Pmdwng to teirNpoPiono e etide s teue T C 495 a ,ant protn VV93943 4P 4 (SEly HD NO' I according o aacast some etibodiients ('th1 lvaention has wn.1, ad o- a ece c rded by nniAMp 33 T$ *Etf ID NG:4tA ripeon ohe relationshipof dni vannm potein according tolest some amotiMent olhe inven in to kown proteins .m as fo! lows: Comp> isonic~i report between W94394 Pl4 (SE:Q iD NO 1 and known roen .N.RI\( S,-AF N VSIRR1V iAINE P1 ~ lMMNLVC aA. Ac% Is -ae 205itoenic. -- (Svppt. QTo priNO, a irst d diuno acid a4$c e jsact kG liA kVSir0ANGGfdL IADC HP'YL DPLVPLDEi.GPGHT.DCPFDPTR JYDTALAL WSL~aAOF&AALiYC A la1. vGIPC.RKDGLQGQc COTnanOadtt 10 tflnoi acids 1205 ot .known pnroein KC'P P \4?AN (SEQ) iD Nd' Aha conlWpans to 90% a mos en"'' 5%.. t cipepdehvsg the sepenc YR K. f~~h;Q -D pic: 100 cosponding.to amino acds 26 2.21 oa acid Ieiec hre cotnuu and An A siqnonimi g&Ov Mwmda 1.An slated pohpeptid conrespondot to an edge portion of W9394P ( ' KEQ i NO: 1, conprusing anaocd qnce being at least 70optionanat keanttoa $0, zuCreA at wast abg 85%,te pre terably ot last about 0% an! mot prd'ra)ly at ka.a u 5omoog to the seqene R An U t)wL emo 'o NO: a7t W ep 9E9t 3 OEQ D ID ,pi NP 7252 (SEQ I) NOS: A. An isoatd Mmew covtMac. cvpflsin a lfirt atn acid seqenc bein at Wan 90% homologon to NI(NN APA UNA RAIRPNA NVCVLLXA IJ sTY.RYANPRCA \PE \NYISVSGLSYSVGLY cepondin to amino acids 1 8 of known NrotNa IDNPJSSEQ )NON:$ whih alsocoresponds to arnioaids .1 -78 f WZB0"434{$QI NO j t a bddgng amino acid A conrespoding to ainoacir9 o - 4 (SE1) ND I a seond amno acid sequel big at least ene Gwto~~us to -ANX X \VNLEiACSLdLAV ANORGRUADCHP0 LD PL DI OPGdTDC2PFDP irPINDTALIPSW AAAS NYCCV A\LTLR YV(PCRKU( 4 Corrsponsadg to annino acids 80 2015 of known proven, P SEQ ID NXY$0 Shkh also orsponds to auno aids 80- 205 W939 4 3 P 1E D NOwi I). and a MW ano aci s-oq~n am.l ira Ia q~ O~doi? at a.t01 po sealslv a st mre oels 0and prfaly at least o5% ogos to a poypepide havinghe sequence VRKANRKSPDW EQ HD NC) 47Mrespon aino acids 206 221 f W93943 P14 (SE.Q ID NO: 111 'WtIrdDflo acidk) sewtmtld, mide coivgioa tn . sn ucni ~ ontw. ~ 80%, pr fcratly a eas at8 k mot e nrefeiblv at least alot 90% and most orefirahly at least abou 90. honrolonous t tt NO: .147)~~~~~ ofS793P1(17 umbe diW, fM soh ware nPgrams and analyses. da aayses r ShmaP and othr seea ied roxarN.The7 enm wit proein S A vene to be located as fboos , l anrItrein W93WAY A WS M9 Ni: M aso ha the pWing noni-n a ndsat pos on 739the trnscript d as ise inw SNPs , tied a I vn t . . detd tou ec T C 417 ait rote amino aSiDN e At teativfe amh ai4 sf litexann of e hexdin4U eat om lamWo mntsnii ftinndon to N' n pin PCompan portbetwee on WY919 9ot WiSEtQ UD NO:, 12) and known imtmi 1 Q MA-'NSEQ13D i NO,7) cot A n pos~o>.l The m cp lso hsp te& omipriitig au...aid ,inqkable.Itie istd 90% g PEYTANVSVGGI SVSGLVL ASNLGPNW LA~l 1LLVACS LOLuLAVS -uLeVANGGRRADCPLDPPLEPHDFFPRDAA aCids 1 205 of known protein KCP3_UMA N (SEQ ID NO4: which also correpond to aino acd 1 -205 of WV93943 P7 O E WD NO: 12 and a second amino aci seuec being at least 70%. optional at least 80%. preerably at least 85%, more preerably at least 90% and most prefmbly lenat 93% homol0oo\t a poypptide~t hain the sequence VVANCDAR VKQ KANWQPRFP KVKAL (SEQ ID) NO; 1) conesponding to amino acids 206 -2.31 ofl WW93943_P7 (SE I)D NO: 12) whemia said firs amino acid sequence andi second atmino acid \eqenrce are 'ontiuous and in *a sequertial order, B. An oatied polVeptide corresponding to an edge portion of W93943 P17 fSEQ ID NO:12, comprising an amino acid sequence being at least 70% optionally at least about 80%. prefeably at least about 85% more pireferably at least about 90% and most prefemably at least about 95% homlojgokus to the sequence V VO{DA.R V.APQ \ KVKAl SEQ ID NO; of W9344 P SQ NO: 2> Cormpar au Ieport (te W394 SEQ ID NO: 12) and known protein NP7762t2 iSEQ ID NOv) -n A, n isolated cmaric poypeptide composing a fit anno acm sequence beng a least 90% hmlgai MRRCSLCAFDAAROPRL Mr GLALIO NIN LGXAV LR TYI.TifVANPRGAV PEYTVANiiV SGLSVG coimspondna to amino acids I 7T of known micen NP 622 (SE Q TD NO:) which also "ormsp3nd Ro to amn acids 78 of SQ .)nin 4 ud A spoiding to amin acid 79 Of W93943 P V71 SE N0) ' a second amino sequence being at least 90% LLARN Ikil '% \11Xl\LN1IA 'X '4 ~L.AVLJANOGRiLIADCHPO VCPCR KDOLQOQ cooSpondiiato aaino acids 0 -205 ofkAown protein NP776252 SEQ ID NO;\ which aso corresponds to amnino acid '0 205 of W9394P 17 (SQ ID NO 2'' nd a third~ anuns acid sequence being at least 70%, optionally at last 80%> pnferabIgl at least 835% mor preratly at meast 90%- anld most preferably at least 9 homkologouse e to a opepdtide having the sequence VVAGCDARVKQKAWQPREPOW KVKAI (SEQ ID NO: 148) comspondig to amino acids 206 - 231 of W9394 ntP S1EQ ID) NO21,whrein said i arsmino acid serquensce. 15$9 bridgin amino acid, se cond amino arid sequence and thud amino acid sequence are contguous and m a sequental order, B, An isolted povpepmde co responding to an edge portion of WQ3943JP7 iSEQ ID NO:1 mp n a a c Nequenc bn a a optionaiilly Ot anaDst about 80%, prefernbiy at leasd abo t 8%, moe preferably at least about 90% and most preferably at leas about 95% homAoons to the sequence VV AGCD)ARV KQKA W\QPRFPGKVKAL RSEQ it NO: 148fof W9394TPJ (SEQ ID Theodtlon of the variant protein wadeteian acordngtoreus arn a nmber of diffeent sft ware ayin inans f.r .' Sig naP uad other spcialized programs. thevarant protein believed to be located as ow with reganid to the cell: membrane. \?Map r oan ian WPS94tPu.SEQ ID) NO' 22 alo has the following none -lent SNEs S i deltide Po morpnm aswlisted i 'Table 12 (evn acaordirg to the positinsn on the umno aid sequence withhe iemntie anino acid~s sated). SNP Posion onmn Men atot K idoK acid s a i ' en\ts ' ( L t The codag portion of tra )43I EQ ) NO asat position s)tld ern5 at J905 ition: 769. The(et'ltVI ittc foi)owassv~o SNNsa isev T-ble 13 (gven aceons'ing to their posdOon the nucleowid, tuence witnu acidsted T-> C N4 1 ^7 A 865 iiant protein W94 jS(Q ID NO i according to at "eas zm embodiments of the inton has n anuo acid sequence as encoded biv transcript W9t943 §014 (SEQ IIt) NOtk) A des crudptlort ci; tO'w rtoshpo h variantpoti according to at least some nbo nent ite invention to i-own prteiasias foalo : 160 IG Cmariso rport between I9394 {Q D NO nd known protein KCP3 tUMAN S3iD NO:) A. An sOclatedKinc compng a ia amino acd sequene n at teal% homologous to MRRCnSLCADAARaOPR RR(3LIi.VGfi VNAXAVIJyaLHV ANROA A V NISMVSGLLS SVGI AL LASRNLLRFP coiresponde to anno ad I 9of known protei K12P3 HI) MNSEQ M NO:?) YWaic alo coaeonds toamn I Q I N 3 an a secn no adaseqece oe t leas 900 hoogoo<~ Or DL-A1 fVWIPS LLMS AGNA A GLSGCC V AA G VGPCR.KDGLQGQ LEM'I ELSP KCKRQEN DQNQERASQRSY cotrespon dng to tmino acids 61 . d40 known protein KCP1 HtIUMAN (S.Q ID NO: ) vh also corresponds t ino acids 92 171 f 93 P18 (SEQ ID NO 3 herein said frist wnino acid sequence and se ao na et a meuec secontguas tu n asquertialJ OrtT 1. isolated chimerc po ypeptideOnesponding to an a e portion of W931-43J E I3 UNO: .13) coo ia polypeplve litmn a, 1 ngf 4a.weeinn prefvabl at atabout 30 ant aaPt i lant Wor t 20 atiin meatd ot41 am, ntn acdg in lnwth and most reeray at least about .50 am ads n eng wheren at least 3 aino acd number 91m to 91 and ending at eay of aMuno acid nubner 92+ 2 t in which x< wvae haom 0 to n-2 ompaism~on mpon nm en W939C A IS(EQ ID NO1 and kaown proten NP 776252 ( 1l. NOS:) A. Isolated chmkeric po>eppide comprsngarst amnoacid seence being at least 90% homologous to .MRRCSLCAFDAARGPRRLMIRVGLALILV(HVNLdLLA LHCCVLRHVANRGAM TpeY~~~~~~~~~~~v~1 \NIS'GC 78Q SJj\ omsonn oatii si of k, now~n protein NI ;7&22 Q 0iD N 8t. which afso corresponds to anuno actd .17 of W9394318 (31Q -D NO-M a bridging amino acid A co d u Annacid i9f W3943 P18 (SEQ D NO a second amino acidequence b e og oa 90% NP 776252 (EQ I 3N:8) which also corresponds to anruno acids 80 /91 of DTALALW 1PSL LMS AGEA A LSGYCC VA ALTLRGVGPCR KDGLOGQLEEMTELESP KCKRQENEQLL.DQNQER ASQ RSWV co rresponding to amino acids 161 -240 of known rotei NP_776252 I1SQ ID NO:8) h whichi also corresponds to arnino acids 92 - 171 of W93943_P18 (SEQ ID) NO: 13t wheremn said first amino acid seqouence, bridging amino aQi second amino acid sequence and third amino acid sequence are contiguous and ma \egjuent? aicor NN3. n I o3 a i ad chitet poypptd d~ .te ortio ot z11 W93 4tU{SEQ ID NO:.13 conipdnaa potypeptide havrng a length > herein a i t bs about i ann acs i ngth optoaly at east about 2 amino amos in }eagth preferably ateast about 30 amino acids in length, more ptferab ateast abott acids in lonyth and :kst peferably at leas about $0 amino acids in length heren atieast oano am comprs, a atcet ns io a equence staring ar ny olaioacid .numnb"N 91 s to 91) and endin at any otl" anino acdnmes92 + 0(n-2) which :5 vanes fhom 0 u n- 2 other speciaii programs The variant protein is believed to be located as foows with egard to the cell: embane. Variant protein W9394 P18 SQ(8 ID) NO) 13also has the follwing non sent SWis (ege morhiw4asline ee according to their pos~iians on the amino ac sequencewih the atermative amino ad lte anP pSato n a m no WrntivPe ti*$ntiettsam m add 'N s s. c &1. I "e0 oing moruon onnitrnscriptW9943J 1 EtL I) NQ:( tassa pXniti 97 dn to at posiin $59 The ranscript afr ha he Ibow SN U N ised in TNbei gi ccordng to their ositon on the nueceatide sequence withe aemate nucleic G S 6 652 EXAIN 2 2 ANLYSS F TE IXPRSS ONOF KRTCA P3 TRANSCRIPTS f%48341 ED disc ove'rv engine descrVO [ a LNaflC nenom W used tO O.ssesst the en Are CsciinTs MNA scripts woe Wuxd & noer exp rsd Q ng asice as s de nomated in R, 1p naphS oAffnetix piWyr'set 2351483 Figmre hows the espresksio of KRTCAP3 i tcpts in un Cpfm Jung ind as orma ermea Aq ea be KR1CA r3 re ps r c ovePeonressed in Cgnmc issues (iamnnd marersi ret in: TIS .i--pa tung a j ' i I", ) £xgre$so 4 L - PS fA s ci protein W93943 traner t& whih p 4y issdepid in pp e 9 pt k a NO:94 in normal and cancer'(ou Oonrv &nasne Exprss of o KIZTCAP3 (teratnoext ocav potetJi I. acrhs OclectrAhfe 1w or acocording, to seg?7IIP-lR I W9~4, . ~s~ (;SEQ ID) NO; 941) annplicon n ptlmners WV9394 g se (D]iSEQ ID NO 92) and W9394 g O T(Q ID NO 93 Wts metasSeud b s hsd e 9CP tR ovary pan and noraed parrnt The sales used ae detaied n Tables 3 antd 4 accOnn n amp I [0O485) Ovary p ane PoC each RT ape to he osn of' the above sn~ was norola'hoeci' to in notia~1~ acor alaltebfam" tho ornoasion ofsvea hotisepii s-" " desrsqbed n examp , The nonnaed quantA o each R sample was then diided bv the mediwu ft Owb ~n' the: norm.' nw t mNrmle 52782 PTal-I 4 ~l~ to Obtain a vao d o pfegna oR lOt each sanl te relat e to meoian of Cise norol gixse 2li a h tleano sh ng on exp enica of te above. indicated KR fCAP3 normal saomle A is evidenrom gore 2, he person of KRTCAPS transcrpts detectable Iby the above ampcon in seroos care nons mucdnous carcinaa endometroid and adenocacnoma samples was significant lige than D' the non-cancerous anges x 3 a or 3se Swamk Th e oendlo i I. f KR-AI de~ ~ ~~~i e unbyh eapwoa y sous 'on SapOY ovry spoapus toedno m 3 ou fJos carca ndomaio sape.i 11)deoutr 2crcarcinorannnmae sa lue m a of 02 e 7r d sampkIb and tno eserctiunya hacked b Statitica anMyi wapp nd oveiy! th si iaNAMe of AI ths i .a escrbe The;Iol MP 5au foldr differec inteepesintvo fI ICP nsros eactaber e 10048601 p cnonnach RT sumwled uktre fe aa enMcacona samples s teenobeal is suple washe deteraled q oi eatR as , tmple w e4 a y de-d by - medh awu f tMe quunf es Dof te ovay samples nmple number 3 ab 6 i3 abiuye) t id heS vlue of reand ver xpesiof sAh faounpdt r eti ertme ieti e oury ora. t is histogtn* c sma ing o ver exie .ss ixto i i '-d'APon) acye wit sal poe 'W93943 anscri.t iSa and d eAnb re spcica as decikted iv eacOP SEQ ID Ns 94t i differetn .sues Por I sme t eo of e abv encompassed with n the pret rrdprin DaNt9 cdtW 9h e se R eerse ep es a the wedu of yt . grianite o ; fheor eamples stMrpi nuboer 31.~mm -3. abeS boe sscated proten3 in pnsts whic a e cabny nip s dbeped V.ntco \vai 0bt~t K a two Am t tiuAtK Ora& ntme onY of a nItahmbl phon V939A3 ..... tt,' 10>I ~F~(E 1)Nt 9 fOrwtard -Primer (9343-w I'D F }tE 1)Nt2 Reverse flivner {W34kgi4 'SE Q I'D NOh93): LA CCACACAOC.AC DACC nauscriptu detedcabli by Or gcoi to W9,343 62 arnpfic.n (SE-'Q [D OmppkW95945eg3 6F2 SEQ ID NO.3U69e aFi W9SQ943eg j4N6R94 SE-Q ID NWd7 wa mneasued by rul m PCR. fi pl a h geso of s a m cn 'PT GenCCaA AccessionTNMTAC0G9CImp1 con HPRATpC d Ct6PD fGC~TC AccesOAO GV No, NGI 040 ConG6iPDaCpOr p n ees a edmk No n atu ded auh nd ethod ,fwnkilao real To Ow A v prasnmeed o he oe cmsated pram Oaep l3 of these tstgcrind T Ihe am~r deeTal 'vic Ompics divirx byote (11 oi44ftWb 39 476 andi-6~ 71 (SE D Amoz toI in ana aenfbd oe mm aytsat 4 W ajtoa -shbowdg Oxee re~dl onf One <bo ice katenpessanoegt assadajed p .KRejmioCte asscipo W IKRTCAPy raenript decoative to OhoR nmlpleio S NO 7)an pier W$~te~jdP SE T O:.69 adWO9IN~it As4eide F ingure . the p? kendont0 fl0H t nS tsap s kterasetefCt associated pret 3 (KRTCAP3 ranscrips detectal by the aboe mhcon in serious' rcnot 53 6. 61. 63, .64 6Q. 6b. 67. 43, '71, 72 73 A. "esm a -des (sade c number 53-. e :nd erta/oe and 77 Table 4 ae Notab over passion alet 5 d was fM in 25 ot No 3 eose carluomaanaples.a hi6ot of rtmu acio sanpexad t~ outo Maitia aayssWas applied to verify th infcneo hs eutas dsre The P vaue for the difference a the expressit eves of Homo sapiens kewt ocyte assocated iarotein 3 (KRTCAP3r p dttae by the above, pfeo in oamry c) J," n cl, t oo i s, s~f Jvao in OvaTrys-I SCEOS Cta ff itranomsam ersus theomaissesaeseas dtetedicl rw' testa 03e-06. The P vale for the afferene in the ex.pre on levels f ono sens keratirogvte associated protein byKAP tmIse pt5 detettb IY the above amplicon i Ovary emcns cainoma sampers e alatissue samples was deternnedy 'T est I 6002 The P frf the rle m the O4pfs e s I0l eaoctessocad protin erc R i detecae by thea e amion in Ovary endomerid arcina samples ersusi the normnai tissue sinpes wa dete4.. ined by ITtest (is i4o4f. The P value for the di erv'ce in tde expression le elsoeo sapiens~ Iretanocyte assoilied protiP 3 dKiRTrCAP3 tanscrips deectatlk 1w k t60t ampiteo in Ovay adenoaretuo arnaples. versus Ohe noma issuepak neswa determined by I e as .ie-)9 Threshold of 5 fol over epsonwas found v diffe rendate between seros cno1oma and normm samples with v e I 5e-04 as checked by eact Fser tst Tr esholdo en over e soession was roundto difreenite twenamuirous careinni are normal samples wh P vale of I 44e4l.2 as cekdby exact, Fisher test. Trsirld of 5 fold over p reen a foud to ae atse beten endoetro arcinon and noral sample w P Pahso of 1N,003 as cheed i eact Fisher test:. Thresboic of5 tol oe.. eprssin asfosund to differentiae between rat rom and nra Smps i P value04 s checked by exc sheer est The above values demniostate statistical significande of te results. Prmer Pars arealso opaiy and preferably encompassed ithin the presen nveon; forber the above e riment, t o i air was oed as, Forward 1Imer (W99N43 Deg 3 4aj 4F2)SEQ Ine9)e N 6n E RWV9394iS4j4- P2 R I (SEQ ID )ii oma 1)e. Ekwwarci (tte Y93939gj4Y3 Ne~4F)(SQU M6h f Nd7 'N' C - 4~ko 6F2R1M{segR 1 SOE7Q in dgNO nom a e Express on of ilono sapiens kenatinocyte associted proteins KR3 (P3) ai detcle w-or accordin- to W9394 eg3j46FR) nplic (SEQ 1D NCG: 17Than prime-li rs W939,gi.-E (S,"EQ ID NO.,9 n W3~sa~4-R 10E if)NO: 171 was :n iaoed by, rea,,l tiplePIE. 1, e)ac& .tt i~of a weral Aekeen Nes, (Gnan0 AcessoN M 68; ainolicon SODA atpio) Uarit n eteaCnkAessn acc44n a pl-on ni i and TATA o mGennk Accesson No, NM,-X - 94 AT ampoo} was trcaNtcd siarlati. -or ea Ri sanplem the expresron of the aIbovein am icon wa .normalized to the norrnnalawfion fatk vnalcae from' (1-w- *'*.'~io these kej'* deesried ineris ad mehods" sctn The n0razed atity of each RT ample was hen dxded by the median of the qamtier of the Mary samples samp e nnoe3 se I 3 3( ait tThelove to otna n ayau of rein spresso)of each sarserela v ato mdian of thel o0 r aoiltl'Xi Forward Prifber (W93943j e 3j4-6tF2): A-- -, Ai keverse Primer (W93943_se43 46 ; R hi- . KA-J Ampn i on (V9943_ egj4 6 F2 dereta b or acconing to Ww94sg 2 pcon SQ I No; ? [0O4881 Clong of KRT'AP3 open leading famne OR) fused to EGI as anled ou a deednbed~ below fowi ng that the non fued KR'TCAP3 ORF cloning was earned out the fint step w 1 ('Pepesn vector wds cosrctdtflow',ed by, a ecnstpofC "sbcing KRITAPIM ORF -ito he EGPP exnsiO conruct EGPP e xpressf v. to wa romoimted a ow: 6oE0P-N I vo (Ciontech catalog n 0t5d -) was estt.d w' N4 'md Nt to exie the 1!w " iset was tegaed into pIRESparuo3 (Co3 tech catakoe nt er' 60 69'4which was pm ioudyddgested th the Saw enze ines order to obi Gth ' pEp vector Con o th K'A f opnen ena InneO n a ona tawo rinsess [OW04901 1, A invesse, 0inmcito re~waot.o w, a,Te-rin out as lbiw's Itpm of un d Iun ccR RNA 'was nixe N yflO'3 50q, Maoom IleAne priiet Iioc otA CA SA, 4S ivisrue:' I'0 od 50a NPs in. a talvohmmwe "SI'i~d The mxure was ncbated bi 5 in at . then glicky chilled on ice ate' p o AX SipereptD -i strand bufferBntrogen t og Syned80 4, par number; SN , ' 241i 0 M OPT and 400 unhts .N'asin (Pron'mega Milwaukee-, WS, U. SA, c mtdoo ie and tt t w :tneuated forO nun at Yc. byv~e~ ftsrffiz cr ator at 42'C fo~r:"" hn 1 i0 (200 rnN o Stprc~'ot S.tda name 506 4) was added and the react finall aoime of 2$ (Edg wDN was If 50 ainl t42T and theM TumvaMtd at 7pHC fos 1S I c restmtina cDNA, ,i was diutd t20 in TE buiffer, (,1aMk Th'. f1 r '47I: pH8) t004U PCR detads concerning the sueloning of RT(A\ ORE are given~ Tn'able 16. R #1 wa designed to y kid CAP3 ORb DN.1E NO: 2 wich then was sbelkmed ptem to the. EGFP in the E0FFPIRES piro3 deseed abe. while PCR #2 aesned el KRTCA orE DNA which su a downed to EKIE p REhpuro f u; above. 004921 2 PCR as done uing Platimna PFC vitren. adsba , US catalog number 11 Dn der the folowing ud oditlos: 411 Pet inuma 1> akt h0.bttr sy n A m thA above: >1 10 Wo JNTs 12.5mMA O mh cletid; 0.5.0 Piatnro e20 nd f each pier M n atotala rntti vflatil of 50pl: wih a traction' program CS -:i' 31hW 5o 9 C 'C. :30 secomns a( 94*C 30 seonds at 55"C, 50 seconds at 68%; den 10 mnnrtes at 638"Chimea which were msed include ene spcin aequenesenowcaponsng t e desired coord+4ates ot the protein. estrticon ennye sie and Kneak sequence a V ,ted inbtdle)6 oke RAld letters I Table 1I present the speeinc gene sequence o the tiction e etensioms utilized for cloning r-urposes are in bImic and korak sequces are unierrined [004931 91" f PCR prodet as loaded (ot a 1% agase gel stained th hiditAK bromide, elect o resed in TBE soution at 0 and isualized ih UV uli Ate Veicati of epeeted bInd wze man PCR prodht a procesNd 1r DNA Wnausing (Quick PCRt pnrit'nA n, 06). The xtracted POR p W'udua erw iese e &h the appropnte restictin enIn Ntoes (New [nd aarm-l hiab\ evedrly MN vs u listed in Table .16, After di cedi on DNAs were loaded onto a 1% ag-rose e -s deL-e ed abo e The rxpeck'd band slze wa es&cised and extacted Way oMe gel ung *m~ (ieltrat Ai ('Qiagens [0 0 4941 The dsted ORP DNAs wee gated tokEGFP RES pro3 vector using the [gafstTM upei DNA l aton System Promega alog .um M22. The gDNAs were mmaormned into competent E.0ol bacteria DHl5a R(RBC Bisacience. 1kmpei Tawan. catalog cutrHPU816) according to manatrfs ntlcln.whn platedcin ac-ar plates for seleCt ot recombinant ofamid.and icubated o-vernight at.37%?. WOn Me v anOr each ran Ahrmation that reW on the selcnve latest were taken inr anayiv by stre-plating on another selective plate and by PCR usIng GiT aq ReadyMix (Proeg. cataog number: M7 2> Sreening positie eknes was peroformed by PCR usng pIRESpumA3 vector specific prner and gene secific primer data not shown). After ecaletion of all PCR cycles. half of the reaction was analyzed using % agarose get as described above, Afer verifiation of expected band sIre, 2 preadse e0|0omes fr-m cGh ignton reactionls were grown in 5 ml Teni le Droth supplemented with pg/mipicinin, with shaking uvernight at 37*C. Plsmid DNA was isolated from bacterial cultures using Qiaprep" Spin Mimprep Kit (QIagert catalog number: 270M. Accumte cloning was verified by segaeneing the inserts (Weizmann bustiate, Rehovof. IsraeL Upon vedification of en errorr-free colony 0 >e no muttins within the OR I lrecominant p asmds were processed for tuher analvses [004961 The two RICAP WE contrctsiomnabove werused for subeloning KRICAP3 plRESpima constret. Sublonn was done as foows: .lRCAP3tFP pJRESpro3. was double digested with B piand Nbh restriction en me(New Ehnghd Bioktbsf Bevily MIA. Si A.)and a 220 base pair fra en corresponding to the 5' end of KR 2AP3 va eised Foboowing that. E.GFP-KRTCAP3 piRESpuro3 was also double digested with the saNme resti ion en;nes (New ngland Bob Teri MA SA aia a 29 bs pan fragment, correspon to M 3 end of KRTCAP3 2nd pRESpno sequences was exaed Te O N t-fagentsjere lgateed and tiansforined aU3icli as Aderedl shy > ree ting construct was named KRTCAP3 pIRESpr 03 [004971 The D sequences of t e um KIRTCA.1 EG#IP EGNP-KRTC:AP3 and KRTCAE3 n- swnin ires 6AC gene vpacn sequence crrespondi ng to KRTC A P3 ORF sequence is nuked in hold faced, EGPP seiequence is :n itadies, andintermediate recioN ar boh Fz Fgure A r ethe DNA sequence of KRTCAP3EGFP (SEQ ID N0 IlK;t[ jaw 613 represents die DNA sequence ofGFPKRTCAP3 tSEQ R NO: I Rgorn 6(n-p -e th DNSEQequenceof KRTCAPS (SQ ID NO; 112) [049 TdTCAP3GFP; EGP-RT P and KRTCAP3 are shown in Flees ACI amino acid sequence coltspouding to KRTCAP3 OREin arliod in bold faced, LMdP sequence is in talics.and intermediate tinker regions are umbok. gure A represents tte amino acid sequence of KRIdAP E~i}protein 11170 Y". toy OR F = X l! a ,a p R DAw INO 6 GACT TGp te RTCAP N g A LAGCTC pIRESpr TTA N ICT T 101",1-1 tCGAC(if'CC 3 Age)i EW 869 Tom0000 , e i AC PAACC ISEQ ID L'N" \.( M No CCTfAAAC0CAA NCO 160) ~\ M12 4 DLTMMINJNG CELL ID"AUIZAIN WF KRTGJAP3 ot as pedited to be a tramemi-ne protein with r eiIorde to vndf KRTCAP3 celur caiiada KRTCAPK3 wa oned P deen ur cent P&oteinuen roen> a described Tove, Pro tnIoahton asosre on trC~a e feto tenc t oecdcVso 2.002 8; 32~3 8 sung votfocW m arocpy.he cell 'ere cersed for the prsence of {0O5MD1 NON BGC'HKRTCAP3 piRESpuri ISEQ 1 N : 111) and KRPCAPIGFP pi~i~prn3I SQ D NO) 10) constructs Wcit subsequendy tersdentlv ranstected nao UHK-29T cads as oilos: [00$i)02 HEK-293 iA TCC. A t.268) cells rated o ere as ce:e phase non ng a preswarmied DMEM {Duibeccoi nodined ulsNedna. lioloin n dine Oi nmIek. srae) uatlo nasnber 5 SA] . % 01S [Ftal Bm e alse nannm ee NP i WndStes [Bat lisEknsek aog). talne nyu +; 0 4m021>1. 500000 ces per We1 were transfected wth 2' of DNA owunse ut sing 6) FuGENE 6 eget oche, catalog number: 14443 01 diued into 94k DMEM. The ma-re tS }cuaed at roots temperature for minutes The coInplex mi'ue ws added 5% C0 c-ntn to n"cal and ph< ,x im oo opTet a 37'e washdb [005031 48hnsms tvwansiet4it vanskecfimln.cells o.t ovmlps were finrther pr-ocsxed to.e *illultani)&ar a inay Th ~tr)mirs~y e cove r s~ips wen wavhd- v phoriat bffre sain. PE 4 tenfixed. for 15 minutes uwithi a- solution,- ot" 3,',>e p~toittidehydle (PFA~ (Siggn eatndo mber: P 6 4 % lcose (Slgmna <itaIogt msraber: G5767) dilutedd in PBS Quenching of PFA was done bs a 5 nmte inubation hi cXe (igma. taoW number 7IN ) (Mimed h PBIV After two 5-nute washes in PBS. cels were permneahbred w&h 0%I 00 -med in PBS) for 5 minutes. ter two 5eanunutewashes in PBS. ocklin of msopi ecic eons was done wth 5% bovine serum-I album (USA)igna ca g rmnie: A03 (diluted in PBSorr20 mtmiet lhe coverbps wea then incnbated in humid chamber fr hour ubbi ani-P antibody 5.-M 3I.. .ntermaodnai Orportion CataoS number diled 1:00 in 5% BSA in PBS followed by thmee 5-minute washes in PBS, The coverlips were then nbttdd in. Imand camber tar I how with eCOntdariy antibody:donkey an -alibu CatNggsate t toCsS u-ohore Jackson Antmmno ent cateng number: 71y- 10-5) dited .:200 3% 1SA n PBS. After bee.ninute washesonPrS the bred overs ps were ~ ~ ,,0- mone-nsie ihGel Monieteu neimntAnal<3 atonkber:, 00918) The Csdt are presented in Ritu o. 0I504I IKR TCAP3 pasmia membtrane local rat ion was demonstrated using both EGP fused constructs WGP'-KRTC AP3 piRESpuro3 and KRTCAP3-EGfP) pIRESpuro3Lt Cej aa>Lzation was observed by either detecting LOP fusin protein fluorescence Fige A) o r immuntOstainig uin ntftfi GFP (Fire 8B). Data is shown for tonly one construct EGFP-KRTCIAP3 piREhurno3) [O05t05] PEgge hA demrastrdes Lvven toreatence G diV E hat [E KRTCA3P NSEQ U) N& 9 4fserotein Jcahees ote cob mmbrane upon eXreresklon in 8EV Z93T 005o Th e ewsobtainmd u5fingh Et 4 objectied or he <5inlO~2 microscope. tO636 Pigur S dectnonsandes h e fuorene e of nti GFP antiov conjngad to t> lrophore that the OERidC AP3 _2 SEQ ID NO; 14 fused protein iocaizea to the edit merine upon expresson int -ELK 293 cell. he image wasobtained usng h 4(o obiedtae of te enfcad~microocpo [0105071 t)E1T.RMiNIN ORIENT lO0N OF KRTCPAN'TE CELL MEMBAN [A s rientan xhi h \eU was detenine d 6t was done sdeibed abov e hot tinse" antibudy \tai ng was dome usa gnon pene ab23zed riieth transiected K 293T c ( opposedto Eample 44 ofCel e Cella o on t v enen epit wl n be detected. [00509] 48 hors p tr ent tanfeodot te ces on coves bps were furtherr processed for mmunos t aining and annaysis by codtocal nocroscqp The coversips were washed 2(ins &n cold PBS and rn-specifi' neins o i cove ip\ locked with BSA (Signa catalog number;A '3) (diuted in PBS fo 20 minutes on ice, The corslps wer then inetbted. in a humi chntner on ice for hrm wIth rabbit anti43P antibody nont itemna Corporaton catalog numfbe: 9 diuted vi500 in 5W SA in PBS After 3 5-mninute washes V: old PBS, ceHb on co erslips were Exed for 15 miut wih a slon cf3% paraformadehyde (PFAi (Sigan. catalog number: P-6148)/3% glucose $Sigma. catalog number: G5767)tdilted in PBS), Quenchinga of PFA was; done by a s iniute incubation in 3mM gycine iSigma, catalog nnmer G7l261 diluted in PBS), followed by two 5 inutes wash i PBS, The coverstips were then incubated, in a humid chamber fo~r Ihr with econdary antibody: donkey antirabbi conjuated to Cy-3 tiurophore (Jackson timmunottesearrb, catalog r mber: 711 - 65-i52, diluted I :200 in 3% BSA in PBS. After 3 5-minute wmheN in PBS. the fixd covexrsips were mounted o slides wi de! Mount Aqeous medium (Sigma, catalog number: 0918) and ceds wem observed tot the presence of fhiorescent product tsing conftocal miucirscopy. 05101 Me ress presented in Figunre 9 date hat the aitito termo n reeiz of KiRoA2 l imueina& to th ll ad~tace v e ree tesoenae or EiF 'nn otservcd an the nen ermeabised tanin nutted EGmPn T A i 1 cS. deninstrat he localati the us prn to the cell membrare Figure 9A hoee k h bsne of rod, ofoesec ri',n[ ('P awbodv il-. thie 00115. 610atOta thle kQ} ?I.\&ttn-tan~ Ottf~ tbe tllasn m:neibi 4ihis ;.'mlnui t nal faang the To og 9.) he im ages weare obauned uing the 40 bjc ofhe cornfocra nnceroscope I\ AMPtIE 25 01511 PR-*, ODtN ( I. I tON t.-PMtYCLONALANT!-13OiiR-tES SIFCIPX", TO KWICAF3 [005121 AM pol2cni Ans poducon prceddare. ind g pptides syhe nep e CONaauonan tin zatons bleed and antihodies purimemaon were prfrormed at SigmnaA Aric n srael) [00131, Anima-k (005-141 Iwo pm of M-i were to puosare at odte Or KR TCAP3 tabt numbers 5257 and 558 5259 and 526) A aniai ca, handling and injecto e war pewrformd by Sirfla [007:161 The peptide Wlicl Were ied tbt rabi im :ioa w'a lW EQLLDQNQEIIRAS'QRS-C &KRT223 (SEQ UD NOr ll5Y, a jquence taken from the Caomus corespond to a 22-2&3 of the KRT teSEQ NO:),ini which Cystein was added to the C teri nus of the peptde for KLI conjugation, anod L.DEGPOH1TDCP9FDPTVR {KRT 143 SEQ ID NO:Ilt16r a sequence taken f romi the ECD loop correspond to n i3- 160 of the KR'CAP3 protein iKRCAf PP2 SEQ H) NO: 7). 2Smg of ea ich peiptidces wetre 5ynhesited with 95% purity of which 10mg were conjugated tM K U aiarnerA" [0051.73 I :utjOik 100518) Each pair of rabbits was umtufed vwtth the conisponding erograted peptide as fsllows :baltt 5257 and 5258 were ironnzedi wah KRT223 peptice iUT723 SFQ ID NO 15) and gnabits .5259 and .5261 were immsna zed waih K i l43peptide W(K ' 6s IDND : 16) Ain nah were J.n6n)ited ear two weeks .3 test bleeds N 2' 3f were colected and andayzed by ELISA. 0OW pod roducuon bleeds fnom eacl ratsbb wvee elllietedt 100519 Andhody puridcation 005201 Antbodi were purified irm- two abbit 's serun rabbiit 523:' nitnuned vnto upetpide UKRT223) and riAbt 5261 itnvuited wth xpptdo KRT 143) Affhnity purifiaton twas Perfion withwhe peptid against which the respective anttbodes weres rad Te pOr:Wied antibodies wemamnlyzd by ELSA. EKFX AiN- PL E '2 1 CUARACTE R IEION OF PURiFIED KR!TCAP3 ANTIBODIES M' WESTERN BLOT USING KRTCAP3 TRANSFECTED CELLS LYSATSS [00522J i order to 0-fy tew specificity of nibodies kled against seeed peptides of KRTCAP3. Westem blot andoyes was dons mno p0ruied scrm from rabbis 5257 258i 5259 ad 5261 d bib and KRTCAP3 I"sti~ taN ceVgSn [O05231 Twoably Pasdeetod pool wee genended, RTiP4RP u ro3p al ik legate conl rit plRISpnolO. thconstrcts were trausfected anto . 924eTil as follow NW524 lE CC 2IC e were pated in sediile 6 wel plate su ubl for isue cm rc uin 2nd proewarmed of camp lte ia, fliMM D \eet ON ! % + 10% PBS Pt ovine Scranwa aog indutres (ei me sral catla umer 000- 1A] + 00M t[itan BiOigia induhtis TBei tiatne& sra. : nmbur 012 . 50 0 pre were uifeced 2 gf DNA constrc esinge m o u E h :reagent cnhe caaog tunonIa 4 saOI diluted ito 94u HDM, 11 ixatrune was ic bated at O~ntmcmporatue for 15 n'mt eicnmpex matue was added ioMe e nd swWed. placed i incubator maintained at .30C with 5% C20 content 4S hours following transfeeton mnsedaod cral were nsfe"rred toa lacart tissue ertafl ask caute I 15Oi of e eectstmedia: comnpe:te meri apsiplemeonted nti gunt pummaycl (Sigma. catloc number 3 Cell wore placed in ncabator, md mld a eanged every 4 da utlcI neminat ob-,served t.L [005251 [posuicien t ti ot edh sang g selection , 'niW5 ni eoen were harvested. Cells were v ed in 30h1 R1PA buffer m ,M r iI F, pH n50 mM Na( 1 Ni4, G.5% sodium Deox yoode . SDS supplemented SD S teasee (noRs oee catalg nu er: 8118735 5001 f at own ('PtnC~3 at r 4T' far 15 oinutes a NA,Oxg Me ernnrat ee t"'a n terrec Wo cft awndx Wo adiOW af 414 NuPAGE®F- LID sa-mple buffb (luvirogen snbuw urbe NPO10i7 was added in addion. 4~.litliiotnreniIDI7; a redicing agent) was added to a final cotcintation of 100mM 1 - ules~ were then incubated at I0C for 3inutes flowed b a ue spin at 209 ,n" S -SOAGE (Laemnuuii UK. Nature 7IG; 227: 0 w685 s formied upon aiding of 25 of tmpl per iane into a 12% NuPAGENi nmaog nbffer tnviroen catalog nunberb: using he Nei Mn nrogncata nu e 1 according to anacture separated protcin5 wo transferred to a &iocelse nrune Schle cher Schuel cana o ntmba1 4085) ina :ibe XCe' bhut og AMpaoin O n:rgen c rog [0O526. h~~ecictr eon oaitag :b'aed proe n ploce ncfatiod i 1d e ki Wk diknted n 10 buffered aie iTSS supplesnenend i 0 05 Me-20 TST fR hour at mrooi peare .aimubsequet nebationo ace r al o temnperattu' Bkxl g 'tf$ uOhdo was then~ replaced wt prinnary antibody ohgtion: ee {beori. a ann)of rMbbi YanteRR MnuOW desobed above dilutd I A W00 in biockiag schnige -xt~ A I Ib-mnite &hes$ secondary attibOdU w7as appued goat aiO 0351 t diud l00 rbIrockin studn After 3 10nmue ashe ECt substrate iGI rhara catalog ?uber RPN2209) s xppue for 1 , flowed by rxposm to r a ai o aog unmbe I0NUI [0052$I Irre AI motrt that "All ionr 52r ,5M 5258, 5259) and21 KRTCAP3 p nu respect vef Specift is denontarted by the dferant aw- ige btied fforthlat NK'flAP3 tckl Cellshic is absoklt in ellity p IR E",Suu rndeced cells, EX AMPITLE 2,8 [005291 CffAP ACTER IZATION OF PURGED KRTCAP3 ANTIBODIES BY tMUNOSTAINPYG OF K WkA3 TANShEC'ED (ti [005301 in onter to further caractcn e the affihty p;=ied antibodies raised against KRTCAP3 poiypeptiW anubod pown nteractio was studied ungu mmunosltdntg of KRPCAP3 stable lrnfce II K o lk -'3 0000 celk per well of HEK.3T> ATCC CRL- Ii268) stagbl spssng IS S orte emp t vece abv e ted on stile sl aSS ceralips. 3mm diamee (Mrientd. cr g number: 01 1,5 0k dahv we plaed in a 6 We pLIae ung p ed D EN Daneendidd Engls Media Biological lWaUstres (BA Einsmek Isa) catalog noUhe; 055 Al I [j2etsi Bovec Semrnn B ieiaa hehtties ~'eit HaT~nek. iel),ecaalog nue 0440 A44 tuil Lttnie 1-4lWkgi idaniBeineOW Israe" catalog number 01201 Al, [0l$32 485 hours po0A pleong the ei5(3 CevertZip5 they SeJ'L trirther prcess&ed for' in a gn t tys y codal mitoRpv e oe mi e W Vada! in prspatea bhWred =0 Oten Rid A 5 im nei with a iIon of oMin \olntdo. natural brred 10% Sigmra eatadog nyietr: BTfO0I5) After 2. >unite wase in PBS. & werpenabaized ith 0 ttnX1Td) diuted in PBS) fA atiiS After tWO lihI \kutt ies~ int PBS. Nbing ai ot n~ see 18 reItJOns \Mats doe.e wh 5% Wine Remm-tim ii hAjm atg alano e A frtedn.BSio 20 n se cmwaese were he incubated, in . a u aind er ir hour with putld abbt aMiKR fntibodes desenbed above: anti 5R2T( 26, n g0 m w ash ted li2000 in i5 WSA in Ps and anti Ki Ug 2 mgn as dilued 0N)00 in P % BsA Th I bodies vere washed 3 tues for ttaues rin PBS. The caneasips were thent incbated. i a humid chamber r I houn witsecondary an11hody2 n er-502 dVuled w 't00 0 in BSA in PBS, Ater ,ninate wash n PBS the flrxed oveidibp were mounted on slides wih Gel Mouna Agneous mnium (Sigma, Utalo nimiber 00918) and cedls wase obseved fo the preene of fhuoresent printA uu e~on o OCp ~0O3 Spefi cell stnig was osaved Asng pl ified J KR 43 anmd KRs't2 ntlbodies onKrTA3 traneted celWigtes A and speely however, no stanung was5 observed using these antibodies on pilESpuro3 HEK'u93lansfected Ceen Fi rs 11 and 1 D Despecti elv The red inurescence obtained in [Figvue LA and I C as opposedd to thfle obfee 0iga1 il Figur t &mlB aId D dernonstmee the specificty O KR]'Id and KRT~> n 16eabdt.o KR ICAPBS B i 1)NO;T0 05. I -9. IMNW \9 ThtMNOHISTOCiEMISTRY ANALYSIS OF KRT223 and KRT 143 ANTIBMDMES ON ISV'U S, IPLES Antibod OtrdOt eWpents wer nucted a LFeSun Biscience USA) with rabbit polvclondantrse KR1'2K2 3 and lKILT 43 to e stabl :,ish, ' ola resu .i ininimu al bsmund and maimai deteton of signal Seri diutions wre performed at 20ug/mi., Ougt/mL .5agmd. and 2,5tg/md on faomain-ixed. paraffst embedded tissues supplied by UfeSpan BioSciences RJSA and on HlK-293T (ATOC, CRUL-1 1268) cell lies transierdly transfecied with KR TCAP3 as positive control or empty vector as negative conmrot. This studs demtrte the hihstaido-niertoa cncentraton of 22ug/md for antibody KRT223 and 2,'egiml nd 1 25ug/ml for antbody KRT43. Antiodies KRT223 and KRT13 were used as the primary antibody andt the principal detectin sstem conisted of a Vector anti- rabbit secondary (BO and a Vector A CAP i (AKK-5000) with a Vector Red substrate lit SKY M f k which was used to produce a fucilorcd deposit. Antigen retrieval was carried nut by steam-heat in sodium citrae buffer. Tissues were stained with a positive -cotml antibody (CD3I andvimentin ti emure that the tissue anigens were preserevd anid accessibe for navnoitochenocal analysis Only issues that showed positive CD31 and vtientin ta g wee sehctedf thetad e negade conto consmted of p-tonning the entire mnadnhtstochemistng oocedure~ on adjacent secions in the abs ence of piimary antibody ides were imaged with a DVCWO4 digital catumea coupled t a Nikon mucroscope AntibodyKRT223perfnned webl in the positive control cells und showed a specifi tppearing distributtot of staining issues Staining was membranous and cytopami (data not hown whi antdbcdy KRA W3 showed a broader spectrum of positrvtv Antibody KRT223 was erammed n samples o rmalvary as wel as n a seri s O aan carcinom as and mataaic carcinoma n r astrointesinatmor Staning was carried out a described above. with Antibody KRT5Z3 at a 2oncLntion b"2.ug/nl dte nonmal ovary sam ples positive staminng was identified in benign ovarianssrace epithellun (mesothelimn and waser staining wasrequently present in oocytes grnuos cells theca cel ano omrian stromna. The ovarian eacinomas showed weak posnie staining in approximante -0 percent of samples, as shown in Figure I2 while more omrliant steaning shown K Figre 3 was identified in metastatic carcinoma samples homn gestrotmcstinai tunmors. which oftssn nltei die to ovary, and arc somnettimes reterred to as ~'Kralkenber< tumors Pinre 2 demonstrtes tense immunohlstocheinical staining of an ovary crentutonit'isampe obtained rom a 52-eat old femaeusing Anibody KRT223.he signal was quantified uing a 0-4 se and was gien the sgnl intensity 2 W 5 Pngum1 deno stratea prondent .i mmnnohi~sohemtical sain mgo n ea ofe usa ne aaIwt oa a d n y4 scale e n a eoa Ayn pn eams of onao OON ARMi *ar 'er nd d n~crob iofio debasi at not shown)t Pvsinge staa was idetified the sct the Itnt lv Themst pg, 00Bt.t"in D Wda ',mp IC'Iif 1:nt nob sto uelt atnrdvs of KR'T'1 he on on n caner Cuht pe ar d Weann siut ii'IJs oancm " chances. xnlidi beast.n colon la . ov awI.Io w os w.0 An itonc al panne unli typof' s nin tained innf m this studywas pepery od. and a aioce ncyaarnnod musci and :terga gn procsiofbr *etomca weQre also scaon peumve (dhwa n iotic deeso ) cbos mt ded was the "ed inatio gnbody ICRT143 speech ETE TH-,REGE,0 AS A DR'UGTAkRGET .FOR PRODCIG RI AND IOLOGK JS Cpe T82906 n t 7304721 mn 3 n pt(s) ofed wear Tin2om ceQ n N Mtli siing in a ace (ata tb. Additiona postmc cllivs 'cue nln~wr es einr}nread o el Vascular smo Di uslN b: ni 4r)aefhonsua tonawr loocsoai 82906 P3 (EQ ID) N~D:16 Th2906,jI 5EtQ 1P NOus2 'I906_4 (&EQ IO NO PS) TSOO& {SEQ ID ND: 14 These neenes ao variants of Ohe known protein hypotheticd p nt LOC441 168 Q ID NO: )Swisrotcess:on idenhte NP 019, ynonre A M2r6N I FAN 26F {fa 2y a iasequen sdnd o Ranber F) S oe of the lenes bed) th armttakof chro osoe Nu eta 003. Ntwre2(P 80 No species inomrton was pubsshed ci M 6F. O3. one other memubef thez M26ohs been Anotated: f\ dalcium homestasi tdaor Iprteln tDr es_\?ringloeret at208 Cen 11451fl FA M26F nt nhas beea reorred n Wa200 0251 38 patent fppcats which purports sequence cl 6t AJ7 ih and Ib.54277> clonnspamiing to FA.M 6. is dfrentiy expressed n melanoma, idney cancerand Ubrotc wO O ha e 2003258 a t plac d I n e th t respondidant a0 mphrn~tOcyts leukemia chrmn lyomphocytic lenkhemi acute mjedngerous enkerm na chr mu Koenus e a mye fllt~h tVlomTi Hodgkh V grphomsa or Nom hymtndgkint lymphaa and/or Iimne related cottd fltionA he is no teaching SN WO2003025 8 application that FAMZ6P can be usedF ardm- taget fo atrearen ot ovar an caner, breast cnneer presite cancer renat cancer mnmoma. acute lymphocytic Tu emiaroc ymphocyde hemiaacute myedogenous leukemia. chronic yelogiotus leukennle myeboma Dodgki lynphoma or Nomutiodokia's invroo ;h ad cur/oritlonelated coditos. forteomaroastenof.thrsn Wacading in WU 005 02"8' app ttcatton hat antibodies eCihe for PAuM26L ip solhe ectodoraen antdor fragmusenti theeeof ca used as therapeutics fom trtmetttotnt of OVtlrtAn cancer. brast cancer cancer. renal cancer oelnnoma acute Iymphovti-cek crone ic hurpheyte enirennda acute.eoaingnous jenlcemi a.chronic my'elog rrz3U5 leukemnia, moutinie myeloma. I-dgkin's lympnhma or Nonl-giodc gm lrowma and/or mtimune reate conItons. ortor hrtoosisteef FAMv26F antgeeu has been also reported in die following patent apphcatdens W964.. . W2'50I9258t WO20050392, WO2008079406 tWhch purports hat sequence corresponding to% FAM2P s usefulfor diagnosing treating. or preventing selected irmmune related disoirs. Hlowerer, there is no waching or suggestkmn in theseaptications Ohat FAM26Fecan be used as drg target for treatoemt preenticheor diagntosing of ovarian cancer, brest cancerprostate cancer nal cancer, melanma, acute yvmpitocvtc tenketn.

ctnc m inphocyt leteimia. acutce i4hgeus lenkeinia. cronic. nmicgenous aidemandia.in% DICryeloon Uoe a' Yfisphoma or No-Jodgkin's yr~aphoIa. WO2G0 72.92. MO20t006719. however. there is no thing no suggestion ii these appic ms thA - car be sed as dyugnarget Aor reatment prevention or dagnosirn of ovain can at cancer Prosame caincereal- o cancer Miano . Ice lynpoeti lukmr, hrn saphocytic ieikna ae i meloenous ieukei a chron e ya i en~i~iU edtinaniorn megna oagk lnmpha or on 5cotlra and surprisinsy. e.resent invetovae found that FANE% nt sad dscrete pOrtions thereof may optionaliy be asea a dra target br tenpe n smal mncies pepndes antRodies antisense.NAs &RNA iozymes. and th lke. Diagnostic arid terapeardc polycionna ard nocind antibodies anid frinrnt ts t that bimN E46 and pooiem an4d vri ntthereof maya lso optinn a bl e pro ed Acco-ttHng :to at eastoome embod ments of te inv ni, thre is dad s use of antibodies and untbody fragmeasea andNMst FAM26F antleen. as secreted Or soluble fonn or Eci: an/or vait.eune.of fr agments there& and fragrnerNsx as'-variants' thererif for eating and iagnosing ovarian chance bre.r ticr pR)Stai cner rnl ar u hona ate lniyeogenoc kukem~.choi mu kS i mye m a uge hne~am or Non-kldgkir mrphoma. swheen thns antien o dffret ab expressed As noted abo cuser T82906 features l3 ri pNt ver 'iwv sted in tb 17 abov These rns eneccatorpisOci kpo n \nO ch e Am a li' isf pe wpoiheticai proe 6 SE 1 5)A desr pIio 16f each ID hat p)oe. i according to at least some embodinents of th iet i n is now pmo vidl \?yap rotei T20(-I3 (SPi'Q If) NO:', jpi wetriit at least someemodmet of the invention is encoded by aseniptT29( 0SEQ IV ND125KA desCription of relationship of he aat proi Ccording to at least sie nembodJtz his of le inventton to knomn poteina is as ao wis :oompa son :port between TS2 906Jfl (SEQ I) NO: k and known protein Q5Rk2 HUMAN tSEQ ID NO1 17): A- An Cia p eulvpetide. opn a fstino acd seqence be at least 10%. options at y ea 80% preferable y at 4east 85%, more preferably alt- east 90% 182 a ntp vaai at least 95N homoig t eo &popptidea ringueh asquence fSf corresponding to ainat s 3 of T2906 P3 (SEQ ID NO d at a scod Wooi acid sequence best at least90% homodogorai:to VLW. <LAVV f1L ULFTS VTRCLSP VSLQLKFWK YLEQEQQKSK ATE ATELAK ENIP:CPEOSH~PKEYNT'PSM KEWVQQSSLY TFNP KGQY YSM LHEY VN R KEK TS SiR STfEoTfVIPVLGFV)SSGINSTPEL corresponding to amino acids ,9 158 of known protein Q$R3KHjUMAN (SEQ ID NO:17, which also cuoesponds to amino acids 4 143 of T829069P3 (SEQ ?D NO: h wherein said es amo acid *equence and second amino aeid sequence are contigums and in a snquential nsier, The localization of the variant protein was determined according to results from a lumber of different so ftWare progranma ad an 2Vses, i cuding analyses from SignalP and other pec iadbZed programs. 'he variant proteinli believed to he located 05 to110WS wt regard to the cel:secreted. lhOut protein T82906 93 t5EQ 1D NO 16) ao ha the following nonahmn SNs Sinate Nucleotide Pol norpshisnams listed in Tabtle 19. (vren according to their POsituO (s) on the amino acd sentence, with he alentative annno acidisdlstedt I ie IV A miw acid mwons SQR KST TI0 coding iion of trncmm 29 606% lSEQ I) NO) 125) st m position 1651 and rnd\ apositon 593. Tbe tmacript ue ;s t h f i N s td it tle 2 (Iven a C ordng to their positom on the auceotide segme wth the aemnIade nuclec bi ele aid&U A T 6 A 68, 496 A .420. 44 T A 524 T (1 52 4 U 612 G4A 612I Variant protein n T8S2906_P4 (SEQ ff3 NO: 18 according to at lstsome embodimenta of the inenRti is encoded by transcript TC.906T 1 ASEQ ID NO: 14 The lucalization of the FAM26F prti wsdtemfe accordngto rsults from a njnmber of different software programs and analyv~ss ncoading analyseN from SigntaUP and other specialized program. The FAM26F protein is believed to be located as follows wIth togard to the cell: moembrane, 'Variant protei n 'T82906 P4 (SEQ 11D NO: i8Y also has the fllowing non-tileur SN~s i.Single Nucleotide Pulymnorphisn>4 as listed in Table 2 L(given according to their positionia) on the ami~no acid sequene, with the ahernative amsino acid~si listed). 'ab' 2] 'Amio aCd 4nulation 99 C NA" 100 W 110 P> 1, 259 QA R 283 K T4 Il > oding poion of o s VTE2906Y15 D N r a po 32 and endsat. pet6on 11 ra7itdu a heflown N sa nee al egmn accard-ing to their po :-don on the ncesdggmewdh benign acid 1ied C A468,528 C G 468 $24 57" G A 469 529 1195 C vT 560 597 A G 07, 01 To G 1 195 :EXAA8PilEafA2 NALYISS Of 9 7E EXPRESWN OF FAM26FTRANSCRIFIl.

[OS36 K MFIdi sOd enne dested i Exan hern washed to snsa the exprsn of A2F truscripa M2& rn p wre oid te ove eanreenadin Nu;igrs and 5 sAm ral siow gaphs of Affmeti" proho nV" )Onu. Pio1~ 14 hows h expreson A FAM2F transcip i roarrt ps n breast cnerg and breat normal experhnentsAsanbeseen 6 traiN iapis is vrexpressed in bm WEcer AR5TJ5 isiufonDS winter) f~aive to it rs now"u rionj breast 1011 irAe mrkrs, Nwre 5 shoxs te expreon of AM E traoccpts t aiaaen newai caner expreiients, A can een in Flgure 16 FAM26P transcts re overrapressed in ial e teer reiatato nOnt oary samples.igure 16 shws the erall expresson of [0 0 5371 'FANv 2N4 qR1 PFR qestify: 1005381 Re PhaIe RT PCR ;ni vsys catrid outon i5g template in SIl dm in rial VolUMV of 12 P' 1814 we1 phn-es; The aw lfgo w fceda olol m Ci s fin 0 m) a then 40 e E f 5C for se ffoilowed by 60 C for 30e folowing by di awsnon step of 9a w for by 65 'Cfor IS sec and funa sen of 95 C for It qec The qantiis was calcsated mising standami eutrae of seal diltions of he PCR pouct T2906 seg$-I0RI1 0E iD N096): GIA A.AACTAACTXOGAGATAGGCATCG Apflcmn: T'52906i..fP.tas%- PUR) iSEQ .1 NO9I) OOCCA A OCCGGIMACGT Y .CGGACCCTGA AGGA TCTGAACGCTCACGCM AGGiTTOVKGGCTOd. 4 'iG I \AGVCAGI T LI TCATC.ATTfICTOATTTAC ATCTOTCA(CCGTCAT1 1\(CCACFTTAGTITTC The tissue piane sed for tis qRTI PC sR nalysi IN drscrbed inTattl1 herein. The hstogsam represendtagt the qRT PCR tiuit s \hklPi ame17he reasu ho the caerexposson of FA M26F ;n kidne.scxi .reut caner lone cancer NH-L lyphontas Ortmenn pancreas e erano rd prostate tae-i &prresfron { f L0C44/ M*AM1 Th2 904 Prascapt whih are detetable ky tamwiwvn paonl end in diferent normal rksue xpreaon of L 4 if AM26 tanrpts Idetecabe h or according to sep3 1loRS if2~e$IPR smQ) N"h, edpies15.%sg 900 SRl ISE N; 1 andQ I (S N S, ) DOu: 12a) pnte ady mA re PCR to b byrd paebl e 2 and nonna panel able 3 Normal pane!- For each RI sample the e:<preion of the above amplion was norm~alized to the normaliation factor calcolated) from the expressen of Neveral hoose keepmg genes as deserved example 1 heret. The normalized quanty of each Rt sample was then divided by the median of the quasnies of the kidney samples (sample xmberA QI Table 3k to obtain a vaine of Adativa expression o each sample relative to median of the kidne samniesas shown in Figure 1. figh expression Was observed in spleen and PBMC samples. Blood pnel er blohd pand e norm redqu iy ofac s ne w een divided bS the mediu f. de umoa otes of the kidney nm ampes sanie numb 65 67, Able 2 above. to ean a a of relaie eprsion of each aupl e idvate. to mkedlim of the hldelle rnrljup The ret thi ; re depicted in the his ogram i Fgrwe 19, CSxpresio of lheamvoidir 1,0e OI4 1, UfCg l transcript lrN i PI3MC, 8 cell, (11344s Fomard Pmek 206 sg IOF (TIS2XU- ,g se - 10R5 (l N , Reverse Per 290 R N 12 adN WTC CT CUT CC Ampior 85290i6 se 40FR$4 (SEQ If NO: 24) A PrOTTdT CAti of pC AMMT A rZ (7Ff 'AGTTi'ITrCTCCAGC'T"OA.AA'TC'fIGA. AAA'TCTATF!"r'GOOA.AC.AGGAGCAGC:AO ATCS2 Prfoductionl of poydnlathdWsseii oFAM.26F -P4 rotei Aly aabod prod ion pr001ur6 0ndding pepadesg nthesi. pelptdes Peptide snthen I The pepide: which were used for rabbit iraization were as follows: EKFRAVLDLHVKQ (FAM26F- (SEQ i) NO: 1 Px a sequence taken rorn the Ntermirus coresponding to aa - 4 of the FAN126FP4 protein (SEQ ID NO:. in which Cystein was added to the peptide N' trmis tor KLH conjttiin, and CNQA KASDVQDLL KD jFAM26F-2 (SEQ 1D NO:I 180 a fence taken from the ECD op corr spending to aa 156i W f the FA2A2P4 Prten (SEQ 11D NO: 8) peptides wereY synthesized v4h 5% pay ad were co agatedt oK1I kn ~arrier. Inmmuniria'i, -- F'at to pairs of rabbits were On~~r~. wit bov.e pentmies WA o 00mn smum beach antibody e being cected, Antibody pu- Antbo e 1 be puu ifed rn . traits' em Afiny pb0 a on wl be Jperomed with the iepte against ew h 'he ree anto, es were rad id uzn an tnmno affinity chiwan F ANttSF- I nptipde seqaene'e, 5Ff) ID. NO: 1)7 EKFRAVLDLVKH FAMI26F-ptidsqunc SEQ- l.D'0. O;18 CN QA KA$ 5R-WQV 1 I.E D EXAMPLE 3 CLONING OF FAM26F FUSE TO FLAG TAG ki.'of F-AM26P onen qp r edillg frameu CR fiutted to FlAG was bayie ou h Ra 1"(.1s-as tone Usnng SrpeV hermo (Roche catalog nmber mE wi t using Ilt cDN \ cf MaiLynrm frn the blood pane d'es e b and 0 ) o each ptimer #n021 (SEQ ID NO 172) and W71- 922 iSEQ i) NO th 7 in a totl yezdihn volume of5 wi h .1 action prorant of 2 da in 94"Q 45 \y of: .30 eonds at 9C30 seconds at 5W 1 mim nte - at7.*C he 0 mn ets at ' Pdmners v".1 ln'd \CI vU 2i Agerte aie eneew O t.aoqed nab vrstco vvM(! 'atAev dgst md FLAG ze N R ded nte a 2ed. % agoeg as2 desied baN Th"en expee ekdr n ionviaew eletrcreedin 10 AE \l\QUon at 1004V aed isalze wt, (I j h fervtl'~ to of eedta bd rau t ds vas ified a OiaWuiodiN PeM (ifkaa kitg Age i e~on ns ie {Nw Egind tioab. Fver.MA 1. bAR I Akir dIsdOM DNA wa od mn, a1 2 % ag, ae A~ as dscibe abo.'xw 1 <i c v.d ic a nuntei: 28707) ,he dijge-d DNA was ten ligated inn 1 pREvSpuro" veet previoly digested with e above *estacuna enzynws using RagaistTM R d DNA Ligadns Sstem (Promega catalog m Nbr: M221). The resting DNA va informed into cr:ment ECOni bacteria IC I senca e a ataog ther l.i 16) according to a tre instenes n plated on a piin ag 10s scobOn of =01minran eeanusnd incubamxd pvernrnht M~ W7C' W 7Nh ilwing day, p o onies were careened b P sR sing p iR Spuro3 veor p <. t. power and gen pe f p er (data not shown), 'The PCR produe was analyzed usig 1n 2% agarase gel devwl'bd eAfte renfication of expected hand n po e COimiVt Were rND W ad T'e> Wrth supplemented with 10gnaod, mnpiciln w alrl o venigh t at37" P asmnid DNA was solated frO batctedaunulr e ogn Qiapm ppa Sap Miniprep Ki (Qiagen, a'talog numbtet.2; 6 L.cU ae cloning was verhied Iny .~ aequna the inserts tweirman itte. Re ov ciIrael o n eriiao at an errr tre olony lie no (otataons within the ORF r,,ecombnant piasntmds were processed for frthtr analyses. The, DNA -sequene 1-,c the n2sultLAG iSEQ ID NO 174) is shown in Fb. e 20, FLAG seguenee ls in tndenined. Tne aino acid sequence of FAM26 P.FLAG (SEQ ID NOD 75) sho n t Figme 21 FLAu epIexe in ondeilmed, EXAMPLE 335 DETERMINING CELL LOCALIZATION OF FAM26P4 h order to dtern A cellular IocaZaii. mA was kmed in :me o FLAG ta, as described above Protel iocalhion was observed pon trasien trane ton (as deseted ia (Tcan et a loeesar Visio 21 8' s72s388) uSn rocal

INS$

n'tkroscop~.4 ones fk.owing tan.feedtonhe res were Quned wiah nti FLAG pttibxodies enmed to Cys3 fluroitou (Sen raictong waeeA50ad ere o~~evd orte rsence sdPn sent ga-n P SFKTXQ ID NO' pPRSpr3 cont tctas trned n tatected two e ow O 29 'C C 268) es were :ed on ee ins ceips3 nunt ae aienfed case g nuner: 3). whch di iologW ndusries (Bed mkn sra. ca nu ber A] - 10% 04-0014A) + 4mM 1huamine ikdogica tndusries (BdA Ia Enek Irae catalog mt e 0 0-1 A] 5OOO m- s per well wew eected s2 o DNA cSt 61 ( uGENE 6 reagent (dd e cata irnme43-Th0) diluted into kIEMPd. Che , oti was inuatd at m pe fo , In she:n 013x-5uVC WVi~i ".idran Inawise to" te cekand mew uelld were placed in incubator ninintained at 37G wo"ith 5% GO 3 conven 48" hour-s postm temera, 'ans~fmnos., cels onm further e r ine and 1,e cover Sp was washed n 1 hosphate buffered saline. (PBS). (hen fixed for 15minues ha soron f W % zrafornldehyde PA)(iPPA eSa, catalo a :umber: P- 6481% a5 m r a tc baton 3MM glwe . (Sin gmes'4nuntme GD6 1(dilud a PinBS). After t rwo teWaskl wsthes in e 1I were pnutablirze .ih P %.d tritonA 100 d used IPBS) for 5 mu t a tr -o MadeuNahWs in PBS Wosking of nomite Mt~Ott5W.l$ "orte W ,itA ' 5-c aitstu albun-' (S33.aA .. ~amber A 45031 2)ted inBS or 20 minutes e ov lip was then nbated in a humnid chamber for 1 hoW. wab rnuse C3an avibodles (Si arna. catdog number: A9594 dined 1 5% SA ns PBN folo'v ed by e 5- use ashes in PS 'The coerip was ito oilte ~ a sQict' Ow ph(4Ma A"e'aor-ir Sigsta.ctlgaote:GPI and cen were observed for the pesene of zurescens plOdt uingt ntca micreopy Cel koclirati on is shown in Figure 2,, FA)26.P4 as -c ed to the cellmembne. EXAMPLE 36 I>RAC ERIT-N O PURIFIEDFAM 6FM PANTIJODI. BY ANING OF PAM2ti 4TRANSFECTED CELLS 1110 ba order to tneran enee n~ ffiity punec anuinodt aird a Jest TiMwa _P6 transteeced 8EK2937 cells 2i'wo y sta~v anseetd POOa W1e rtd.PM26,111 p1RFl~pur3 And the negatf"Vte :n rol. empty talR rnp eth conrivets wee infected nto HEK2 T e as (AYOC C R. I2685 1 celrveii plated inelen el ate stable o O znhiture asnag 2n pre-wantned of complete media. lDEM [Dnecco\a modified ea.i.' PBWetda Boloica d ise. Ei ekar:e 055A : 1 j1e {r440 I I +j ±e .Lfllutanine Biolocial knutne Beit liMEmnek Israel). catrdog number 03120-1A, 5000 cc%, pe w e trasfeced with 2gg of DNA construct rs6ig 693 FkGENE 6 reagent Rxoche, ata number: 11 414-44VC0I00 diluted ino 94 EMEM. The nvnxwe was incutbated at sore ternapeiralurre toyI 1$ tnra4ute s.The oupa miee wsadas s to the ce arid wired. Ce wearplaced in mitbator maintained at 3t i 5% cont 48ahours kolo'sm transfecetron, transfected eels were transferred to tan tse . c ang n ofP election 1cmeda: media snup N lruted W' ni PUrM an sig n g number IN8313 Cells werIV played na incubaLtod and inedta was changed every 34 days util clone eburnation observed MMU I NOS TAIN IN OF FA M26F RA NSFECTED CELLS 56000) cells per wft i of hK 293T (ATCC. CRL1.1268)ab esn FAM26F or the e t rpty vectorc pIRES puna, esete abov& wete plated on sterlegas nelps Wpm diameter .den . .atag number: 01 Q k J5 e placed in a 6 wel plate us p aed o a Pubee a de Ea e Meda. Bikmmeal itadustries . Ha Emt <ratalog mntbe: 01 :5A 0% NBS F etal Bovine L-Oi tamn ae a ftograldadustncelt Ha'Enk salcatalog nember: .3420-I A) 48 hour obSpaegte celL on 'peoveryh tey ware ote proesed r oJmnt nnostatnmJg nad anaidss by contocal mienlnSopCfY he cover siips wen washed ine phtosphfle buffered saline (PBS then fxed fr 25 utes with a 37% (aPformadede PEA) ir 19 catag number P-6i48 /3% glucose (Sigma, cauaog number: G5726 After 2 5- oMute washes in PBS, cells were pe rmreabdiized with 0. 1%§ tritorn-X100 (diluted in PB)1or 5 inutes, After two 5-rnrute wa shes in PBS, blocking of nonspecific reons was done with 5% bovine serum albumin (BSA) (Sigma, catalog number: A ( ted in PBS) for 20 minutes The coverstips were then incubated, in a humid chamber for hour, with purified rab anti AM26F4 antibodies rAsed in EZijiohbA described above were washed 3 times 5 5-mit i PBS. The covernps wee ten incubated, in a humid chamber for hour, with secondary antibody: donkey amti-ra~bbit conjugated to Cy-3 flurophore <1Jackson rnmunoResearch, caalog nmber: 211- 165-152) dt 1:200rm 3% BSA in PBS, After 3 5ninute washe:< R PBS. the ixed coveirsips were mounted on sides with Gel Mount Aqueous medium (Siga, catalug number: G091 S i and celhs were observed for the presence of U uorescent product us ing courfocal microscopy Celm staining was not specic airing was observed in thenuceus of both on iAM26d transf&cted cels as e si RSpuro3 .EK-293T ui purified and FAM26P autibocoes raiSed t EZiioib tans fected lls negative control (da n showtt rasing a need to ect aner dd na FAM 26Fetid a in rdr o frteranayz er'rssonard iaiton oi PM6F prein in tra eetarts EAM26$P protein tSign aa ogtunber .PAOl 948 diluted .150 in 5%BS5A Specific CCU 4aing toc eet to celm mmbrane wu obsen d g an FAM ant~botesmo FAN-MA1tt tn'siected cels(figure *.A), however-, nostingwsbevd Usig - es abi on RESpuro3 HE-293T t umsfeted cells (Fi Wynn 2313) The d uoresceee obtained in Figuir 23A as opposed t the ab er of aigoiin Pip demonstratethe specificity of FMM6 F tntibodie FA M 'P ier to determine endog eeno'~ .\i a' of AM76F ii P 226 ( u (&CC cat#COL- . we5 rinmnjnosta e a\ de Ncrbed above ung spenfkc ,anbodie gains FA .P protein (Signa. agnumberPA01794) CIa nfeg wms ebred utg he nedle antibodies gac. o conmer UP A 7948U on RPME22 Th etlline Howeser.locahzat tn could notdhe determined as membranal data x Yahon U.XAMPtL3_: N UNOLJISTi ANA 9S VAM26 ANIBODY ONTISSUE SA MPLES Ai bdvtitration experinAnt wen carianed atf feSpan i Osciece SA wt rab poetonal atbod EM2' 1S0M A ca~ tImoAnosi pesalsh concenatonsaa k utlt iin; nmaial ekreund and n aslmat detection ot .sgaal Ser d iotw wes performed at 5,4/mI . ug g n anid a5ug/m on forimainfed paraff embedded tissues 'suppled by 1 fe pan BioSciences (US and ~ ?of ifK -2931'1 ATC IN12 c68 oil lines tramsilentml nsfected with AM2 h posivecoitrol orentp 'ector as ite~itttvgn Corol.Aittibhody FAM26 (SIGMA c- # HPAdj94 tys ist. aSthe primary anibiA &u the pricipa dectna SIse consisted of a Vector ntbrbbit tecnarv (B A I (1(10)) and i a'Vector ABC-A? kitR (AK-5000) wvith a Vector Red substrate kit tSK100Xhhich was used to produce a fidesia-cooeod deposit Antibovdynston experitrents were conducted with amtibodv to CD20 k Cat # MO755 onse monoelonal) to estbU d Utons that woold reseah n miison hnkguonnd aiui aw- 4&(v6in -eto ofrsional Yi-'a" dilluto:its waelv t rmw VXX-)OQ I 'KX) nod :4400 Antibody 2T '!0 was used a the prg antsady'and the pine 6pal Lctdon syte csinistes t aVetorao ait "Acndrv (B 00Wi ,nda N r ABC-AP kit (AK-000) wih a Veetor Red sstrat. kitS-10 wh a d to prtduce I colored pden l'isesere also Stained ith a pos ite coin antibody 4D rin d vieitin) to ensure hat e tisue antigens were preserved and accesble for imnmnonistochemical anagvi Only tissues that showed positi e CD-3 and vinaenti dining WtRe selected for the study. ThC e w it i ootNoOf dfrnia e enlno Unnrt 0soen1 stry ioce lqamtidcent senn in the absence of prima anybody. ide were managed with V 13i> dig taera oued to a Nikon omiosIope Anibody 5 <xl t m Arams/m showed promIent cytoplasric nd menaous showxn n normal issue the n ci t staying was preset in subsets of nanocyte de'ed 'l types imaCropageS and ifS ti S and in Occasiona ymhocytes whic she dbth: ctoplaic and snear sininy; (data not shown Compawd to anybody to S92 C2)0 the aining patternn as morn pmi entdi nonnocyt& ed evpes and iymph ocyte !trnwa naot ited toolice ne typioa Thowed we '4pJMhemiW and cea stan must oder ell te. Puter anaceraat i EX'AMPJX4:M052493 OLYPLPVIDLSAND PIOLYNTJLOTLADUE 'THI DC AS A DRG TAR.Ek'- POR PRO!~WN DRA AND A}OLOCi EX AME 4 D: EWSORIPTOON fOR 'C LtS'WR A 320 Cliiate AA21 3320 ii~r MD 6 93 29 ldmzi otre tra"" knsck'ripts k o I thtres. l aes 'or 'wh'Jth in Tab I 2' The eke pitein v nn ze g ven oI ta:be 24 T~W>23'Ttnc tiGo S" ~ ~ ~ ~ > \tk.'" 0 t) AA2't (:282 - 6 (SEQ DO N20 Pro\m:""ame Crerepnding Transcrdwip \& s AA 5Y)PS D3 +)4 Nt)'i Allz:J 1330l ilD Q' NO 1i AM S$. Ph (1 D) O0 0 A21320. 1S FQPIDNO 'Q1 TeSe seq uencesnv ereaatf the knwn hpodeitwai proteknnLO48378 (SEQ ID NOD . 3' .(Sw\P ressIon -- tNP'24' sy n: MC5249)' \1C92498 also .knownas AMM Q$A famidy 'with sequencedinm aritv h9 membe n v; wtwre scae ' tudeste sieeted pmatein ant ae tC. R U 'a 'i- 203, Meonesarch 'Ut Ph' 'Pr 'O' u'lu kength TIN A (noqjmv Nt hLea 0'2002 PNS 9 %26)68 i 9t) Hovw specic study as puhished n tMN 'pro trn SE N 3 's'rep~rtec in WVO20OMO8 99. among oher hum genes shoingr altered. paierntexpresion in annune ti scae 'for 'ue n (Iagwtsi preCVedttOtanrd retment The sequence oespondg to A 38 4 SEQ D NO: 135) ALso epBored in WO2004(72 among other human gene' avin epresson pro un a-ct] ratek-d 'hmnC~D4vT <zu!5trcJulo ftedausaadteteto nrn ~a However, none of the WO20408 i9 r W02004047728 apilations teach o~r SKgest that sequaece correspondin to AA213820_P4 (SEQ ID NO:.133 is differentially expresod in cancer. WO20408 I 99 and WVO2004U7728 also do noi teach or suggest that AA21382Q.P4 (SEQ ID NO:135) is differe nt iy expressed in lymphoma, especially Non Hodgkin's Lymophomna, Multiple Myelomta, leukemia, especially T cell leukemia, or tung cancer. A ,here no teaching or 1ggeston in the WO200408 19 or WO20044728 .applicatiorus that A A)l 3820 P4 (SEQ ID NO:135 can be aietd as drug Uret for treatment of cancer or for camcer di agnouss. Also. there is no teaching or suggteston in oi W020f08$ l 99 .app.eciUon that atlttbodies speCt f. for A A2) 3820_P r (SQ DN:3 its soluble ectodornain, and/ur fragments thereof can he used as therapeu tic or diagnostic agents fre treatmentotancer ,AV colnst and susrpr-,,ingl. te irsent mmnvtors have found that -MtC5249$, anigen and discrete options hieeof nmay optiondl se as a dr.ug target fo thantic inemolecules peptides, antihodes. ntsens RNAs. siRNA rdone nd the e Dignosti c and denapetic polyck)onal and nionocional antibodies and franis thereof that ind MC5249, and portions and variats tiheao may cponaly be prdxced. Acordng to a least some erodns d the :imvntiit thir is provided the use of aknibodies and an1tbody fragmpets against MG3C52498 ntige its secreted (or soluble form 0t ECD and/or vadait, coni ugates. or fragments thereof amd fragments and variants tereot tor treNk,, ad diagnosing Ivynphoma, espAcialy NonHodgkin' 4'mphome Mainple Myelona ukeca, especialI en leukemia anlug cancer herein tis antdgen is dientidy esoess ec As notedabovecler A A2 u2 reamr.s 2 anscrpt which were ijsed in Table 23 above. These tiosenpti encode forprtein which are vadatis) of pteln hgpothe al protein 1C 3 r2 {S3Q ID NO:132), A deserptan of eaet variant protren according to at least someemodmet of thie inve ntion : o poid aiantprotein AA2131s20 P4 (SEQ ID NO: 135) acco tngto at leas som eboditnets of the invention has a3) ento cd sequence as encoded by scipt AA21 $ 1 T(SQ NO 3) The loc ahzation Of he aruant protein Was de maTAned according a'to rs ults from a nume of differetit softwas programs andnalyses inciding analysesrom S gnalP and O ctaifeoogr Te vaiant protea 5 beiewed e to t located as foows with regad to the enmembrane.

-. rae A\A2132tP6 6SEQ 11D NO: 19 deoeing tlatsm embhodunentf thien jno ha> a anna acid sequence as encoded bt nnsip A. ~~~..Q D NO'0 \ dt.etstpou of the relatinhip of the ariant protein aceordie at east sonie r ientiff ( ih' tinvenlte tO known pratnas flket : Coanraaison rport beten A A28N P st 6(SEQ ID NO: 1and known protein Q6UW HUMANSEQ 112NO:I35i: A. An ilued chieri polvpep de. comipisng a ta annnoazd sequence being atf leat 70%, optionally at lea 80%ptnfern y at ent mor preferbi a least 90% adStiOst prefmbly at ;t 95% hom oigos to a poy:p dk having the 5sequencC MASWPSALTFNTDANI(PGPLGCGOWVRLCSLYSi

T

PPCGR NPCLSAPAPNAPR LTAPARC (SEQ ID N: z53)< conspondo Znna LcL Ii 4 ffA2 20 Q, ID) NO:. 4 9).an a second aioacid seunc e gt least 90% nooogous Cto *SIJAIOLSVAAV IAYTACVLCi LSSKPTKi DL(LSLQTAGPEEVSPDCQ VTOIMAAENVP$KNVPQQSYSCLUNPQL5SNEOQAVNSKRLLHICF.MATVTR$DPOS PEEASVP~NPDCoPVP (sEQ ID NO: corresponding to amninoeids 134 of -known prote - Q6UWV7 I MAN SEQ 10 NO: 135 which aso correnponds to arrno acd 6 *53 l\ s 1aNN 0s (SE l)NO: hn nsi is n a mA senc rimS ~ ~ ~ ~ ~ ~ ~ ~ fix~ second) aminol sea -'In t Oft~'t "asqenlotr B,. An hotdpolVpltde corsod oaha f "A A2 1 MR.03>6 &EQ ID NO, 9t0 cmrpartqsing a popept de be6ang at leas 70%. opti only at least about 30%. preferably a least about 85%, mre gxeftrabl a at Ivst about 90% and mos prfefry at et. abot5% bomoogous to the sequence MASEWPSAL.TFNTDANIIOPhlGCOWVRWCSLSSLTPPOGRRIN PCi S AMPNAPR LPAPARC (SEQ ID NO: 153 of AA2..382. PS EQ ID NO 1k.9 onmarion repo between AA213820P6 (EQ 1) N: cKnonproten Q(ZRG4Tt % UA N ISEQ [D.-, 1 3 A. An rsolatei dchimnc r 'Ipetocopiigafr: ttorti s bcu imgr bsa Lat709- 4 optiomnl at least 30 remter", at lat 35.:sr rfrbyatlat and ntost preferably'. at9as5T%, hfnmoioaMus to, a pol'peptide "havingoZ: the seqence M ASIMPSALTENTDAN IPGP FCGGWVRLCSSSlTPPGRRLVPC LS APAPNAPR ARCSEQ ID NO:153) corresponding to amo acid - 64 of AA2. 3820P6 (SEQ PAPAC (SQ I NO i~l D NO: 19), a secod ammo acd Sequence being at leas 90% homiolgous to S1G AL IO.LSV AAVVLLSAEIVT'ACVLCY LFISSKPPTKLDLOLSLQT AOP corresonding to amsi acids 61 -- 109 of known protein Q6ZROU4.UMAN (SEQ ID) NO:15 which also correponds to amino acids 65 - 113 of AA23830P6 (SEQ ID ND:9). and a thin amio acid sequence ueing at e optional at least 809.0 preferby at least 85% mnore pRmferably at least 0% and most preferably at* least 95% hooogu to a polypeptd NSAnloou MadottdedoatW Q havgna the se(}tee EEVPDCGVNO MAEPk VSPL QQSYSCLNiPQtLiSNEOQANSKRLL HCreMA v-l SOIse nASyN .v(SEQ iD 5 coependatngo aman ci 11940o AI-s2OP6 sEQ 1) O . woereinsd an t H)t equence second anino acid sequence and Ibn'id amio acid equenct e contiguous and a sequential order. Bn Aislat ed polypeptide correspondig to a head of AA2 3820 P6 ISEQ ID NO; 9).oni ngapoiypeptde being at leass 70% optionaly alent bon '8%, preferab ly at last about 55%. non preferabn at leas about 90% and most preferabiy at least about 9 .omologous to the sequence MASLWPSALTFINT DAN 2PGPLGFCSCGWYR LOSLSSITPPCG RRLVPCLS APAPN APR LPAPARC Q0EQ ID NO: 153) of AA2N82&P6.SEKID NO9 CAAn idted polypeptde correspondingz to an edge portion o- A A22320_P6 (SEQ D NO 9 comp rising aammo acid sequence ben at least 70% optonan at last aboat 80%3< prefetabiy at least about a85% nunre preferahi at least about 90% and most preferably atlet aIbout 95% homrioount the seqlence ESp DCgf)QGj:VT~ xIv EVKVSPL .QSYSCLNIPQIMSNEGQAVNSK~tIi.IHCFMA TVT.DIPOSPEEASVPNPDCPVP (SEQ I.) NO;:1 oS', AA238 6(SEQ ID NO, 19 he loeazaan of the varint protein was determined according toReslAItom a nmber ifferent software programs and anaglscs incling, amyer SignaP and othec specalized programs, The variant protein i beheved to be located as oIows with mge4 to thecl membrae .be ' coding pordon ofscrpt AA, 820j(SEQ D N1:202star0s at position. and ends at position 496 EXAME 4Q EXPR ESSIONANALYSIS OF MT5285 CRIPTS 4 t~xr - x *>vl' kNlSlSCESt3 be AIEa) Womb ane. 'scr bed e pres n n ancerVA aS demnst d 4n NA N and in weukenad a demno <rafted in Eigurc :5. Eigtrrs 24 and 25 Jsho esasx raa~ o f'xerxprobe se't ndl cne and nbr n aiood edentn As can be seen MGC3249 tansd i, are overpressed i vanous ekemn sames(aaond\ markers reate to is eaprsson tn normal blood samples {crt square and fre markers) .Rprodn Qf kypothkical protein AJGCS2498 A AsS2 transfer hk are detectabk by nnmplico asdepcM in seque neutne AA21c820seg84 U' 42 .Q1 At;Wh 0 i blood rpec panel andf in Stieen nrxmtd-.a tirsatse Exprosson of hypothetical protein MGC52498 tanscrp detectable by or according to sghF-I IE2R2 - AA21382Qseg8 F 1 P2R(2 {SEQ ID NO: 109) anplcon and prine4 AA2 11010 eadltD tF?; F ID NO;- 107) nd IA.312_e >I, lR2 t-Q DN: 19 wa measrud by real time PC t b ood panel and nonrml paneL The sanres used for blood wanO are- deraied in Tables 2 ad 2-1.I samples usdor no-Mpanel are detde d in Tb 3, Normal panel For each RT sample, the e xpesion of the above amaplkeon was normalted to the norma Fuad-on fe acltdhrn the expression utsvea housekeeping nnsa in Examp 1 The ronnalisd qmuanti of uc RT samie a ten divided by to obtain a valuef reha e epresson f cach sample eltive to median of he kliney sample as sn in Figure 261-1,h N a o e PI an Neen Blood panel, 197 Fr blood pae Fr each RIT rpression of the above amicon was ormalued t the nomaliaion factor caclated from the expreo n of several houe keeping genes as described in Example 1. The normalized quartA of each Rw sampk was then divided byv the median of the quantities of the kidney norma samples samplee mnmes 65-67, Tabe 2 above), to obtain a va0e of relatve expression of each sample relative to median of the kidney normal samples The~ C rentso his analsi are depicted in Qhe himstnum in £4nat 07. Expressin of the abovendicaed h pod proeIn MGC 5 ascr a i a die do Forar Art \2 82~s~ -IFf2.) (SEQ J D NO,> 1078 ' CA(iC AT3COCTC T C V' CGG Revese Pkimer tAA2 3820 I 8 R) (SQ I D NO 08 1; (N00pQ000 Q xQorc(d GeT~e(GT AriTCAO Amp0,1'oi (A.A21 3$2/Lseg%8 I I P21(2 (SEQ ID) NO: .0 9)>K ~CCACACAA EXAMPLE 4 3: CLONING OF 11 W NGTH ORF ENCODING MGC5'2498 71P4 [005391 P Lengd ORP d MlC fsed FLAG ta ter at the t foom540 PCk wvas done"i usintg Gwolaq Ready~ix (Nonimg catalog asuter M7122) raierth fllosi;gcoditionsm,5 eDNA tfi the blood1 paeldes-crbe -above XNM yi Mantlel I) t~o ahprimer 5p11 > 1 Rea i. wit ae t tin e Of Z i in 95 40 'C yde Cs of30 sec 9CJ0 seconds at 503C m-tei 'ait. 7miT iY iit .10 mfinstes at T2V.: Prmr he eewd wkv m er'.9094 EQ 10 NC: I76) and pne #0 94 SEQ ID NO I) n order to enhrance the PCR inws' to 43( toa generate Flag tam at te NC i tias fllowd b Nhelarsrictio site and K a sequec a well as n comR resin se at the C terminussecond P wa do i 9i nimEntP proc a% a tnplate ned ppell pman as row f pa i 00 SEQ M NO ) and prner 00 SE D N f N "en0Fg ier #100-954 1 1D NO: 08, and pmnner #10(i5S OdiS for de C Cnfl Flag PR condlionm w thet same a0 desenbed aboe fOO541 The P(R podcst was lA ro a I % agme O strN o emti e opecuxi ria an wa exntmed Uski Qpa e eagnoctio option bit a e ae CA. s aa bers7064 Te esracie piduct wadigeste th pp tet on ezyms Nh and EMORINe w ngMAad Po lbs eve After digestion, the DNA was .laded ont a I % apos gel as described above expected band svew~Nised and etaedfromr the 20 sing O kcmY Gel Eaeno to ue sal.uogasenibr: 280o) [00542] The digeted target ORP DNA aga'tedis RESpnre3 vector previously ested with the taue enzymes, using thetg TM Rpid DNA Ugiden Sen romega. catalog mntner l 1ktresulting ONA weetransfoimed nto competent EtCi bacteria D[iS t. tRBC Biosience Taipe aiwan. catalog number R11 81) according to nI udhturer nscnons. then plated On ampeilin agar plates for selectin of recambinan pisd anc aed emnight at C IO ] Tht folkowine d. a number of oneS frm the transfonadon were screen by PCR isng Go'iar RedyNx PNonega catagume: N 1 122)usig p rIRESporo3 vector speee primc and gene specif primer (cslm not shown. Ahterification of expected band ee two posin~ve coomes were grown irn 32nl Terrife1 Brdi \sulermer ted with 1000/n mpd igiin, E \ak gin o=0mnght at M Plasid DNA was isoied frm bacerial utn sing Qagn aprep'\n~Tnp Kit(Qagen catlo onter:a2106 Accurate coning was vecrited thj sequ'enchig the 'seem tWeizmann Institute. i Peoo ia Upon verifiaton of 2n 'r-ree ny (iceno uations wid the CR). recombinant mi d was processed fo th e aissi. [}0S441 Ziges 28A and 28$ repsen the DNA sequence of FLAt(MCT J (SEQ ID NO:82) and MGC.F1 .LAG (SEQ IDP NO:183) mspectlively; FLAG sequence isne e 00541 *Fans 2PAW nd 70B eresentte am o a seucenteFA G_ I 4 pirtm t&EQ 1) MY: 13SO) and MIGC__I I P4J{aAG (SEQ I O 5rsetvl:FA ece uderlined. PROTEIN [OcSc! :Detenng e O itl of MGC.248 VMS done Using t dm morit m oe MOO n I LAG pdRES or I t.MTGC ,,I4 co4ntrun dew bed above or p mREmpu3ur mpty ere ab qeq d yr tranfeted into NEK293 celL a\ F wo (00X548j, MiK22 TC IAIM$I c~ls wttI plated ofl Neie ls tF 1n daeter Marrded atg number 0L15 30 wihciwere placed in a 6 well plate using 2nu prce-anned E,011 [rDlbcecc modifed Eagle> Media Baidiogica idu~ase~s(Ifet Iit~rn~. IsaeL clonge number: 01-0455-1lA)I 10% 345(Fetal, Bovo Ser) Ga mine 0000 cels per we wer tra ce wih 21 g of the D.NA onstruct ang 6p FGENE 6 reagent (Roue. catalo mba 8 14-443-00) d ed Imto 94u1 .D.IN{1I 'The fli;X ture was incubated at romy. fttp~aw or' I- s imates. h scrmpiex IiNt s added dropwse to he ces and wided CAs werA aed incubatorr mmintaned at 3 wth 5% O2 content 4$ hoons ao transfetie tronefactiorn the ceLs wem furIte rcessel for analis in coedocal toosopy Thecovr slp wre wvha.3 imes in phiosphat. buffered stne (P1BS' and; fixed for. 1.-5 minue wth a fxing SUhNI composed of '7% pamaformadede (PFA *Crycaag wbr P-61 43) and 3%f gttko (Sigma.ctlg ubr (5 7 67), obowed by 5 mn Cih ymM illn (Si ei taIon (37Uh6), sluon for minutes Aiter 2 washes n PBS es were incubed li 5% bovie serum albunr LBSA) Sm catalog mwader: A4503) in PBS soluion for 20 m Tes he As. were then icubateid wth And E' AG a1ntibdy donjVu&gaed to cy SIgmacaog nvm X B 1 n 5 SA in fPB for 1 hr followed y hree 5 ninute washes sn PW , -he coversvns were ten muntd on a side wt et Moun e ed <aG catalog muer G09IS and eI.ere observed for de presence of fluomescent prouc et (3 cntQ~lmirosop 0U05491 The red uorescence signal obtained from ceiV ewpwresoing MC_wTi P4_EL AG iSEQ ID NW:!4) or FLAGAMCT _P4 (SEQ 1D Nt: 15 to opposed to the absence 0 sigd obtained fromP pJRESpWro3 empnty vectosr indicates for erctopir: expresem of MGC NoR'withsianding,. the reombinant proteln could not be detected in the cell membraneU~t of HEK 2931 cps dana not hown in order to further Nderstan MUG P4 cell locabration epndgenous expesion instead of ectopc exprssioi wiHl be tested, 110 1 EXNNPE 5: 0 A NQA POL-)YPEPTIDPE' AND POLUCLOIES AND, USES THEREOF AS A R TARGET FOTd PROD DRn AND lOLGICS EXAMPLE F EStRIPTION FOR CU STERN F10649 F"1erEl0649 (inuernalO 1) '7284551 feates 8 -uwoknscrpt of iuoterest. Ohe 'aree--s f(or which Tab 2 h d pin aa a n i a e 0 no'e 0 oD4 0''X9 TiSEQ3 ID NO:22) FP0649 14 (SEQ ID N:2 P10649 6 (SEQ ID NO:26) F.10649 TO ISEQ ID NO:28) 0%eeMER~~~ I t ".' N is &MN ann F 0649-VP5 GEQNNO1 F106d9 5EQ ID M)d 4 9 7(NE 9N 06& 4 4 EQi Nd F10649 PIS (SEQID NOt:36) F: 0649-IT (SEQ ID NO:2-6 F.10649 P10 (SEQ ID NO32) F0649T& SEQ 11D NO28) -ies -epeef the known hypothetis pond LOCS$026 (SEQ VD NO:>) Sw vsPmt accesson dcetntfer NP 06(1400 synoni n ' N/ M7A nAI: 1 a,7y iwtseouence svddrits70 membe" A) wa idetife e sieve proM 'OtOf iaidt'P :7(ir ea206, (1en(e Eec :)li: 5$65: nrn--om02iPn of chm~iiosXii \ Rmri~ et, Y)205 Nature s34Y('-0 t.) 33253.). and fu11lth CONA, pdO~C5 Gehad e al, (14 Genwnme4 Re" I 4*i I R):2121-?: Strmausbe-rg et of. 2002, UINAS !99 Ct.1i)P}99 : OU e a). 2004Nt Geve )61t :1>5 UowtYer no research was published ab t EnAF.ben pheaifiaek Seqenes cor0e'spOig to a049 4EQ O N a O649 P SEQ 1 ) No n wereporteda 02t00 039 among otar nov e ' p petid'§ad te nlei ptvw;~C~ Mod15C inSu\.10 no Ti) a crespoastin 5ee C.eiat orgal) of an unvsri Seu '9ce 4 cttrsndma to [10649 P SEQ D) NO0 and 0649 P SEQ ID 0) 3ar ds p'or ted in EP1 2t9356anTgrtg otletr novel po gpept de5. rd the ;'udle' ne d eodnt then) S abreing i Oolved in eural cr4 dnfferantiaun. Netheir O2.003053039nPOr W12934ey5 teach or uggest, however atsequences coresponding to F 106499P4 TSEQ in NO:30 and P0649 p5 ($'C)Qi O 033) are differetilly e-presse Muldpie yoma k-nIney cancer ung cancerklver cancer and breast cancer so, ere. is n fti1acthing ul St: n in these aoptcatons that qxl049uP4 5E r UD NO 340 and F0049 5 \I0 II0) N c a I bet used as cafuttarget t treatmmfnent0 CA-CV speciahi for treatment o& Mh'tple Myeirma, Iddney cancer. lmig cancer. hve4 cancer. anci breast cancer Snd/of fitmleh:tffed conditions Clr for' dagnlos s ereot.Also, there ~s no teaehing' Of aggestion 1 tS~e iat0i0ns that areibodies specific for F10649_P4 (SEQ 1D NO:'30F i0649P5 SEQ ID NOM33> its soluble ecioomai. and/nr lagments thereof can be used a the apeutit S fiokr Tlre nt of caneer e-speciaI Iy or treatment of .Multiple Mylonut, idney cancer r&g cancer,ver cancerand breast cancer and/OIntmme slated condition or fo dignsis thereof A squens~u c oteponiltg w to-P 493>10 (SEQ I) NO:3j as reported in 203057616. WO2002( 2266 WO200403995tc and WO2004 .0.0 among many tpeltr poypertn related to anceramd/or imne rel-ated dneaes ln country to the present ZppliltiO W02003057 160 deinotistriteds elegladon of the sequence c oepon'din, to i P10i49 [t 41 kidney tumor as compared to nom kidney tmssues None of the W02003- 57W66 W0200403996 and W02(0404.177 applications '-teesor suggests that the ee corespondng to [ 0649 0,P 0 can be used S drug tare ore 1tmnws or M.dp I )kl olXJa. ktkidea cancer, t:ng. tice; lie -cancel wd breast eand/or -inm e ated c Itnditons. orrdinosis there AM r, X IN no teaching eo uggestion in these applcatkms that antibodies cific to E1064 P- I soluble etodonain, and/or fragments thereof cn be used as therapeutics fAV trentnent of cancer pcniay ot tftrnetm of Mrlple M orm. ki-n cancer hog cance'liver canearand breast cere or for diagnosis (hermof.

B" a~pd aj iv. Ton, proe mnt ineato03 hav Rtedj that -FAM7OA rmti'A 3v contra nd t aMytomd thuiwo a >=. mnoikwcea, ~tptpade anfibodie.atiease RNA. siRNAs. rnbozvmnt and the dika oianoostiand terpeutic s plcoa nmonoclona ant esan faygment.e eofnt bind PA A and pordions and vacant thereoE miaoponay be produced Accordng to a east some embodents of the present ~eienti there is orivded the use of iintiboties and atibody Vagments agat F [74 Ntiign as sereted or soluble faim or Ed andoar k mi se myg c r ca me f &ns h were and fa ments and va j at hereof far ntung anadittaflaig canepcaner, n . stmteatment 01 Mupe Mveloma.a cancer. Ain cancer lier cane'mab""ent cancer.andfrtr nitnne related condiinss. crein I ndg Ovs ffereNntialy ie pressed. Asoe abokve castler F1064fa S ransripts. Whih wee sed in a e 2e above' These rnsipta encode for proteinswhcare va aneo illtypothetical poer, lDCX$02.6 ($LQ ID Nti24, A desutpoon of eac. variant pIotel acenedrting to ,a leas sone embodinents of the .inenti n rv pmvied ariat proteWin F064P sSLQ ID NO:30) accding to at leassoe embodets of the present invtion tyisn amino acidequeoce as eacoded bytrn p t 0649_TO0 SEQ ID NO:214 A dscrptin of theM ralionship of the vaant prot acO cording to a lest soe eodints roe vto t tDoWv protens r a fows 1oason wport betwr F 0649 P(SE Q ID N00 and- nown arotrio *Q7Z455-IUMAN SlEQ UD N(IO ) A An slated chtne t p pepde conprising a firns amino acid eqence bei ea 90% hosnologoau t MHQSLTQQR SSDMSLPDSMCA FNiL R. KR NSlY YTVJ Y V!, LGTqLAATT TQN VTVGCYYPVI.AF3SPLiGS.NI.EN KRQMLVASWFYISFG VA.AFCCAPDVDGfAA RH IDLKPLYANRCHYVPKTSQKEZAEI5ISSSTKNSPS'TRVMRNLTQA AR EVNCPBILS REPCTPRIRGNTCFCCDLiNCCNRVUTGJYYEVDSSCQ DIIH YYLL SATILNI VCWLLIUTAAVLCOGFKDM N PTLPALNCSVEThPTVS YYAIIPQV SYNTYYHSPP ilpPPYCSAjDQMjSGjxsPSNilGj5EpQSAS eore patnd ng to nnno acdds .1 i of knownprotein07&24h IIMAN tISEQ DNO:3 h . ich also corpnpesdo amino acids -- 15 of F9649.Y P4 (Q ID NOiO), a brdgin anino acid P correspond ng to amino 90% omologous to S.PSYMWSSSAPPIR YSPPYPPPI§PP P corresponding to ami.no 2(-P acids 20 3iaof known potein Q7ZAS$_iiUMAN (SEQ IDNOW 4 whidhaso corresponds to arnino acids321) -449 of El0649 P4 (SEQ) HD NOdie) wherein sad tort A ,o m k a eunia d fie cxb ah. ',I RifIDIXPLYAN RCHYVPIKT'SQKE.AEE V ISSSTKNSPTSTRVMN4RNI FQA AREVNCPHIS REKCTPRIRONCCD CN EGYBiVSD iHLSTN oparson reto nentaIds 1 44of k Qow pIn NPO:3 0408 and n NOGO b ding amno ac d Pcorrspon a nhomino c345 of F06491P4{SEQ M NOBl( 30 and a second an7tino acdseq uenwi.cei'gngat kaaswt 90% homo""gan s to P SP eNesPoni4g to an adds346 -- 349f 2ofon NP:06)408 Nnd Q8D7 OMAN hin alo d ueqesps ne i iav6 d9 o FiseoP4 ($E em squome oncign:aaaas senan e ICmnpadJ"on' repon bew;em F169P4(SQI ~0adka ne Q4NW8 HNIA(EQ I NG3) A. An 7 sdoated al meOe polyvpptide. c maprisint- a first aninO aa seq 90enc , being at Ea Idst ei ens h'm0llg0 to a pol pt0flQOe4to MHOSVTQQRSSDMSLPDSMGAFNR RKRNIYYT1Vi VYSI LTVCAATTRTQN VTVOGY TOVILGFOSFL.GlSNLIENKR QML VE S iAFGV IA AFGCAI VDOVEAA Rif) KPLA.NRCFI YYPKTSQKF AEE.SSSTKNSEPST)1 MRI tQA~ARE VNCPQLD NOn pondm t onmino acids I - -. 34 o 65 kown lmeSEQ11 NM;34and an seOnd a secn nouec qcg at least 9mdsd toos to V N CP t L SREFCTO R RONTC Y N T -- DYN, R o EO I1G B Y VsCQDIII p -. iN- W.SATIJNVO.LPIXJITAA 4100fE1XN11ACVANT 1-{3V S YYAUPQVASN S YUPPHL.PPYSAYDFQHSGVPSSPP~SGLSLDEPQSASPSPSYMSSAPR$SPPY P flffppy se owpnna totunmoasL.e~ of kantopn nn aNWN$ H"MAN SEQ 1 n NO 32 vhim awn corraspcnds t a aci 166 -349 of Eln4J4 SQ ID .NtO wherein iad155 aminoacidd seqluence and secon amo cdseqnee otiguous ad in a sequent alorder. An isolated povid cesonda i a had o 649 SEQ D N&30 O!3 Qing a poMpMd O NtS 70%, NOoa at leat aOO Y . pn Qia least AMo iSO. moepeeas at ast action 901 an! wnioeadlVa es ioi 5: IV PVE OES (I C 1Si EN :KRQM v SP v ISFGAA CAI.VDV FAA RHIDEKl0.YANRC}iYVPIKTSQKEAEfEVISSSTKNSPSTVMRNLTQAARE (SEQ I) NO: Y 55, of 10649P4 (SQ ED NO0 ocnalinta othe o arian protein was detrned accorin t resuts fro a nnmberof different software pmgaar and anals unading anadges r S gnaP odter specialized programs. The variant protein beheved to be located as iollw J w t osarim o -wl th cdl -10649san (ingle Nucleotde aolymorp s listed inable given ocrd n h positn(s) on he aino acid sequence i the ternativ uno aid sted SNPt un h n Mninaffe ap6r ifadM6is} s' a 7 'P 31 P 'S TH Codig pr, on wnse vip 649 TO(SEQ IDI NO 21) startspo i o 24 adn nds at position 1294The transcopt also has the toIow SN's as lsted in Tab4l 2, tgva .accorciig tothir position on the nadeotde sequnce. wi the alternatie mncec acid listedt C 2S Nceicacis Sr A 60 Cc A 18% C 1 826 T A \ mv f'. Ian froei 1049 1" (SEQ I'D ND M' origet Alatsoetioe of oeIfntiOih1a5nnii 101 acjtieueuC encsd be sripteu 104jISEQ ID NO:2)Adescfiption of the eationship of the vriant prote i according to at least some mbodimes of the n ento to known proteins is as fohiws 1. Cru ison report bewee ' SF0 N nd known prote Q5;RV8iH UMANSEQ JD N0O1 f. A, An isc (Id citr pcp onrn a firstamino acMi sequencebeingM least % homnok ous to MHQSLTQQISMtSLPDSMGAFNRREKINSIYWTVTtI.ISVI.TVGLAfThTQN VTVGGY POX SV iOSLOS Nt IEN KRQMId VAS IVFISFOVIAAFCCAINDGV\FAA RP01ILKP61LYANRCHYVPKTSQKEAE SEQ ID NO, 16 cnspolding t amno acids I -11 f known prt'en Q5JRVSJUMAN (SEQ b a wcNC'OrrsoS to amino Mcgc I - 1 Af F 10649, PS Et) -11) NO: K4"I 3<nd a seodasnoacx enunc being at lest 90% hO no mgu to VNCPU LS REFCTPIRON~TCAFCCt Y NREI YYEYUDVNSSQDUIHLYHLL It ASPPPYSAYDPSOYSSPPSGLSD EPQSASPSPSn Y SSSAPPIYSPPY PFEKPPPIY SIorresponi to 1i0no acids 166 349 of KnSOown protein Q5JRVSIUMAN SEQ ID NU:30twhich aso correspondso amino acids i-42 325 of £Z0491P5 (NEQ)D Ni "Itd e rein said trst amino addi sequenceand econd amino acidlasequc are conoinrm and Qn a sequenta Coher. B. An iAte chinreric polypiqptole cowndu.t an edge portion ot Ff0649,P-5 (SEQ D NOg pd3)a ppesing a legth wbth n au is sIt akbow 10 aou0 a o a i eng pn more erab at a 20 amin o acs 1.n prefernbly ac least abut MO anlio ac ids in lt, mo-re preittnablat lea about 40 x1 nino ac~i lena an )tmst prfenig at estabont 50 amino adcid ileng tren east two a innn acids corpse EV hI g a Sctum as folwowS: a sequence starting on an of anino aid u nme i4 1414 ad endinga t at amino acma imnu 142 i 2 , N) a Which xaes from 0 t n 2 (:arIson reportbeen I (1649 5 S1Q ID) NO:3 a;n knoa protei Q774 8j1UMAN (SQ : NID last 90% hornologau to MHQ2 VQQRSSDMSL DSMO AFN RRNS 1VinNrStlIOLA ThRTON VTVOGY YTGVR VI IGSNLHENIKRQMLVASIVFISFVIAAFCCAI VDGVFAA R IDLKPLYA.NRCHYVPKISQKEAEE (SEQ ID NO, 156) nomsponding to amino acids I 4 nwimptotein Q7Z43t.IAN (SEQ-D N1:34J wIch also oomsuonds to amino A 1 -141 of F10649 5 (S Q R3 INO ?arsecnd mino ad sequence b g a least 90% hoologomus to VNC.IALBE YTPRRONTCFCCDL NONRVEITOYYEilDVSSQ DiI LYULL WSAINIVGi FLG iJAA l.O(FKDMNPT I PA \iNC V&N If:PTVSgyAMPQVASYN 'YYW.SPPHI PYSAYDPQ.H(VFPSSPPSdtl SOFIMQSAS coiespondng to anno acid 166 -318 of known protein QUM2 -UMAN SI (2 DNO,3 wich also coesponds t advino Aids 142 -- 294 o-f P949P5 tSEQ ID NO 30 a tbr'gn amno acid P corespind n~ t amin~o an d 295 ofF F0649 P 500d ID NO:2 Land a third amino acid sequence bei g at ast 90% ologous to SPSYMWSSSTRYS PY PFEKPPfSP cosinponding to aino aids 3:20 -349 osf own protein Q7Z4S80JRMAN (SEQ ID NO:M wdedo correfeptmdS to amino acids 2.96- 32$ of F10S49P5 (PS Q ID NO:33) whei oaid firstamino acid sequnoceaecond amno ad sequence ridging anno acid antI tirEd aino id setence are cool s andi aB sequenl aOrder I, An isoated ehmeic polypeptide corresponding to n edge portion of F106495 iSEQ ID NUX33> comprising a polypeptide having a length 'r',,whewin a is at least abot TO amino awids in itngthoptionas ald au aboat 20 anmino acids in ength. prctrabiy at least about 30 ano acids in lengthi more prefenmbly at east about 40 ammno acids in length and ust preferabl east about 50 aminacidsin lenath where la least two amino acidis tompriaeL% E tasing a strtdw\ as folloss a sequence starting o ns any of into acid mber 1'41- to 141 and endig at any of amino acin es 142. to2 IQ 6i2 Which x varies lmma 0 to n2 2117T a. dson eportbetween rEMs49 P(SEQ .ID3 aigntd kCn wpgotens NP(60408 and Q86W72 JMN SEQ i) NO:9 A, An sohtad cbi- E d omp 1 n tE amino acid equenc eing a ast 90q hotoenn tI "MIS U SSD tEo MDSaMN!A!N NS -, s V V orespondsV o in o od j 0S9 P. Si D NO 1- a eo aio Ad TN Y4LfiCIt p C C0,10NCEN Ko Q F1800AS1 It Q ISYACIIi VA TlilIYBSPPHLPY SAYD FQH S GVFPS SPPTS CLSDPEPQS ASPSP SYMWS SSAPPRY S PPiY 08 12) 1AN R24SE 1 SQ 29AL Svh Q ils NCaiE 1ponds sn to a mto dkin42 320do *PT'I to141 w&16 4 of known prowin\ N1P,060408 andQfitiUAN(SQBN:29 hhWo 06x P3y SE 0NO ad:gamnDd P crspnigto andro' acid 3n F 049." EQ1D N 33) ad a d~bi d no addg sleen beia ade ':K) SEQAom- ID ND33%coprii p epdde ha4i 6 a 3nt4we9aes bu N0 :mino s ain o p i na. B atao t abut2 mi o Pa d in saeng pa sequence, baTml at a s ol lng thhgr yii j H.PBRECP IRNTVnCi . g NCiNV2.FPrYYY i)VSC.Izilw, YUI..4i.. 10PP auP no Rr OntA top unano at lest Abiw .30 mat Kd~)oos P 06'M 08k mbnd W 6Y7.2.J30Jon" nSE o L aci : 29) welg h tc do coRrry'A eons t ami aci "ds 42320 of and m ast ptvferby at least abod 5a amino acid emnc bhere, at east wwomino aiOIncamtes 4t ) fe dino amno a 4 3 fno wn p A 2oten CP "-x p Pn Let e0n 1MA4. Poi a Do co ) on d 2o in 2- in I W p o pr eceF1064) P5 (SEQ IDN Q33)wi ansadfrs mn ai keccd ain aci seq SHU A nence IrDgn amio ci 3a d tida oai sqec r tritutsadi seq oent~i a order A. An isoted cwhmedepolypeptida. compsin a fist amino acid sequence bemg at lean!70%. Opliall at eas.t 801% prfrably at least 85%. more preferably at keat 90% and most prefembly at least 9t homologous to a plpeptide having the sequoene MHQSLTQQRSSD LMSLPD)SMGAPNRRKR N Y VT VTLLIV S VLITVG91 LA A TTRTON VTV GY YPt3VILGUSPL ph SINLIENKRQMLVASVFISFGVIA AFCCAIVDGv FAA R H iDLKPLY ANRCYVPKTSQKEAEE (SEQ ID N 156) roresponding to amino acids I - 141 of F10649 P5 (SEQ ID NO:33 and a second amino add aeqence being at eat 90% nomnologoosu V NC(AmuRS RXEE" CNCFL.NCUGN,"R UTIUG MEJI VSQ HY H L XVSATILN}VGI±I AA VL FKPNNCS V ENI PTV SYY AHPQV ASYN ''YyHSP~hI LPPYSAYDFQHSG FPSSPPSGLS DEQS A SP .. WSA SMRSPE ~ Ppgppp 5 cn priirto tO 'ntVSBO acids 2 - ! 8. ofu,, 'kIw protein QQ4WNNN8.J4UMAN SIEQ ID NOI2). fwhh aos ciusxds toaprtit acid4 14 325 of F0649P5 )SEQID No 4 wrein md [rst amino acid sequence an cond amino aad sequence ate contiguous and in a sequsentid order. cotnmpisng a) polytptide being a least 70%. optioay at least abot 80% fe by a least about 85% me p f5b at leas about 90% amd most preferably aleast aboat 95% homologous to the seuce - .SLQQS DM lvNRRNi~ tISULVIA~Q VTVGGYYPG V ILG PSFLGUGSNEN KRQMI V ASINVFISG VI.AA'CCAI VDGV FAA R.ID KLYANRC.I.-IPKTSQKEAEE(SEQ I NO:15 of U-) P5' (16Q ID NO:33. lke moczdtzaitimol m Ihe variant, prtinws eeraes cordig WOtsh Iiu nmmbes of different software progranM and anal se, cding ana xses fo ngnP a other specialized program. The vacant mpotern is believed to be located as foilowwith regard to the cell: membrane Va it protein P1964KP5 (SEQ ID NW33) als has the following nonsen SN4K ingek Nuentide PoIyOYrhiOM ) a sted n Table 29 (gien according to the' t anheamino ac ; eencewteenatie amno as e T N M29 Atpe pi mut SNP p hion 'on anh. e n eKamioX ei acid equenc RQ he ding prto Ot pt ! 0 6191 SEQ ID) O C22 Ats atnostion 248 an nNatpsto 12 22. 'Th Krncrp a11hsdn oloig$I h ~di a o. n4 c o dag ttr position ohn .e a e attheie u atcit listed G3 A 627 6 -> C 62 C -> *. 1130NA: A "A. '~>~N A C 2043153 fC-- A 1451,754 s C vC 101,. 17.54 T A 2351 T.>G 235 T n"' 2 N6" A T 355 N nit prcnetnm P106497 (S0?, ID0, t' ' corrling to ait least somenbodrtn of the invenhon hm~ a n ial~o acid sequenweo as encode bV Feeot p 0i)_) (SEQ ID -NO:24 A desciption of the:rititonlsbp of the variant protcdnaccording to atlatsome en)(adimvnt of the invention to known proten sisas diows mparisan report between P106492S7 ID NO35) and known poten Q5Jt8URAHMAN (SEQ ID NO:30) A-k An solated iclumerc pal ypeptide. opiin is amino acid ,ecuenc beite. a ast 90% 0 toogonsto .IQSLTQaRSMSLPDSMGOAFNRRKRNI T'i.VSVIi1VLA~iA}Ri'QN \? Y'OYPG9V.iLGFSFlCLi$NIJEN YRQMIA AS.NFISFPGWA .AFCCAIXNDFA A RHEDtLKP NANRCIV VPKSQKEAEE SEQ 11D NO: 3.6) cmisponding t minoacids - 141 of known protein Q5YP/8UMAN (SEQ D N:304 wich ao corresponds to an no acidsI*11ofE 0649 P7 ~SEQ 10 NQ3SI, and a secoxi toxnino acia sequenice NPTEP ALNESVMENTHPT VSYY APQV SY NTYYH.SPPULPPYSAYDQ7RSGVFPSSP PSLDEOAS4PS PSY MWSSSiAPPR YSPIFYYPP0BKPPPYSP corregxonding to amiro aE 250 - 349of KowD peNoa corresponds to m acids 142- 24 1 of FA09, I?( 'Qf) ~ weensi i amm raaddxe andc second ammio acid sequencse (itiOUngo andI 1n eg 'jietiat order It An isolated thimc poipeide corepondi o on edge portion of FIM P7 S ID NOa owning A nr" de h I<n a lein wheve .n 1 i meast aFOw 10 arino sic in lengtoaiat least agooan amin asinagt.prefdnib' at dn most prcfermbi at '-'st a&bode >an ir idd. n I ah wherein at least to anio acids omne EN hang a struteas follow sequenestating fr any of anino ac nmbe i1 to . d en 14 1 aad cnii' n of am numbers i"n-2 in h aue xm O to na m s port IXween F406 49, 11), 0J and . sinown protein QO N\NS .UMAN(SEQIDNO32), A An, ited,-, chuneric pOYoTie cotrainsg i lst ing 00 t elncl Fe easOt 0 opimal least 8w pmerbly at eat 85 more peablaatieas90% nd most pretfrably at least 9% o acs to polypepode havg the \eue HQSIIQQRSSDIMSl.YDSMGAFNRRKRNSIYVTVTLIVSVL1CT\GLAATTRQN TVG G YYP3VIGISFGIIGSNI ENKRQMVASi VSRV IAAF CCAIVDGV FAA RHIDLKPLYANRCHYVPKTSQKEAEE (SEQ ID NO: 156) .onsponding to amino acids o- 1 of 110649, EQ in N0i and a secon amino acid equence being at leas 90%~~ r h -ongs to NPAN>~ N(i VNTF PTVSYYAI-PQVASYNTYYI-SPPULPPYS AYDFQUSCVFP SSP PGCSDEPQSASPSPS-NSV S5APPYSPPYYPPPOhPPPYSP colsponding to min acids 86 - 85 of known, protein Q9NWNSIMAN (E \D N which alo edniwtponds to aano aids .142 - 241 of F10649 P7 (SEQ DNO:35rin ) wh -said first amio acid sequence and secondl amnno Sctd sequence are cont'guous and in a netit 11. n isted polype-pddie correspondino hea poneon oft Fl 0649 7 SEQ ID NO35 i.opri n a paypezude beina at I-east 70%, optionally at leas about% really at least about 85% more prefratly at east about 90%,and most prefembly at NM lIQ STQ INS UMSL-S MC(-jAliFNRRFTS.YV AYTVT LtIV S V.1AUV CLAI4E1 RTQN: .. S2.1GL1T~Q VPT yO~ YY-PG V.11%,'iPSIIGN.JN 1.R! fV JPSi AACA DV YB .IDLKPLYANRCH Y VPKI .KAEE ($12 ID NO: 'ISO fP04 Y(E NO.5 The leaizaor of the variampoten as detrmi according to mtsolO nt ofntfeen t iae pogna : and anatvs, e fi ing ymalyses from i;gnM and the 9dai red oeran4 h atl te. bi eT!ved b) he Jcaded 3 ioAws ith regand to the Oe CAnemihtane. Vaint protein El0649 7 (SEQ ID NO:35) asoe has the Mion g non - Ie SNX *S:k .Nneletid Folyiophs as td iable ia econding to thtl poston on e am ino acid senoene with the dhenaire naino acd s)fited SN position aron Aiin emain mo nnoacid it P 127 R ;-Q 211P S Te codanx floriofl0 tttisrflt Y10k 61cQ (10) IDNO24) tarts St postitml 48 and ends at poua non 97The neaer also has the fiowing SNE: as listed iz Tal yvsen according to their paos on on the nocato de .seoene. wih the alternative nueic tQid isted. CN 95 G A 627 G 627 A C' 9 58,9 01,3 C a (1 .199 1502 I 199.152 A >1496 T >A 2099 T n1 2099 2903 ar tant protein F10649P8 (SEQ ID NO:36s coding to t eait some eibodients c1 th 0 vcaiot hats an amito acidk sequene it encodepd 1 rpt FI649;T6 SEQ 1 NO:2v A descriptin of the reiadonship of te variant poen according to at teast sone emblodilientc he invention 1e kniOwi proteinsis as failows Sht eenF 064_P (SEQ D iNO:36) andoknow protl QJ RV8 H UMIAN (SEQ iD NO:30i: A. An isd chec polypeptide, comprsing a frst nano acid squence being at east 90% hommologonsto MIHQS ALQQR SMSLPDSMGAFNRRKRNSAlYVTVTLiVSVLLTV{L AA'TTRTQN V'f'VGCGYYPGVi K4EQ H) NO: 159i corresponding to anmno acids 1 - 67 of known protei QSRV83UM AN SEQ ID NO:30) which alo coresponds tr amino acids * 67 of F10649_P8 (SEQ ID NO:361. and a second amino acid :sequnce being at least 909% hornologozrs to (A~iS EGV IAAPCCeAYDG VhAAR IUDEKPLYAN RisYVPCT'SQ KEAEEXV158 NSPSTVRVMR NL QAAR PANC2WIdiSRECTPRIR GNTYCCLDLYNCONU KrmLII' YYEYIDVSSCQDHIL YItLWSATNI iV'LL:nGIITAA XLGGFKDMNPTLPAL NCS V lENTN PfTVSYYARNPQV ASYNr YYHSBPP PYSA YDFQISG VFPSSPP$SGLSDEPQS A 51SPSNYMWSSSAPPRYSPPIYYPPFEKPPYSP conospioning to(am)o aci9 -- 349 of known protein "i R tMAN (SEQ U) NO;30. whc as cnpnds to anino acas 68 - 128 of F10649 PS (SEQI NO:6) wheesadnamino acid sequence and second am ite id seqete ne contiguous and in a seqiuenal order. B. An soited chieic poiypepdde corspond~ig to an edge porion of' 01649LPS (SEQ ID NO36t orprioing a p0o\lpepde having a lengthn" whenrn n is a east about 10 anano acids in ienm l touan at 2a0boys0 adto acids in vn preferdy aG least about 30 an4no acids indeng ( moimably a en abo ut 40 amino acids ineath and most prentmby ai. l am( 5d amno acida' length wheat lesttwo anino acids comprise IL having a strucnre as tolows a sence starting fom any dc anno acid muMrmxts Ota to 67; andw idn a m of +its acdnmes6 i K) - sx). in x~c vardca fhm 0 to in2. 2, 1 ",os'lpitisoti orPort between t'!utsa P8 (,SEQ 11 NO:36 and known protein Q9NWN8 HUMAN SEQ D N0,32 A, An No atdom ce$md ppode compriisin a rst amno acid sequence being leat7O%. opoonals at least S0 P ir at leas 8. re preferable a 90 d los( pferably tla t 95%,hm u to a polypptide hsavi the se MHQSL'QQRSSDMSLPDSM AFNRRKRNS T NSVILTYGLAATTI'T VTVGYYPGVLV AS IVSF GVI AAFCCAIV DGVFA AIR HKDLKP Y ANRC YVPV , SQ KEAL:EV4SSST KNSPST RV MRNLTQA A RE (SEQ ID NO:. .159) corresponiding to an no acids - 144 of F10649 Ph iSEQ ID) NO:36) and a second amino acid scquence beinga at least 90%. homnolttoous to VNCPHLSREFCIPRIRGNICCCDLYNCGNRVETTGYYEYIDVSSCQDI1Ii YHL WSATiLtN I VLFLO ITA VLOG(KDMNPTX LPALNCSVENTHPTVSY Y AHPQVASY N TY YESPPMLPPY SA YDFQMSGOVFPSSPPSGL~SDEPQSASPSPSYM4WSSS APPRYSPPY YPPPEKPPYSP norspynmg to OO acids 2 185 ofnown Pfoten Q9NWNSHUMAN MEQ iD' N(>37.whih also corresonds o anoacids 84 2 of' l010649 -PSEQID NO6 herein saidfstamino acid sequence and second atino acid sequence are contiguolan d i a sequential older B. An isolated polpeptide comtsponding to a head portion -ofrl 6 Q ID) NO:36 oapisi a polypeptide being at lest 70%, optional a least about 80% preetaly at least aboutA9 ore prefetably at least about XYE ano most preferabiy t toaot % hongous to the sequence S1QSL TQRSSDMSLPD)SMOAFNRRK.RNSIYVT'VTLIIVSV LiIJVOLAATTRTPQN \TVGN YY~POV I V ASI VFISFG VIAAFCCAIV DOVFAHIDLKPLYANRCHYVPWT SQKENEEVISSSTKNSPSTRVMRNLi()AARE ISEQ ID N:O 59) of F10649P2 (SEQ dU N0 6 'he localI admof the varian protein was determind according to results from a unbn r of diltecerent software progms a als i og anle flora Signn6P and otherspecled poyams The varian protein is beeed to he coated a,, ws with regardto the cell, membne Variant protein P1(649 P(SEQ I NO:lo hashefolowing a:i lent 9SNP M iagle Nucleotide Polymorphim a listed in Tabile 33. ien according to ther po oni on the amino acid sequence, wth hid(s)ted) 7t tile sa - Awningarwd aiantl SNP poAtion% c.*amtC % Af ernatin tiano add K 4 a > 106 R > p 106 R Qo 291S P 4> P 'e coding p[ttion Of WitaCxer pF064T6 SEQ ID NO:26istars at position 248 and ends at posion I 1The transcript aiso has the fbow'ng SNs as listed i Table snkn necJar.n to ei pontion the anudeotide soecuna wih the attrtvenuec I dc k CId 139 T G" 1157 A C 206 600 T ~'A 2360 G ( 2360 C N. 270 nrit pcatotein F106P9lO (SEQ ID N 3 ecoilia to t least oml mbodidn; s a the invetio has an anuao acid sequence as encoded by transcrit r106 S (SEQ H) NO-23. A descrpion t the relationship of the variant protein acecording~ to at least some embod inens <.4(he ita n o known proteins is as fliows Coann'iasn report beaten F 0649 RiOt)(SEQ 1) NO032) and kowanotei.n Q$)RV8 HUMAN .SEQIDYK:3 An ated ehitneri l vpeptide Comprdking a first amh' kndd segntC :being at a 70% ptionaly at leas ( pretern ma least 855% more preferable yea 90% nad ost peer' t eas om- 'pnde having the swe ndac dseqence be at 95t 0% hooalogo to VNCPFII SRERIs IR 1N TC I C )CCDYNONNRY COYSEYln I SSCQDilIH wL WS S fNT VCLPXlFtC I N&XILGCGFKDMNPTLPALNCSV ENT PTVSYYAlHPQVASYN 'fYYSPPIHLPIWSA' VD'QSCVNPSSPPSOLSDEPQSASPSPSYNNWSSSAPPRYSPPi YPFEKPPPYSP corepond g ano acidS 1.66 349 of known proan k5lPN8\3iM AN (SEQ ID NO:31 whch alvo coflespond: to ana osi 2.15 of' I 1(140 Pi0 (SEQ 2) N:3 hr naald -f st amno id sequence and second aino acid sequene am. contiagiusn and in a sequoential order C r ao p b e0 (SEQ 0D .N&:2)and known protein Q77,4SttUMAN {SEQ ID NO:31 A. An donated eobiinnc. olvpepti compsing a trsamnacci sequenedbeing at least7O%. 0piilaflg at east 80%. pmftably at least 85% inore prdferabN at least 90% and mot reergaaleat 95 noogo to a po}ypepode having the sequence arresponding to amino acid del ofFI%49A P 0 SE 1D NO:32) second anonacidM secnec b a s c % to VNOPSlLSREFCTPR IRGNTdFECDEYNCGi RVTGG VYVV DV SSCQDiiIJNHIYLi. V S ImIy GPMQOUTAA 0.Q.xIvADMTPA VNYY AHQA sYN TVY$ PPIPY SXYD lISQMVPFPSSP (N S DEPQS AS correspad to amno And 166 31M o known pote Qs UMA %l Q 1D NO: i. wich also coriecpoands to t 2 - W of H064900 SE WD N k a dying amino acid P corresponding to amino a dd of m0649 P0 SEQ ID NO2 and a third amino acid sequence beh.ng at least h omokegous to S.PSYMWSS S AY YSP EPEKPPYS P cosrsponding to anino adds 320 349 of known p:rtei Q77Z IHUMAN (SEQ ID NO;3 wh otrneoonda o aaono acids 156 - 185 of F!U64 PIG (SEQ ID NOD:2i wherein said firs amino acsd sequence second amino acid sequence hanging amino acid and th rd amino anid sequence are con geos and in a sequena1 order C. (Jompati son reponrbetzhween r10649 P0(SEQ ID NO32) and .own proins NP 0604085 and Q86Y?2 HMAN A. An 60ain ado Upser on J kgp'~ccrltsnaafrtiihl ~i eunet~~a a70%, optionaly at least t0% prerabl a das 5% mor ptera valeast0% and mos)t pufete.ndbIv at least 9% m to a pol peptide having the sequence NI cornsponding to aino acids 1 of F10641> P 0 SEQ ID) NO;32b a second anoacid sequence bent atlat 90% hlonmllogo.s to NCNRVEITYYE D VSQD \SA.Hlt'N.GI klf4AAVLCGPKU I N PTLPAL NCS VEN F.IV SYAPQ\V: N TYYHS PIPYPSAY DFQHS VFPSSPPSCILSDEPQSAS PSPSYM WSSSAPPRYSPLPY PPEKP c0rrespond ngn amino acid, 166 344 of known proteins NP060408 and Q&<OY '2, RUM AN, wi also rr' t amino d2 -. JSO of P10649- WP10SQ ID NO2 3 bridging amino ac i P coresponding to anino acaI of 1 06491>10 (SEQlID NO,2. m al a third mino acid sequence being at least 90% homos to PYSP ;onespondsng to ain acis 346 349 of known pmsteins NP J06V 48 and Q86YTQ jHUXM.AN . w'ihe dio tis o an1dna adads 182 -15of F f0649910 (SEQ 2>14 &ct0d itrd mnuo acid sequetae ae conti%$US ndet ae soenti ode:. The 10a izaton of the riant poe as detened acordin t miIts fronm a here a pa s h at pAt. s eV) be 10aded 3\ wilows with geard tao edi mertanc Nant prtei n P 0 SRI TE I NO32) aso has th nt SNPs Zngk Nuclotde Pnymohss) vaed the Tale. a .ienead i SNpositi on amino a e nat t arnat amio The MS Amc an o uindF1s The cedings potton oI Drcenti v SEQ NO:28 'tArs at posit on 0O.3 andedat positon 657, Me tr'scrpt aNO ias e f. owng SN> as wd able 36 (gin rtn to the-Ir ponm," nit teOw h~~ti St'tKi wl Ov' tenvnve.f :a'x 565 A - 65,290 C -:,- N0 IA SON G $86,189 A 83 1% A 1 786 T -> 0' 1786 T-C1 4) .16 A 90 \XA E: P UN ANAL F FAND#A1 mRANSRIPFO M~ OCEV dic desCe in a l herin. was Ised to es"e - (en of i dmns d. FA mA n wip ver thnd I t hed ove r pres in l ung cace. t is denrtnsuraed in Fionre 3j. n liver cacrFsi emntrtdigulere 31, in hias cerw , is dernn-lmIs." airdk in Pin 3 2., andQ i n id ncv c aacr as : Fig5 30-3 t.mmK4'~ 4 ~h ofH Alfy\Th4.x be 2135 a, ur3 shows . es gressn f A OA acri i imaa av cpips aer and mng nomal experiments. As can he oe FAM itA acip are re presed in live Cuer snes iaond narkers)eae to i expresnion a na lung caz e emnm er ags).kk R'gur 3 vsw he expossion of FA MYrA s'r'ipt in tal arywnk chip -mmy easneer and noadinr Axednts can b seePA7OA anscrips are verexpressed in lier cancer tissues (damnd makers eive to its expresiOn inn non'e idnley nd. re aeshdage akr Pigau' 33 hw h ewpwrff sio of FANvIWA trciptn uricrowaa chip'rs in bde cancer and nonmar reast satpedhr As can be sm tnsc a ovrs nase i res cancer ti sues (&.aond make4redlativ to is cxc Issionin borast l kgtidey rs crnd k trangle mi'md:kr accoring to sowseg9di e 4i eg -fin sipQ iN 3) am-pa frma pdm er0649or0-lF dSEQ xD NO 10A) and F1064e .- 2R SEQ ID NO a Te vmesnbed if timoes PCn ti ood psues anad nmnonna pandTh plee tossri bnord panel are detailed Ti 'ces 2 and 2_r ke r ac.ed for nonra pantA detailedn 'Tab e a din5, (a1 n reaa a e e ibpan a ortanTes acf he odan of e qunhdet in The k d e samples us for nmal ae ae the. ortainavaluanof relte ex i of excressmperal oue eian te kidne decibdinEarpe ITe 1311ittsPnftik01ec P atnc a he isier n saesas 0how, in Ngue p eryho epesion was observed in arv od delg ighbC~ SKf speme iuev n (rnral btinnd hear. {005521 For blood panel -For each RT sape t xpe.n- of the above ampbcont was nonmnahed to the normainion famor cakulated from the exprssiom of svraf hMe ke genes Y ao m described in Example L The normalzed quantity of eaeb RT Wampe was then dwided by the meiaon of the quanones of the k samples samplee numbers 6167. Table .2 abovem to obtamx a vaine of relative exprexssikn of each sample rlative to median of the kidney normal samples. IOO5~~31 twe resft of Wd anlssaedpitd te.sora xbnr& Epreason of the axO v-dicated hypohicia protein FJ20Y 6- AM A rarrt p very, hio) in, mWxr an oxtr tarp-Ilaexs nd deadbic cells samoes. and in two ourt [054 CLONING OF FIL, LENCIT ORF ECODING NAM 115 FUSED 10FLAG o00555 CMing 'f 'FV Le ORy cow ig FAM (fuid H i we d a desdhed belw [00'556] 1,A ree l rIoaipdenmaco km -krdi m as foow 0go pie RNA ten\.tracted ni-6 RP1 8226 Aell TCC CC55) i7n d \h iAfd irn -exa prnsAGA O d CA, SA a u 6 n d, 0CepmN -q l GUn cm toh ke af56d henaur w)f Ssincubtd fi,:s 5 m .nd 219x buffer ( invitrogen. catalog numbter: I 8064-0l 4 par n.urnber: YOO i46& Ky at-lM DYI and 400 unit> RNatin (Promega, Miwnkee, WS, US A, catalog number: N25 I I were added, and the mixture was incubated for 20 min at .25". followed by further incubation at 424C for 2 nn Then, 0 1 2000 uit) of Supersripi Invitogen, catalog number; 8064-0 4) was added and the reaction final vohme of 250plI was noobated for $0 Min at 42C and thesl inactivated at 70"C for 15min. The resulting eDNA was dhned 20 in TE buffer i0mMl TriO I M EDTA pH 8v 2. , p~ wa do Y unGtioTan Readuhi K Pronmea. atawklgn numaler NT 2TY under theitiow tu cndittns 10.p ~ DNA from the above; I 4o ach pnte I i lathWe 48 v 12.5g! Read WAidv witharatokrgrmo, iue in 9,9: 1.30oz W o- at3() secondA at 94% 31'e ) nd at 5210 ad oiuts at 72>t; then 10r minutes a t 'r Pt ers Which wer Vise fiude acespcfi equence~s car-esondung to toe desired coarstdmatres of Me pro e n and ie fd'e ti enzyme sites and K ozk qs ejo .as listed in Table 37 bew, T old letter I Taile 37 represent thgocfe ore spec.wiefe etitonst exten1smn" ut"ilized tot chann punoses are in IAk and kmntak seque'nces are unceranee. LA tag i n t d ord to eance th PCR product, a second PCR was dion singPtipiintu PFX { it( ge Carsbad. CA. USA. catalog nimnber; 1 7802 1) aA :0e prntict as a template ppi. PCR0nd tos < e foiows I PlatIriun PN enzyme; g t1- 10 raM dNTTs 12nWWI of each nudeoide) 0.. Su n M MgsO and lof e'an p-nrer s0MI in a tota eati n volume of onPCR progam was as folows 3 innesin W&92 30 qv es of 30 seonds t 942.3N! seconds at 52>. L.5 minutes a 6$>U thpEn a riutes at 6STC.Fal 1-, E-AM7OQA conig. pia eal [00557 lfabte4 '7 D Primesmnennce Po u Resr tnt 92ItTG(: CCCACCAtCCA CACTCCCTGA(TC t 1 NSf:) 1,6 ) o11 9r A \A2 ATccacCA TIA U TorCoCAKrCTC Rev NotI t / inG U A t (AA I TCTAN. A CG'GG CTTTCAA N0IS NO lSt _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ __ 2il tDO558I The Platinum PPX2M PCR p oduct was loaded orntoa a agarose tel stained with ehidium bromide, elecftrophreCd in <TBlE solution at 100V, and vtsualized with UV bigt,. Afterverification of expected size band. it wax extracted using Qiagoick gel extraction purifiatkom kit{QienM Valencia CA, U.SA,. catlog muber 2801 The ex racted PC R product was. digested with Nheli and Nodt New Englanid Biodabs Beverly, MA, 1JS.A L After digestion,. the DNA was loaded onto a I % ag~arose gel as described W!e nod above. The expected band size was excised and extracted from the ge mng QiatuickN Gel Extraction kit (Qiagen, catalog nmr: 28706K [0,055a1tad PC.E. (iu tCR roto habo Wa5 ligatedinW pNOE". ro3 veco usiag NRapid NA uiationvtern e taognnbetr M l .T re esudag DNA was transformed iao capenIt nt CoI bacteria DH'> R iBC R asence 'Tap ainube R81) according to manodacturels idenetons ten plated ori LB-anipin i pates for seweriofn of membinant plasidt and ineaband overntlt STC 0U 0 l'h 61winga ny'tmnber' of coonia Jon the ornnmtion that grew on e selet ve plate w a iken fot further nalN hiNeaiting on anther selective phie and by PCR iin G ia Ready Prmege caalog nmube mi 122), Screeaning posite cloneN performed by PCR usng oiEMQ 3 vector specc pimer and gene speed 5c *met rdinot howal Afe copkneiclnof all PCR e lsi half of the cuon wag anayzed aIng 1 % agarose get as described above. After veri catin of Axpected band size *' poxiti Coeonies wer grown, in :d TeriAic Broth Snnp etrited WiU Iobpg/ ampl mU hix shaking ove might at PC Plaind DNA wns s iat fror bactenma endtmes asiog ire 'M spin Minipqp 1iQiagen. catalog number' ien6ate cloning was verifed by sequencing the inserts einann Institute. Rebovtaea Upon erfcato of a errofree coo ye no nations wihin the ORE> reco binmant wa rocessed tar firrher anlis 1A05i611 figure 36 repmse-Ns the DNA sequence ofMFAPM7bTI LAG tSEQtD NID 119) gene speofic sequence conpondingtdhe targets fnl length suence is marked i bold Niced, FLAG sequence i nboid {00621 Fig'e 7 tyrm th rahoe acid Ieuoe ofPA7ATIPFA proeloThyID NOT .120Y. gene sueeco'prlcagwa~e1t ky) eizfc of toe peemkded in bold faced.LAG euence is da EXAMPLE 5 DETERMINE I CEf L L tA.Z.A1ION O FAMYOA 0305631 ODeennani.el locah2a0on of FAYA was done Ouith coofoca ucoscope. The A M PAj putESpurW Consta was tbXueov n1 rai3nte wan'Nccvd 10n MIGN2fs cellsasfolkawN [00%41 IE1 rATCC CR1 >2 ere pated onsteie l c!,ps 3an diam t re catwoy nmbe 1 ) whch Nre @ aced a 6 We plate ig 2nd I prmed DMEM [Reieedo s mnodified Eels Media0 BiIlogiad Nm941 i seI nste. Irael) esog mer; 1 )5nI Aj+ 10% pu tte Booi Senan) +4rM i Gutamione. 00000 cells per well were u'ntaetd with 2pg of the DNA coxUnctm durinti 6FuGENE 6 reagent (Roe ca dog numbe; 14 3 D dited 9 t) 94 NlNcMi I tete wase ted a gom mperature toe mnP o e canle x t .ut wa added crapse to the cels and Cwe d Clls were paced in naeubator namntained at C with 5% cotet (00%1 42 hours posts transien te o'ctioa, the Cells were f.- ner processed for anaivs i confoca InecojY. 'The coxet tlip wre wshed 3 times il posphate offered saline PBS) and fdin 4 d 5 min"tth A f g son cordpoed o % parafmrnuddehyde iPPA) rhmna. g nuaoiAnr; and 1% (uS le cai alog ****n* e( followed hy 5 Mmnutesinuhbaon wih MM glycine (Sigma oataloc tu;ber- GT126), After one wash .n PBS, the cods wee peanabilised by ''ubaticniwh 01% to X WB/PS sojulon for 5 minuet After two, washes in PB-S he alL weer incbated in 5% bovine serum alburn a Sigma catalog number; A03) in PS soluMion fr 20 nuts. aPen elisreluu then icubated with ati FLAG antbod coj ated toed (ga catao nttmber A9594 diAed 100 in3% BSA P5 for hi Alter I wves PB the Coversils weregledt a ulesing muong, soOl Sga.caao ub 91 8 and cells were observed for the presence of fuorescence usin codoca mcroscope The sesults are consented in P ue 38.

1.0566i ] c3 o Awt didt Fill FA70ATAPS, FLAC! WOf ND W119)} te oca tce nmane gon r iK 2931 cl Te image EXAMPLE 5A PRODUCTION f POYLNLATBDE PCFCT W A1 AN, pd prlcedur, Sig in b lrch uractm jQt}S$j Peptide ytei e pentide sequence which was use for rfhhiab inrnao was as fSHlOW CHI PKTSQKEEAI;EV PAM7Q. 12.8 SEQ ID NO )1 a e :t int ECD oop ctne pond to a1d28-142 of the FAM70P5 pro eCn (FA7QThb U N03) 2 nnpeptide wevre synthesize ... Purity of" w.ich. lfro ee ais t E an r.e c pepted ufolows;Amral were hm zd every o wees3 test bleed o2m wer [00570A1 bd prfetor niode ilh purifloed froom the, itt sre Affiity ptfificaton wI be 1ertsose using t1he peptide' agailns-t wihtherepce antibodies were raised.h an imandunoafnei columm. The pure fadades wil be anailyze d bye NAL andy es bbo on twrcombinantY .:'JO .P5 as ,presisd in IftE 293c 14wlne adiog enous protin laia wille be tetnneag hos Abst by FAM70 peptide sequence Q ID NO; 12) CYPKTSQKEAEEV PROTEIN In Ar to Pgnea stable pool of u;Kn2sns 93T cus a flFMl oPSot HEK-293T (ATCC. CRM 268) cell were p nated in a sterile 6 well plate stale fw tsSue cahure. using 2ml pre-warmed of complete media. DMEM [Dlhecco's modifie Eagle': Media. Biologicat Indostries (Beit la'Emek. Israel). catilo number: 01055 Aj + 10% FBS !Fetal Bovine Serum, iolugical Industries (Beit H-a'Emet raelI candlog number: 0}440- Aj + 4mM A lutmine biological Industries (Bei t HEmek, iame catalog number: 03-020-11A 500,000 elia per we wer msted with 2p of DNA gc rstrac ming 6p IF3ENE 6 reagent Roche, catalog number: IN 8144401) diluted ito 94nu DMEN The mixate was incubated at om temperaure fr 15 minutes T1he conme mi-<ture was added ropwie to she cells and Swe, Celb were piacec in incubator maintained at 3TC with 5% (CO content. 48 hours folowng transfection, tinmfected Vcs were transferred to a ~75emnA tissue culture flask containing ,I ml of selection media: copletediasu m with Spgml pormycin (Signot eatulog nmber P8833 Ces were placed in incubator; and media was change eye, 34 day,, ani clone tnar on observe iXAMPILST CHARACTRIZATON OF P URI D FAMvOL ANTIiBODIf Bi STERN BLOT ANALYSIS ON FAM70A PS TRANSFII'ET CPUS Sn tiderto v erify he sp epifiQty of antbodies mser agxin4t selected petide OfAM70A im pecitadon flowed by wester blot amilysis was done using prdd serum 1m r whs 566, and 5664 described above.and AM7O H$K 2T stabe ansfectart el sates as wel as EK-- 293ontrasfectedi ce iat. iflE2K-293T stablY expresing KAM7T0YP5LAO end ytaranfected el iysies were unao pitted using antilag atibody (Ani Flag M2 ,tffinJy Gel [re za- Safe Sga Cat A220) and weN aayzed ha Westem blot using tie puriied antbodies Wed axinrat FAM70 peptide d .25ted 25N an nmas described. Figures 39A and39B eprseny the obtained fr. pderfied sermm of rabbits #5663 and #5664 respecteely Figure 39A demnstraes hata specific band ize of 36kDa wa obsed fai pwffed serum of M ,bht #5663 on as& 293T tieetd elln sates foiowed by ane in Figure 39A. oweer, whoe cel yste tsraction dd ri uvealed expended band size(ane INonspecific band of 52kDa ws observed using seruns puified from rabbt 45663 or 4566$ aIne 3 and 4 in Figurs 39A and 393 respecsvely. 2-4 KXAPLE 8& CARiAE:TRIZA1ION OF PIJIPBL PM7A ANi IBODILPB MM UNOSTAIN ING OFM OA 5 PTRANSFECTED CWL in auke ro moter characte w t Puafnty thydaobdsawd&att A~JA antibods-pre& ereacw studied usinc nar nosti nu "A AN- 0 5 stle Mnftd 14Ec293Tt Ke fnarotfl ingfl Of FAMA trim feoed cods 5003)00 elts per well of HEK-293T (AlOCC CRL 168) stabi' xiesi n AM70A or H E~ejTnon trafected. weematued onaeegasegeu u Mafirfed catala nimner 01 it 3 which were naceo a a 0 wel plate, Using 2n0 pre waned DMEM [u eco inodified Eni Medi Biological Iadttie Bet Via)emW Irach. catakog number: 0-05IA]+ - 0% '8S L ua Bovine Sermm Biologienl dusures ten ia e ai catalog number 00i 1A) + 4mM lutamme jEiogc SWUM dit HEmek sPae) catalog number 03-020Q A) 48 hours pl pUing the cI aOn cvers pa they were fit hegr roce;sed for inrUfmOstain and tnnuy by 0on il uirootMt Ihe lower ips wea washed in phosphaee buffered saline (PBS) then fled fora mnutes wah 'a 3 - parormaidehyde (PFA) (Siga Caog uInbei P.6148)/3% gucoseo tiun catrog ntrmbe: G5767). Afe 2 5,odni.g wans nPBS cell" n ~fcubw ihIIwtioti1 d'r- nPS b 5 mndnues.Atei two 5-nlimte Wshes in PBS s okkng o non-peclfi regions was done with 5% bovine serutlid in (BSA",, ita a .aL er 4503)diltd in PS) for 2U mnineos. I coTterips were Ohwn inate in a monid fhb or honr wit pointed serum f 5bb R663 antbodi es ajuted 1:200 1:000 i % BSA ,desc ribed aove ned were wahned3 tinies fou nnts in PBS, The coveralips were inet:ntcubated, i, a thrntd chamrnber for t hout wiseconday anibodv: donkey anti rabbit canjgated to C 3 flphore (arckon CnoanoReseae o vao m '71 1165-152) diloted 00 3 SA in PBSW Ater 3 minte washes i M PBS e fixed oveershps worn mMuted on ides with Gel Mot Aqueous mtedn {Sigma catalog numberG0918) and cell were observed for the nresenze of fluorescent prodttet tusing cordfo croscopy. A shown Figre 40, cell staining was beved louedo tothe cellmembrane usg puriied and FAM7O antibodes rai#5663 and 466 scibed a 1b200veN or 000 onH. 2- transeted eeuts gures0.A and 4B respecte However. posv e 2vi sgna waosefved on W-EK*-93T non trnstected cell nELg I 20K or ziO{00F gure 400: and dOtrspcYs:)aswl as an (IV! K I CA"TCXXCL 1 els(kAe412'n NOWCAR Ait =. CRL 803) cell {Na~r JqwOE Loier to teether etoz Pwnc wktirhep sytv final Uinvod Onth non irasfctd cei h wno e or a specc. Pa) a pe Krfod f"Ta dR M Promeg M1A2B) Ihe Pr mers used were FAM7 species: piner # y O pr? Y ) ;o 16 N 1 and prh 10 iPOOI)4 SEQ NO I Te epecied PTR predn sze obtained from K 93 eDNA wasWriX, edd veified nwb 3'non transfected cels However no product was obserd when using C/CAR cDNA as a lenipe (dWdata not shown). In, ooier to airrther aye Oemeis. [A MICA O-.e eserted S w in n sta ed uin anti AM70A anbodea descred aboac with or wieho inures 41 A 4D deem nstrte red tioresene nal of 293T1 trnsfected cells lowe i ih.5tims 25toie 50 tines FAM70 peptide respeed ely Fius -41-Iemorate fed oreenee signal O 293 tnfeted cells folowed by inubantion with 0,j times. es ,50 times AM pejt de espe e 4As shownr inanabc localization was observed both in trn "'N'mi HFKX-flO9l T~n14 Howeenn specii e aim nas observed slowed by pept de Irloc ing, h" order to, fwrther analIyze. FAA47I0A epesorlyondatibhe anls naditionafl peptide sequence Wee raised. The ,pptde seque nice vlich wawsdferiisintm~ - : 'a, as 311o M.QNSLQQR$SDPMStLPDSA MiA70Ni SEQ ID NO a8 a sequence den fm the N ternns correspond to amino acd resides 8 of (he FAM?0 ptroeiS D NO:33 s.mg petgide were eynhesizd at rae wi 9se pS;ity 0 ica g ere comuted to KR career lnnni aan t wo rabbas ent imminmied with the WOc and peptide as #&Hws A~nim e W gt anTgedellZ e y~?5 weeks. Omi oducetio eeds n eac abbiwer colle cted, Antibo :ifitadonnnubodies au'dfed fom the atse .Affiey purifction tpertoomed Iuing um peptd anst WI$K4 the respectVanibodales are raied, ii an nmldutity on The id antihies are anagi v >-Intstaing on 0 P5 HE&29T transerd cel i descr 1 he abv, fer nmurunie n veriiati these antioches artheriused fgor noenos pritein ocbatin i oa sauearo i NunEH [00-5721 EXAMPLfi 6 UESCRIPTION FOR CLUSTER W38346 Ci7,te w 4r W383 terlD 7 5$ ftire Wrtigipts of iere, the 4e &r w hih a riven in Table 3 The selected pteinmvaranare vena abe3 7d/ 3' .- 7nxc'uer of nteres AN I(SEQ i) N) 3d W3462 (SE, XD NOA40) W383463j5('SEQ ID NO:,4 1 Tal~sh39Prt ner SQ'I34t NQ) 4 W 834 P4 SEQ ID NOSI5 VV38346 2') (/EQJD NO 40) W38346 7SEQ ID N046) W38346_ rSEQ ID N0O 41 Ole ko n ov> pm NO:A$)C WiId s Q 7kesteese are Vcanta of the nown hypotetia QRte.i OI 10 {I99 I N0:42 (SwissProt ae an ndertier NP389893 svnonin: IEM I54 IMEMN S 154 (trer e protein 154 was ieified in 2. 1dJ in gth EDNA projetsStJ5b~eg alt 2i) PN4 AS -9026 16899PO3; tu 60 a3'0 Na 'i'Wett 60 40-5).weer no research was pubhed about TMMi54 .speci y 22"T equence co~n'espondagto W38 3P (SEQ hi NO: adbeen reported in WO241 30369 paent applca on wch sports Onht sea le of R cofrespoQdQig to 3%JISEQ 1D 421 associate wit haman chmnic lvmphocyic Wee a. The applicatdon f r sra t tOr O\monoa at and methods fot' aaod screemnig and productionaudtiruse s diagnose eaker or therapeuti taret for BTLL Howev Te W20041 140369 paten awphcaticades not provide any spec~ ci teaching or ntn e that would ciret a ski lIed arnsaa to use ndes speiic to the TMEM!$4 fo5 the tratme or of go.s of 11sphona, eeptX NonHodgkin's Lnioma. nti CD20 j. Rituinhd resistantymphorna Muatple y a. kidney cancet er pancreatdc cavern d . tnitiute related condiions partinuariv SLE. The W20061d9 patent aplcation s noteach alo, th at TMEM 4 soinhob ectodOamini as well as raygments theof and cr optgtes and antiodies against i an be Used as therapeutic or difaonore entS for treatnent of of eythostor esp liv \onf Iodgkin. L noaani, t CIU2i . itunab rsisIant shonphmana Multiple Mvima kidney cancer or pancreatic cancer ando inmmume related conditions. particula L PR92 173 cofrspondin to W38346 P3 (SEQ I) NO:42) protein has bea rei'td n PRO92 3~' d a ltionrese ann othe hgns tereatos ns of exp son in autoibru disa tor u se pien o eon ad acen theeo. heW02000I .11 atent anpllcaton does not teach hoever, that that sequence and~ CD2t) (ie. itxna estatln/hrN MunieMtoa.knecnerr pcetac cancer he W02Q04081 199 pant app mcathl does nfh deaec o that that sequence corespondin$ to PRC2 173 can he used as dn% tgetforIatment of SLEY and/o of cance, including avmhora. espec o i l ona ani (ie. Rituximah) resitan inphoma. Mutp e vim ces canCce o parea tc. cancer. andor dia4no0i th0ereotheW20~ ~ taetN applcato does not teach also. thai PRO92,173 soluble ecodomain, as wedl as fagments thereof ana anjugates antd anudhod against it can be sed as theapeut l. goseagen do treAtment of canner e.incg zlymiphomn&a especall N4iod~gIin s mpnthoma ant OD2 Cu. Ibtuximab resiant lymphoma; Muliple Myclotna. kidney cancer or pancreatic cancer addorim e ated e ordaionespendly SL. 22$ TMIYM 54 seqenct crsoning to WS34M - E P iD NO: has been also p d WOO3090694 aten Wplication aitnong otbe nenesiwedg or reportedPoin \t3O oldti mt-it moaimoniag a to nmune and chronic inflanmmratorv disease. The W003090694 parent anpcaton cdoes niot teid oWevet thatjueice correspdg to TMEM 154 en be used as drug targe for tiauneno imne related conditions partiaad S WE The W00309%h94 patent applicatio dnes not teach as, that ueect' ace Cpodin. to TMN~I154 ar fiferentidlyv e>.pnmedin cancer. especllm 'phomafl especially N k 1a ivi Omhtom~aamti CD20e i t.aira at esistant lymphurnm MIult pie Myelona ei ncer oa pancreatic cancer he W 30906P4 ptatnt apuc oes not teach Am that seuences cnesoonda" F MiEM154 can te useds dr g targets for seamen of '\mphoma. espcti Non Ogkin's I rnnhamat 2t i.itu inah) ressmana *I p~hotttm~aanitlple Myelomna kidney cancer or pancreafic cancer. or diagnosis thereof The WO 3090694 parent appaon does not teach Io that TMEMJ154 aokab e ecodomain as 'mot an thwyomit WFrtOf rnti rpjQgate ando andtiows agnw~t iA cane bhi used as thenpautic or diagnostic agents for tret ment of phorna. espectaIN Non Hodgkin's Lv, -homa u.an- Ci U i 1. Iaxinmbi resitant imrnpthoma 14 A u e orn tthtev cancer orwa t ~te.adr iiitICwie ~idts~'~'-~avSLP TMEM ,54 antigenl curres pontling0 to W 3834(LP3 tSQIT NO- )~ has , been reported pwhih prpom to disclose pod ypeptdn anhdie b denied rmn chronic mphocyXic leukemia es and ses thereof 'Wo{X602O26f6 does not tacShto a e s nes corteSponnut tog s TM EM 4 can he -used as- dwgs targets thu rea n of ivemubona, QspeciaQyNnofi~sLm'oe ant CX20 IA tftxirnabi resistnt Ieaphomna M dtpie Myeoma. k-zdnev cancer or pancreatic cancer mndor immune related conditions peid1h SE, The W00Q20266 pawni -A -'t-- d"w" wt provide ,.., te 4 hki,,g of inc tith4. 0-,k, 1.A - d 'eA a il artiNan to an;a nboene snci fie to the TMill- Md 15 'ib s- the treatmmen,,t oar i ago.Isis of ytnphoma, Maitiple Melomna kidne atncer or panewreatic cancer candor rnmne rnm eaed c'vidions~. especdialy SE Twhe WOMO20266 paren appication does not tec aso at Agi nstt can be used as therapeuti or anosui agent fortreatment Of I vtphomra especially Nn dki A.phoma 6x, Citaximna r.ua lymphoma. Muliple Myeionta, kidney cancer o paneae cancer. -ajor imrfleeaed condn. especeah v SE (sstenmie (ous ersthemaatosust.

TMEM 54 antdmn c spading to A386 P_3 QEQ ID No:A2 has bean repotodin WO2008112177 WO 5 andEP] 293(ROM 0ate2 appIcaTons.. E n54 agen responding oW81 I KIM o:5as een potedin A 2008177ptnppcaion Hoeve one of ise pateflt a;ppi C.thicml teaches that eqences onoesptiding to 4T I 54 can be ued as dg tares r treatment or dagn Ing of 1ympaom. especially Non k 'iin tLyypnhn a -ad C aY2(iC CD Rit:utisab) resi idtitut lphonui, Ni Madtpfe Myeiuma. kidney ca.er oPpanerrn cancer and/or imiiunmre relaMed codon especa STE (system i p'setythematos 31eSe ppiationsdo not teach also thiat 'MEM 154d) sol e d ai10w4u as tfrgeata heot and comojgates and atiboediesaainst B. an housed astherapeutaicr diagnostic agents for treatment of lymphoma especially NontdigiSh mphom-a. antd CDQI Lae Rituimab resistant l ymaphoma Multiple iyeloma kdney cancer o~r pancreatic cancer. and/ordinune related conditions espeCially I sy("stem l upa e ieatosus. PMF 15 atign osrspndig o "0PT (SEQ4D) 0:46) has been repodtied by the applients of the present appcra oin i 15 patent application No: I (V-l N.60i everywhere rs no tecnng in tS1 1'/4X86 plication that W346 V {SEQ ID NO:46) soluble ectodomairi.as welva fr~a ts 04. uhn and speci antbod .1ng t' a h-sd;:lttteii rorar~cae t ut itl of lmhrn p n Non.iodgin' yphoma anti C 2O, e Ri tux imab rs ynlphoma Mauiple 'vyelona.. kidney camera or p create cancer. and/or ianune rated conditions espeejaiy S1 (systenatic hpus erythenatous I prtick r thinventionse EM.54 antigen atod inserete prtios thereof asa drus target frt, teapentic mal molecules, peptdes antibodies antense RNAs siRNAs :ibozysynes and the lke Moa part:cuiar he inveiuon ates to diagnotte and erapetc polyclonztl and rnooranaanibodies and agents tereof that IFId MEMiS. and potons and vaiants hmereo Acordig to at least someu ebod mentsfteinvention there ; a use anibodie\ anzId ant ibd fragmyents andast rMLM a annge"n iEs secreed or schle form or ECD snd/or vaintsi conu'gates or fragments thereof and frannents and ariants hereof for rendind diO iang canCer tspdlly fra treatmnt of iygloma, Mu) Ti p e Myloma idne cancer or pancreas ec cancer. antir immune re od conimons especal SL5 ystemiclnpuse them tme. wherein this antigen is diff erenialg expressed, 20 As note-dabove cluster4 '38346 features 4 transrps which were~ listedd in Table3 above, Thes~e ntrnscripts encode for proteins which are variants of protein hypothetical pm niri LOC20I799 (SEQ f) NO:43), A description of ah variant prcacin according to at eas some embdimnts of .h invenion is novm provided. Vanant protein W38.346_P3 dEQ w NO:42) according toat least some emnbodimrents ot the invention thas anO ammo acid sieque~nce as encoded by transcriptsW3834T10 (SEQ ID) NQ:38).and W38346_T1 (SEQ ID) NQ:39f The ocalinaie of the varint potei n etermie accoring to res Its fron a numrber of differn( software programs and atmalyses, iIcludin analvyses from naln other speciz~ed programs.The varianm protein is believed to be located as follows with re ard tO the cel membrane. coding ponnof 'a 3pt WgM Th{SEQ) HD NO:38) sats a xn 'o 23 and ends at posion 78L he iT t rasipt also hmis elowis SNIs as isted in Table 40 ge-en acci n tt-l petition on the nuceceetde se qnce.wihthe ainndoave nmadiic cK-I ited) A Mc 1~ 04-N~kc WdAt C NI A T'F 2446 A G 2 46,301 375 C A 261.030 I n oding ptri qftxransir p 3 83 46-71SEQ f) NO9)tats at position a233 and ends at postn 7a The transcrtpt also has the f&Pwing S3i0 as isted inTle A (gi-en according to ther posiion on the puCl0tida equetced t the aiterta tve tieic acid istek A41 i Alei a N P \m4'his\ : SNPpositims *oU Auetd qeu C 'C 11 A C 104I G 2446 A 2W C a 26U Variant protein W38346 (SEQ ID) NO 4,ac-oxdir to at least sdu emsbodtentr ofth in-ntion has an aio acid sequee basynced transcrtl 23 \'V383A.i f3$%Q iDNO 49I A descnopdn of ten rlattnanha of the variant. ptrotel accrdin to atast so me e abodnens oftee hnention to knownproei: iss as fonowse A. An isolated chimenrc polypeptide encoding for W38 3 46. P4, comprising a amm aid K sequenceK being at leAst 90% humHNologoua to A\.LPILVL1VE ATYKn TKESQSQAQYLSEVV =E DTPSVMSlEMBELDK WMNSNRNA DCLKEEKESNHNPSDS1 ES corrsponing to amino acids 79 - 1 of known protei n QM9NlQSHUMAN. which also conrsponds 4o anmo acids 1 - 0$ of W38~34t P4. The kcazation of the variant protein was determined according to results from a renard to the cell secetecir . The coding portion, of transcmmntm W3S.&4 1:2 {O ID) NO:40)aad at p n 6 a n&n at. posit~on 830. The"o 'oncrp aoJaste.fo'oig SNPs; as lsted In T -Alk 42 .epvan accorvdng to tkr pothion -o tti sequen. th hW e c e A3k;:lneed isl O'4 Z usfien' A ctd SNP L AwT A 6 2493S 3062 3124 C A266 3(79 C,- G 2660 Vrant pmin \V3Y34( (5S Q U) N 4) according to at Least sorrc en~odinetsof the invention has an na acd sqec ecdd by uranscFnis W3S346 V5 f(Q ID NO:4U) N ) A desciunaf the re o' of the variant proeein Acc:Ortig t tlas ater nodnen of the invention to known rtem is as f~os Co n aison report between W38346- P7 'SEQ ID NO, 46) and known oiteins Q6-&lQb' HMAN and NP689893: A An polypept comparing a first am'ino a6a, seqence beng aat least 90% homologous to MQAPR AALVFALVI AL VPVGRUNYEEELNSGDTTVESERPNKVTIPSTFAAVTIlKET 232 LNA.NINTNFAPDNQL0PM V1iIPUI V.LLS VVFLATY.R KRTKQEPSSQGZ t SANL&?1 1 o Woo Co Ws I - 21 of known proten, (IMQS HUMAN an rab 1a% &r ~prefenb yj 90% BAC d mo! prfrW 0t leabj 5%Q NP 698, w hAic als corpod tmoi i noai& 12 fWb3JPiSQlt ce T n an d a sequent -a x Iord836e",isFQ L coA~t.n a aimno aci sequence being ast 0%eatim y0%, eat eaot 80%, prefeAhly at least about fa morl preferrAy at east abou %nd m eb aost plmfeat y aabo us t o the sequence CKIQWKVIPAFCSSH SEQ ID NO: 1;62) FY 3,62 - P7 s NO2 o6o7 I noll ofan7 (SEQ oD NO;) w poi Q6P-Kd4 'UMAIN- SEHQD N:O*': An mnd nno acc e at least 70%. otm at lsequen babout g ,i at 90% homoogous to MA- ,,,,LFA[,,VVdV RGNYEE E lzl'N. d(D-TTV ESERPNKYUTIPS,;T:FA AV'TIKNI KANINTNFAOENQE~uaPI R L coresonI to aivno Jids I know:n p rote7in Q $4jQA ,4) 10 s44Q oned d. on- 92 of WNb38346e P7 SQN: a b Odi ) an d So aonpudg to A.o And 9slae IDrnra p41,), a~ed. opisiaafis am acid squnce ein n peast 90% nodgv to pe yae St h Aogut of kno cothei q2E MAN PASE 10 NALsed) (SEQ as coK2)sponson mo Cotined 22 - 44 f 4 SEQ ID NOM hec Iaid ani ano acid nt mm at copre, nd's to amo ac d -wwn a12 11.12o a tQI 8:6,an hr mn acid u-i seqenc b ig a x-as u0,otchl k t~)' ~ta~ya es ,mr prieabv t est90 aidmotnr~hahv t est95 hmoogu 4 apoyp03d Aotde of an edge prnon of W 38346_P7 (E .NO:46t compr1iing an amino acid sequience being at least '7G%, otiomlyV af least about 80% reterably at least about 8 ,ore preferab at least about 90% and most preferably at ebo %homolomis to the sequence CKIQLSW-K VIPAFCLESSH RN AL (SE D NO: 162)I of W346_P7 SEQ ID NO:46L The locahzation of the variant protein wa determined acrding to results from a namaXer cof different software progranms anal analyses, inchiding airialyse frm SignslP and other specialized programs The variant piuteja is believedi to b~e located as faolows with regard to the cell: mebMne ariant protein W38346_P7 oSEQ ID NO:46 also has he following nonieet SNP\ (Single Nucleotide Polymorphisms) as bsted in Table 4. (given according to their position s) on the amino acid sequence wih the alternative amino acid(s isted) acidk s3 pene wd ~~i~ h, I i h Th odn porio dtasntW84 T NEQ liD NO :4) star'tsat positin 2 and ends at pciitioin 66d~dhe wa nptm also has the following SNPN as liste in able 44 Sven a nling their position on theect dnae sequence. wih the alternatdye nnceic add histed A ,C 63 C0 .- 01 A >G 703 TO A 738 CXAVMP1 2 E PXPlRESSION ANANXSIS OF EM14 Ti4NSC u S 54trae p wreaso found to be overepressed in kidney cancer, as s demonsaed n gte 42 and an pancreatic anc, w is dtunstated in Figa 43igQue 4243 Now session graphs ofA fymetis probe set 238063.a, Fga re 42 showshe expriedon o TMEM154 tianedpts in microaray OSUpS loam ad normal kidney experimnents. As can be seen TME'i14 transcripts are overeapressed in kdney 234 canct' ~sns ivatod i miecito to itj wXaZ55O I T ON kid ney (irce an d lae~t orarpes d acdsae n akr pin je In Q Ka d ae th v ra leratv ne nd the expcrens a ses n tran are vean ' e nda 1 crvttnet2 e anna canoie na nr' AM shoms Kanan-Mle sesal cures of th bA enesion \ e TM: 154 proem. OHM3a samples onr othm -xpreky0 x n l xpression blow ledei abt by aipi frm i eitdb A BCIu A name W y 20F lame 13-cell i 6 & iSAMn !ua od tha iynpoan Is apvidnt tha OfEM1 hih exprs tioFLD2O2 TMEIoraecipstectwthorsriandabe canr servers 4a po6egl 2t anti 20 rt nd3 n i 10r 4313 the imearedhoni byrears; soli lio ne ndg nMEnal 5e etesin tapesedfo li ne repreen t'o IMc'' TEM'"' -154, -epression, bladpen oaf ydeai pin 322& The Amp54 eS&344 for4nowhch are deterwbk ' ampn' jtt diewd in wiqu enct newnw VV84t kw-2W/.R (N AID dOt 10) in diftreen nbwalis a l p c Exprssin of vp'>tnti FLtJn 228 T.I Mf&Ni54 trsctpsdctet Aabte by wr ach Rg sape thAxpsco& 2F th (SE aQ 1 NOf wO( ali:ed ond. was"' nea.tsrvd bl it 41 ime PC"R ini blood, panel and nomlpne.'h a-znniek sed for blood a e led in Te 2 and h e 1sumd for norwa al panedd are <k-tauId .i aInure 3, Normfpalpn Foareach Ip sampl e abve unpd cn e was eto the We4cribed lt exam Pl I. Thex, noaizxd q -antit ot e Wch R1 artpl -:4 :tbz dd Y the mnerl autnof the (niie of, Uh........l nmbe.s 1, 9-23 'V 3 T A4 bove toQ Obtain, a v'adne. of arlative exoresson Of each -sample relative to medx,6,i of thew Idrne samles asshwn itn Flu - 44. .1-ieexresin a observedl in1 noral PIIM-Ca. soleen Oar klood panel - -rec RI amle the epsio 1the a, v anwco was. noroabrct t th norualzati fcto acltehufrm. Mhe expre si of se-wrdos keepng genes as decie ae nt-l F1Th nornalied quan-ity of each RV smmiewa 2M.

(hen d.d te ai te wtid of he ft niples (amp nambers The rea uha this ana va are depicte'd ~f i t t in Y nX$5k1o the above indicated hypotheica puntein TLJ3208. NMM54 ranvseno in blob In EM mnoicte maltiple tie loma patem nmd several - ap -xvr ID ('3 e6.,SEQ ID N: 104(E} DN1 AAAIAcOAAA ATTTaO AG r A T rA r 6Reverse NNINI OrFe W3SGie920R OSEQ FUID" NOo 1,4 : IAAATUGAA\GAOCTTGATAA A TOO ATozACAOCAICAATNOGAAAToCoCAC roAmTG>IACCACcr AAcOAch ACAOA 10A CAA AICACAccca TAG by RT PCR as described below. IS NI MNa {RT-PCR product redsvlted from sample 1 8. Table. 2) and RT19 ionocytes (RI-T>CR ptdnct wdtled from am pe 1 -hie fom them Non ptod pnee diluthted f:.20 i Bbufe(lQn~ mM TdsImnOE r01A p1H 8 and served as emtnpite for PCR, PCR was done Rng GoTg ReauMix Phoagas Catalog number N- 122) unde the fo~owng onitons O JNA decrbe ap) 11hi 1120:. and (5a la -o !en" prmner #10052 (SEQ 0D NO: 1 nd #X5SQ 0 NO; 188)in a otal reacTIon vokne of 25p; wih ;a aci ogam or 2 n tes C. 5 cycles of: 30econds at X4 30 seconds att a55V 1 nuate at 72"C: then H0rirtes a 2 C Prmers wch were 23 PC p rocdc were loaded onto a .2%'i agarose geli sined wnlh ethidiumo bromide,. eletroresed in ixT Al km on at OV. and isualized with UV light After verifation of expected band size, PR roduM was purified ing QiaQuickrM PCR Purification kit ;Qiagen. cat along number: 28004), The purified PCR product was dige~ste~d with Nbel and Agel restection enzymes New EngIand Biolabs Beverly. MA . S A Afer digestion, Awas loaded ono a L2 % agarose gel as described above., e pected band sie was e:<csed and esiracted from the eel using QiaQuickUs Gel Estrctin k. t (Qiagen, catalog nnber: 28707). he digested- DNA was then ligated int pdRESpur' vector previously dietdwith heabove t: iuo Rapid ows sn lazetfD'K~ NA gatf Sstel (Promega. catalog IISM2211 'Tho reasing DNA as ormed cor en c Eoni bacteria ePiBC (Icenc! Raipei. o g iher; P1-lb i6) according to afafuei ntrcos en plalied onIdamiilnga te 10y sclrom of Ircolublum olsnd Znd. itlcubated overnight Mn 3M\' W ~Fh taioing day, p oonies werei 0crened by PCR using pIR Spuro3 veom3 'r p t piimfe$r and gen spesf k preer (data not shown). 'The. PCR productrwas analyzed usng 12% agarose gel denied VeAfe enficaon of expected hand ee po e CDies were gronn i ilene igoth suppleented wth 1eod amipcin.ih s4OOes a verngat ata ' )agen anta og number: 06).. c ae cioninge was venhed In y 4 aeqenng the ineert tweizma Initete. RehodL aeL. peneiain ( na err tre coln' ie. no muntations within the ORF~.t reminant phasmids were processed toi unbher analyses llhe DNA s e of the insulting IMM TE 1 54 TO FlAG (SEQ ID NQ:89) is shown in BZghqre 46; FLAG sequence a ini undeied The amino acid seqence of TLM I54 P3EAG (SEQ 1D NO:i90) shonn ignre 47'EEAI\.equene ein nderiedv 'X AMP flE- 6 -- 4: DETERMNING ELLOAIAIO FTEM,4 inoder to determine TMEM 54 P3 cehMar locahsad on. TMEM 154 TO P3 wakned in frameton (Cee e bd above. Ptote.:in ;cauatio inas ob;s erved pemn tranipnt trapmateon (Chen el Q. oulcalar VisiIon 25;8;372-398) us.inig conffcilnorocos 237r 4I hou :foIwng trasredoln the Oees were stained wiuh an FLAG antibdies conjuated C teephure and were obseed fAr the pncsencv of fluareen pani 54 4 P3FLA (SiQ ID NO:189h pIRESpuro3 construct was transients iransfected into -EY293KT celL, as described above, 48 anurs post WaSie t transfecton, celts on covelsip weere further proceed for immunosl0tainsing an11 analysis by confocal inncroscopy. Te cover slip was washed :n phosphate buffered saline (PBS " th efi for minutes with a solution of 32% pamfomakdehyde (PA; (Sigma, catalog number P 6148 3% glucose (igma, catakog number: (5771 (diluted in PBS), Qeng of PF A was done by a, 5 iutinbtonin 3mM glyin ASngmacaalog nmber: G7126) (diluted in PBS> After two 3-mu ute washes in PBS, cell were permeabihied with 0. % OwA PBS) for 5 namtiAter W5+mtmtt washes in PBS. blokking o Iomtpecire rgin s w one With 5% bovine s3mm albuiO (BSA S inac nmbei' A4503)~ ( le in CBS) for .20 .iilfltes. he. cersjlp vas the inubate-d. in a hunidh alnber fi' hour weith louse -ani PAG.0v3 arnaibodioa (Sima c-atlo g mnbcr A9594>Lred 100 in 5% BSA in PBS folkwed by tnre 5 niinre ahes in PBS The Am= Wi w then molted on a Sinwith (eIMount Amm"een nmed&ggnt catalog rnber; 008K and cele were observed for the presence offuoesceni pman1using confecal imacopv Ce1ecalnition is shown inFigare48. IM I54 socrzed to the cel i bnie EXAMPLE 6; PRODUCTION OF POLYCLONAL ANTIBODJES SPECFIC TO 'rME'AII-5tP PRW'It A po ona Abs producton procedure. including peptides sgnhess peptdes c -ut - im animal i nizaons. bleedia and antibodies purifii don cr eerfored at: Sima-Aldrich (israel Two pairs of rabbits (one pai per pitope' were injected to prepeamu aotihocues (or T M s P-bbit 54n er,1a3s> ansi 02835 6&hd 6e49 espeet8velv4 A:nimaicare. handng and injctions performers 1y Sig wseae) Peptfdes whic were used fo-~reabb mmun"'do' were .olkn GNY FNSGiU~fvESER dtsinat TMl (SEQ liD NO: 9SD a sequene. taken fron e termiu ce ding to ia acids 3119 of DMEM154 PS pre SEQ D N0,42 The se-cond peptide seqtuecr to be used wa: YKRKRTKQEPSSQGSQS designated WF ) Q ID N0,19)2. a. sequeence tAken ro the C terminus c'orsponding to :mino acids 101-117 of TMEM154_P3 protein SEQ R) NO42). 25mg oW each pepude were synthesiaed with 95% p fw m e n carrier. Each pair of rabbits was immnunized with the CO~frrsraiing c.Omjugaited 9ptKide aS fmows: rabbits 6285 and 6286 wow imuaied with TM2.1 peptide (SEQ TD NO:191> and rabbs 6245 and 6249 were immunized with TM01 peptde (SEQ U) NO: 192 Animah werue imnnownized every' two weeks 60m producuin bleeds from each rbbit were collected and affiniy purification ws pedred with the peptide a the respectve antibodisa weerayd. EXAMPE 6: CHARACTERIZIKXhNOP ON WT E154 P NTIBOIES RP" 1IM(.UN0STM NI.AiNG OF TM EM 54 TRANSFECTEID CELLS iA comer to further rhzumaedx th .tluiv zifieI aZntibodies isedl .aganiIE 5 anibdvarte ntratin assudied usi nu unotzng ofTMM 54P3 stable tenwtchtd H4EK293Tc GENERATION OF STABLE POOL EXPRESSING TMEM 54P3 PROTE IN: wstably ransfected pool weeagenerated. TMEM 154 pl ~REta ndteeay gwnu EN 544. .. Spuro3 and the, :new-atzve control empty plRESpu ro3 Both c strue wr tragnsfected into HER .29T ells as preioustd (lCiid fMMUNOSTAININC OF T'.MEM 154 TRANSFECTEED CELLS 500 X cells pe wellot HE 93T (ATCC P G 262) sta yepressing TMEAM5 or Phe eipty vc-or VpIRES puro3. described abov ere plated o steile glass coersips dunn.di~fl'k M'it td. c' og tuttbn01 11> 3M anci ee pae in a 6 wl plae, usin'l 2bidl Bv.~re 4.Mfuhcosnou'ohge e ia. Roogica l Industries (Be' lQ Inck MTrel ca1o A]ntr 01+' 10% PBS [Ieal Boxane .Srtu, Riomogi(nc c Industres Be H1 u Esm;- [aog number 04-f 2041 IA) + dOM L -- (31 am"ie 4,RI rhnca gj 1:iz 'trn'i 4" bok, K Iveelt caai usiabe 03 0 2(01 A]. -Shou as rxnst rI - hnrsle~ cels on caVe Hp til \5. k'om ftahr cese f Rr ri)m nosta-iitbi g saline PS then fixed for2 minutes wha7%paeth a 3.7% arfoxdede (FA Ssgna cmaog nuMer Pl148)/-% glucose (Sia. ca..zaa e G5767 Ater .2rnnte he PB cel en w % tntooX X900 (i kted i PBS) trw 5 parified rabbit Ti'MM 14 antibodien described boxae 1M21I (Rabbi 625 62W6 gThem was inred 1 OO in 5% BSA in PBS and Tv101 (Rabbi 62I 0249. n t ided 1 10004 in V& MA.e lotboes t e* w 3 te on Drin in PUS. The cavers7ips w0re then incuated. n a fmid chaMNber fo I hr with secondary arinbody: tdonkey anmdrabbit von pgated to Q,. OphOQakon inxmurescaxcn cato gunber 71-65-52 diluted 200 n % i PS Aner 3 $minnte washes in PIe. thed coeraipswere mounted On Cdes GelaMout Aueou edani (Sigma. caalgnmber:- 00It918) and cells wemtobser'reciftr "'he presenuce. otW oecn prod uct using confoca n croscapv. S Cifccl tt~n oaie tell l.nenbnexosrvduigp"'nneid i-i2; and TM 101 anubdoes on TMM I ransfected cl Fgr )nd 49 in 50 ectlveiy) while. no" stealing was observed uagsn , w atbo.enes on thseatv ontroi lRnr3 K29 transtcted Cdli i C re 5m hb red aooemee obtaed in gure 49 and supposed ie absene ot ign n Figure 51 demonstaes 'e re'iity c"r I1 and W 10 1 ~ts to TMEPM 1, P3SE ID NO42 S\AMPW DE l ONSFR AT ON OF ENDOGE NOUiS ExPRESSION Ow TMEM 154 P3 BY IMMUNOSTAINING OF LYMPHOULAST CEL INES In odrto deneen dogenou repression of '110PMI .54. threecl inswr slce oi ngsbodie against TMEM1 54.-P3 apotei descbad above, 50000cel raMah ce", line noams (ATCC ca no GEL, 1923)., CES5 (ATOC ca t io TIB-190l, DamdiATCC cat no CC213) ee fed wi .% PFA 3otafle 3% i ke and plated on Irsaps prey iosly treated with pn.0 1 % (Siuna nt o s4 ells were fnrher processed o nmustacasd e bwove and 'ivebye eec cell staina igocalized to the cell membrane wa ob ered ng puried TM2nd T110x1 antibodies onad once ce s hownn e [00.5731 .A.PJ ANTI-GC$24S. AN PVAMOA AN) ANThIh F 54 ATODW ~'00571 Gcnalln cm. HuanMtoln A.tbd ansKRCPA2(. MsoC5 IS EAAN4IO'-A n ,d"N' DME! 15 n 0056) Puna protein coniposed of the taelnlar dom of the KR tA FAMZ6ER M 248 PAM70A and TMM I$ aked toan Ig12 A polvpide a. bst ste addd mbwaoeas ad d as Pigen fom imnnJizio [O0571 'ransanlc Nidab Ntoue M005781 Filly kt min mronoclonal anthe lies to KRC\3 FA.M. 6F.MC543 FAM7A and TM EM 154 are prepared :isha mice from the IJCo7 train of the tra.en HuMab Monse) w Caplee u n al fiNOhd genes. In thi ma sain e SMndoginims irom e f'.app lght cOan, tene ,-ha been Vconp as descrite in Chen et 9 1003) E 1181 1820 and the deno cinuse hem co ne nar beeln, 110; hotnowrgnv disc p as d i Examvple P I ofC P P giation WO {011/09 187 .urthemov tb~ ' muse strain camies a hentanikapp lgah chain mrnsgene.Kfo s. desciihed in Fisw d at al. 1996) Natuem Biotecbnogy 14;4481b and a human heavy chain transgene. Hly, as described in US, Pat. Nos. 554 406; 5,625,825; and 5,545407 [005791 HKAManmnisations (005801 g-i uidlV hna n nkiodonal tobo Kl~ffi, t CA i F( P A i .M054 & FAMYO \ i,04 MN.d 154 yp&yides, rme of ffhe 4-ICO .Ifuhab Jl.ot,.se s ttdfa be i.iahntinel priced recombnan KRTCAP3. FAM26F M(CK52498 FAM70A or 'TMEMI54 fio proei dejed nonnnaiian cells that wt'raneseted wht; an expession vector contanmg :(he gene tencod:ing the fusion protein. General mamr~nizata scheesto the 4HfMab Mouse@ are described in Lonberg M et a 94) Nature 368(6474) 856-859 FiAhwild D et al 996 Natu.e ,9196g 14.t 8414: andO PCI'Pobtcatioo WO( Y8248184. <The mc ave 6i-46W2ikSo u un on e{'t.t so ofnt A puid combat KK APS FM2AM F. K 2498 FAM70A cM E.A1.54 antigen prpmation (5-5M0 nc28 FAM fi'oAn tnMnRfcted urnnaI tan elsCpressing KRTCAP3. F-AM2&E-F MGC5298 N- A-NMIA rTEM 4ful poen 241 [08i l'rannk mice air nnmmiruled itee vith antn n mcomplete Preuncl adiunn or Klbh adjmn't TP, tollowed 13201 do) ON tup to a tota of I i osiuNrcatOu whll the antigen in inumplete reft'Udh or Rtbi adjuvant, 'Itoimmune00 re'>ponse Is m0:liored V. rt3o tital bleeIds The .lsoma is relnel by ELISA (an decibed below' and mice wh Kmt icnt tigers of autt- KRCwAP3. anti-FAMY(P arnM(l2 M ant, FAM7A n tnnr In MEd l~154 hlman ammmoglbl im are used for tuons Mice are boted twdvenudl w\ a digen 3 days beforcenifce and witovea of the spleen 309582] Selection of ItMab mice® Prodnn Amn- K TCA.P3 Ani4{M2&F Antis MGC5S249& AntirAM70A o uAnti4fM154 Antibodnes [O0583 To sect m ricel reducing antiboie that bind KRTCmP FAM!2F. MGC35249 i AT470A or TN MEM154 polypeptdesem mmaied nie P teiy moWied ELJnSA s ognany decribed by Fihwiaf et a 946ar nflynmicriter ates an coated with u ed trecernant KRTCA , .AMv26F NC52498; FA M7OA or TMEM 54 sion portew at Jomagni in PB4S,0alt ilsincibah .degrees Cd overnigt then blocked witl 20.m /welt of 5% BSA in S u f ofpa n n KRTCPId F.. .AM26F N00592 4 KFvMCtA oP . MEM j 54 mmtmized Aice are added to each and incubated for 1-2 ors at amb nt tempertmre. The plates are washed with PBS/tveen and then enubated wh a goaatanhnan kappa light chain poycsonal atd1 oni td with alkaln hohatae for he kora morn tenperagtre- Ater wash. n2 dIepIate are devel pcI with phiPP slbstrate and analyzed byv spectrphotometer at OD 41 565C0l, Mice that developed the highest titers f ant>KRTCAP3. anti-FAM26F inig' e Mt 52498 ani-FAM70A oranti-TMEMis$4 arodiesn:used for fusios. fiisions ar pertoried a esefbetd below and hybridoma supematants are tested for at .

KRTCAP3. anti-FAM26P, aniG-MiC.249YK anitFANM70A or ani-TMEM1M4 activity by UJASA, )O584] Generath io f Hybaniomas Pmducingz HUan Moncdonal Antdboadies no KRTCAP. FAM26 MGCS2498 PAM70A rTME 54 pol pepodes [005S51 The m pleno cuktytes. isoated from the 14-uMab mice ae fused wit PEG to a inca me o ykma cell mne based upon standard prtocols The suding bddomasrethen lmphocytes .1rmnunmunired nntc ame used to onedourtl the number of :PX63 Ag836 A ( CR.L580 no1secreni mouse 'nyeloma cels vith 50% PE Sigmat Cels are plate a% pr~rxilraev XIQ K /we bnP ottomt rmcrouter plJate, toilQweZd by about tWO week incubation in selective mediuma containing 10% fetal calf sernt sutpplemented with o-in (1fEN) in RPM I L- glutamnine, sudiuma py-ruvate, HIEPES, penlii n, siaptamyeln, gentamtycin, 1: HAII and beta-meaptoethanwt Ater 1-2 weeks, cels ae culured in medium in wich the HAT is replaced wth fT, individual wels are then screened by EILISA describedd above for human anti-KRTCAP3 antFAM26F antiMGC$2498. anti FAM7Aor anti-TME M154 mnoelonial lgG antibodies Once extensive hybridoma occurred, meiumt~ is monitrd naa ly safer [0-14 ay s. The antibodv sec-retrna hbridonas am plated. screened again and, if still oitive for human Ig. at. KRTCAPS antiFAM26E anti-M C52498, anti-FAM0A or antdiXM EM154 nmondoal antibodies are subioned at leasa twice by iinmiting diition. The Stabe subcko are then cuitted in vitro to generate small anounts of antibody in thsue cultm medium for fnher charactediaticn. )58M6 tivdomnaiones are selected tfutvrtfler anay vss 05S71 Stroctural Cracteantiorn Of ered anTKRTCAP3 antiRAMOMF ni GC0524%5 anti~MMOor ati-TMEM i54hamntn Montodonal Antib\-d eC [005$8} The eDNA sequenMenceding the o heav anigbt ean vwaable egifon 1 the cabned anti .RCA ant M26RC02 anti GC2- a AM70PIA or at obuhns mK.RTCAP3, ant i.-PA.M.2Of TMEM1.54 mtonocdenal ntbodis are# -btinedifrnm the mtati htytionnws respectitete asng starzdard PCRk technaques and are sequence nsing standard DNA sequecng technI qos [0089) The nucl~odtde and ainO ard egunces the hef M v ihainariabie region nd o te ight hain varable region are deniineddhese senence> may he compared: to known human gemHie inuoglobu h t and heavy chainseuences and the. CDs of eesfl heat and t liafthe obtained an- KRTCA-P-1 anTA-M26F antiMO5249. ani FAM ?A ot antiT-IMEM 154 seq unones iemfi [00590] Characteiation Of Binding SpecicAy And Blin KIserics Of anti KRTTAPT anti-FAM26E ,ti-MGC$24 aJtVFAM70A or a I M M154 n Monoclonal Antibodes 24 [0059$1 Tho bindig aini. naln inetc bnding spoiitsad crsadonaett Ko, cf .and.dK1TCU'J3~ ha] AIMt M \. i a A . or aiJMLMM muabdieK ar exaitied bS Blue analdis. Also. binding speci city is examyined byv flew [005921 ninatntvadieis [59]And KRTCAP3. anti UA.MZ6F adW M4GCS "x antiAMi70A or anti '1 MEM 154 munbodies podiced accoring to de inveion wr' charactered foraffiities and binding neij by Bant i a wn (a Miame AB 'ppaIN. $weder Purned ecomibinautlumn KRT CAP.3 IAM2F NGCO9Z ia IiA or IMENM154. lsion protei is covalenti linked to a CM5 chip (CAsxy methyl derana cooled chip) via pmary anminetsing stadad almine cojninsg m nd kit provided I"sy oo .bding is measured Ibv providing the antibodies in lAUP Nufferi provided by RAcore AD) at a conentadon of 267 ,M aiN a fnow inme of a Uinin. The amtigen antibadl association kiliesC are followed for 3 mines and the dssociation kinetcs ae folrwed foE minutes. The association and oi iton CVes are -it to a .1:Langmumr inding eod using MAevaatimo. software (iacore AB). iniie the efthects of avidin the estination of the binding constants, only the ninid segments of data corespoiding to association and dilsscation phas are used f ittming [05941 Epitoipe Mapping of Obtained aniTRTCP3 and-FAMINP. andMCC2495 anti- FAMTA or ant-TMEM54 Andibodies 005951 Biacorm is uied to determine epitope grouping of antid-KRTCAP.3, anti FAM26Fh MGC5249h atimi-FAM70A or anti -TMEM154 antibodi are usedk to MAap fheepilrper an te K.ICAn PM26P, MGCt524% f,4,MLM0A oriM angen napetv Tn i these different antbodie ae oated on three d ferernt IrfacS of the same cai to 8000 U each Dshalos of each of the mAb are mdn stanin at 10 rrr'' -'nib adnd is incuaed with Pe ftned KRTCAP3 FAWM2I, MO 24 F4 IPAM7OA or TMEM 154 (50 nM) for one u The Ncubated etopa 1 inected over -d0 the ihme s ce5and anaak surface) w the same tirne for 1-5 minutes at a flow rate ni2 '0 niuLmm n. Sinal front each sotac a rod of L5 nitDiues, ar Subacdon <if pPr ae bks h been oted atgant concetntaUotof mAb in the corplx uporta m te dat ti ate (RTCAJP3, antpFAMd6R anti- ICia, anIIAM A or tiiTMElvi154 antihndes ae c htaured 'ad Cniemet epnope granpe ung n 01l pe map 11 ig rendt The tUi C properties uhcreof areaso campr [0L*5961 Chinese hamster ovary i(C1~H cell lines that es press K.RTCAP3. [AM26E. MGCS2498 PAM'OA or TMEM154 proten at the cel surfae are developed ad used to determine the speSciciy of the KRTCAP3, FAM26F, MGC52498, FAM70A or TMEM 154 HuMAbs by fow eytometry, CHO cells are transfected with expressko plasmid containing full length eDNA encoding t nesebane for-ms of KTCAPIVFAM26F, MGC52498, FAM70A or TMEMI4154 antigen er a ariant thereof. The. transfected proteins contained arn ephiope tag at the N- -termisnus are used for detection by a antibody speeCic for the ep$Iope, Bindig of ananw RCAP3. antiAM26E antiMGC2249h si-AM7OA or Hat IMEM 154 lAb i s sed by incubaig the rarsfetied cels wih each of the KRTCAM3, FAM26F MC52498 FAM71OA or TMEM 154 antibodies at a concenutian of 10 mie 11Cn ct. ei are as nd is de-ted v cted ids al IC-iabe le ant- -man igG Ab A a dne antihope ta A bfoawed by labeled ani-murine aG. is used as- te posite control N npreeii huan and utine Abs are used asnegaive contLa The oabmdned f idaa Peusd to assess the p y of the HuMAbs for the IKRTAP3 FAM26T. M-GCS24% AM70A or TMEM 14 antgen target. 00597 Thee anbodies- anud other -ntibodies to KRTCAP3. AM4 }AC25249, FMM7A or TMFM 154 psIgpeptides may x used i 4 e atredescred ant KRTCAP3 anPAM > wii--M6C5s498. ant AMOA or santMiiM A1154 related ei c such as VAment or cancers where KRTCAP3. FAM26PF N-C52498 FAM7A or TMEM154 antigen s differently cpesed such ascoar cancer. oeg cancer, east cancer kid ne career ever cancer. pancreatic cancer prostate cancer ea d heraoloasal ssuh as Mutipk Mv-elona. lynphna. Non Hudgmi 's Iyphoun, anti CL)D'eYtrn-a" erszt vpom.kuctn n 1cl uemi n vong tbe C APS A 26F M C249. FAM70A or TMEVIS 4 antices suh 55 the satl)5or ca ~ners -and inr ,ltnnttory w, autrarorntisems w heernc sucntihodies wil eW prevent eoae mu cell activity agn s dlesid target cancer cells or prevent the positive stimnlation of T cell aciviy temby elidciing ai cesnred anti-autonmmne ffect [005981 The intnon hs hees rbed r-d iophetc embodents pred relatia d KCAP3, ani-FAM26F. ani-MGC52498.

anitVAhi7OA OC aa:INt NIM1 aTibOdies for ose as (hempinoca and diagnoesic tntods: iea'~ the disease or condition o aoneiated tdh KRTCM.3 FAM2.6F GtW52498 which 0iR o Cw. a244

Claims (6)

1. A method of modulating the activity of a FAM26F polypeptide selected from the group consisting of SEQ ID NOs: 15-18 in the treatment or prevention of cancer, said method comprising use of a polyclonal or monoclonal antibody or binding fragment thereof that specifically binds to the FAM26F polypeptide to an amino acid sequence selected from the group consisting of SEQ ID NOs: 15-18, 52, 53, 117, 118, 127 and 149, wherein said cancer is selected from the group consisting of: ovarian cancer; breast cancer; prostate cancer; acute lymphocytic leukaemia; chronic lymphocytic leukaemia; acute myelogenous leukaemia; chronic myelogenous leukaemia; multiple myeloma; renal cancer; liver cancer; lung cancer; melanoma; pancreatic cancer; Hodgkin's lymphoma; and Non Hodgkin's lymphoma.

2. The method of claim 1, wherein said antibody or fragment thereof is used in combination with another medicament or therapy.

3. The method of claim 2, wherein said another medicament or therapy is selected from the group consisting of: radiation therapy; antibody therapy; chemotherapy; surgery; or in combination therapy with other biological agents, conventional drugs, anti-cancer agents, immunosuppressants, cytotoxic drugs, chemotherapeutic agents, or therapeutic agents targeting other complement regulatory proteins (CRPs) administered simultaneously or consecutively.

4. A method of diagnosing a cancer selected from the group consisting of: ovarian cancer; prostate cancer; acute lymphocytic leukaemia; chronic lymphocytic leukaemia; acute myelogenous leukaemia; chronic myelogenous leukaemia; multiple myeloma; renal cancer; liver cancer; lung cancer; melanoma; pancreatic cancer; Hodgkin's lymphoma; and Non Hodgkin's lymphoma, said method comprising detecting in a sample obtained from a subject the presence of a polypeptide and/or an over expressed level of said polypeptide having a sequence of a FAM26F polypeptide selected from the group consisting of SEQ ID NOs: 15-18 or a fragment thereof by using a polyclonal or monoclonal antibody or binding fragment thereof that specifically binds to the FAM26F polypeptide to an amino acid sequence selected from the group consisting of SEQ ID NOs: 15-18, 52, 53, 117, 118, 127 and 149, wherein said over expressed level is determined with regard to a normal level of said polypeptide in a corresponding normal tissue.

5. The method of claim 4, wherein said detecting is conducted by immunoassay. 247

6. The method of any one of claims 1 to 5, wherein said cancer is selected from the group consisting of: renal cancer; liver cancer; lung cancer; melanoma; and pancreatic cancer. Date: 13 October 2015 248