METHODS AND COMPOSITIONS FOR TREATING DEGOS' DISEASE The present application is a divisional application of Australian Application No. 2011223866, which is incorporated in its entirety herein by reference. 5 Cross-Reference to Related Applications This application claims priority to and the benefit of U.S. provisional patent application serial no.: 61/309,393 filed on March 1, 2010, the disclosure of which is incorporated herein by reference in its entirety. Sequence Listing 10 The instant application contains a Sequence Listing which has been submitted via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on February 25, 2011, is named ALXN153.txt, and is 61,625 bytes bytes in size. Technical Field The field of the invention is medicine, immunology, molecular biology, and 15 protein chemistry. Background Degos' disease (also known as Kohlmeier disease and malignant atrophic papulosis (MAP)) is a rare vasculopathy (around 200 reported cases) characterized by thrombosis in small to large vessels. See, e.g., Lester and Rapini (2009) Curr Opin Gastroenterol 20 25:66-73 and Englert et al. (1984) Br Med J 289:576. Although generally considered to be of unknown etiology, Degos' disease has been associated with viral infections (e.g., B 19 parvovirus and HIV) and autoimmune disorders such as lupus erythematosis (LE), dermatomyositis, and primary antiphospholipid syndrome (APS). See, e.g., Crowson et al. (2002) J Cutan Pathol 29:596-601; Englert et al. (1984), supra; Heymann (2009) J 25 Am Acad Dermatol 61:505-506; Durie et al. (1969) Arch Dermatol 100(5):575-581; Tsao et al. (1997) J Am Acad Dermatol 36:317-319; and Requena et al. (1998) J Am Acad Dermatol 38:852-856. Some forms of Degos' disease may be familial. See, e.g., Katz et al. (1997) J Am Acad Dermatol 37:480-484 and Penault et al. (2004) Ann Dermatol Venereol 131:989-993. Degos can occur in patients of any age, yet it appears 30 to preferentially affect men over 1 women at -a ratio of approximately 3 to 16 See eg, Katz et a(1997).supa; Torrelo et at (2002) Br J Dermat! :46,916-918and Wilson et. at (2007) Pea/wDermaaJ 241-824, Degos can naniftest as a benign partly cutaneous torn or as an aggressive, 5 nmutiorgan. systemic frm, the latter of which is generally fatal within one to twelve years after diagnosis. Scheinfeld (2007, Cli Erp Derm 32 483-487. The phenotypic hallmark of cutaneous Degos' disease is the appearance of one or more erythenmatous. reddish-colored papules on the skin, which papies scar over with white, atrophic centers. 10 Death occurs in nearly all patients with the systemic form of Degos' disease, the patients having an averagelifWe expectancy after systemic involvement of around two to three yeas, see eg. Schnfeld(2007), supr Patientsusually die from initestinal perforation with or without septic complications; however, death may aternatively rest from intestinal infraction, cardiopulaonary collapse, and/or 15 neurological infa reton and hemorrhage, See a Ha High et al.2004) Armcada Dermaol 5(6)895-899, A standard medical treatment tor Degos disease has not been defined Many therapeutic agents have had only agnianal and/'or inconsiste t success in treating the disease. Se. eg Scheinfeid (2007), sma_ For example, sone Degos patients beefited from intravenoUs immunogloutin therapy, but at present there appears to be no way of predicting which patients would aspond to such therapy ee, eg, Dyrsen et at (2008) 'Cuta Pa/ho! 35ISuppl I 20-25; Zhu et at1 (2007) Br I Derma i, i C 206-207; and De Breucker et at (2008) Ace (76n li g 6(99-102 (Abstrac) 25 infiew fcn the foregoing; it is clear that there is a need for new approaches and better methods to treat patients with Degos' disease. The present disclosure is based, at least in part, on the discovery by the 30 inventor that an inhibitor ot complement. namely the humanized anti-C5 antibody eculi zumab, was igh ly efflcacious in the treatment of a patient afflicted with the systemicr form of Degos' disease Aecordingly the disclosure features a variety of compositions and methods useful for the prevention and treatment of Degos' disease.
In one aspect, the disclosure proi des a method for treating apatient afflicted with Degos disease the rnethod comprising administerng to a patient aflicted with Degosi disease a complement inhibitor in an amount sufficient to treat the disease n another aspect the disclosure features a method for treating a patient 5 afflicted with Degos7 disease which. method includes chronically administering to a patient afflicted with Degosdisease a complement inhibitor in an amount and with a frequency sufficient to maintain a reduced level of complement activity in the patient to thereby treat the disease, n another aspect, the disclosure features a rtethod for treating Degos disease 10 the method comprising; identifying a patient as being, or likely to be, afflicted With Degos' disease; and adnitnistering to the patient a complement inhibitor in an amount suffiient to treat the disease, in another aspect, the disclosure features a method fo treating or preventing Mg. preventing the occurrence of Degosadisease or preventing the progression of the 15 benign cutaneous form of Degos' disease to a more a n -multiorgan and/or systemic form of the disease} The method includes administerng to a patient in need thereof a complement inhibitor in an amount sufficient to treat or prevent the disease, In some eitibodiiients he inhibitor can be chronically administered in an amorun t and with a fretency to maintain a reduced level of complement activation in the blood of 20 the patient for the duration of the treatment. In some embodinents of any of the methods described herein the Degos disease is associated with a Bi 9 parvoviral infection or human immunodeficiency virus intection Inu some embodiments, the Deg'os' disease is idiopathic. in some embodiments of any of the methods described herein, the Degos' 25 disease pathologically affets one or more o the gastrointestinal tract, the central nervous system, and the cardiovascular system. In some embodiments, the Degos disease is multiorgan.systenic Degos' disease i some embodiments, the Degos' disease is a cutaneous fnrm of the disease. In some embodiments of any of the inethods described herein.he Degos 30 disease is refractory to at least one therapy selected from the group consisting of an "nti-inflammatory agent an antioagulant, an anti throbotic and intravenous inmmnogiobiulin The antiniflammatory drg can be g, one selected fom the. group consisting of corticosteroids, phenylbutazone, azathi oprine, methotrexae, cyclosporinetacroimus and mycophenolate m"ofetii. The anficoagulant or antithrombotic can bee ne Selected from the group consisting of dlopidogrel aspirin, and dipyridamole in some embodiments of any of the methods described herein, the complement 5 inhibitor can be, eg, one selected from the group consists ofa polypeptide, a polypeptide analog a nuclei acid a nucleic acid analog, and a sma molecule. In some embodimnts, the complement nhiibitor can be, c. one selected from the group consisting of soluble CR1 LEX -CRI, MCP DAF, CDS9, Factor V cobra venom actor, FUT-75 complestatnand 176 C001-1. 0 In some embodiments of any of the methods described herein, the complement inhibitor inhibits the expression f a human complement component protein. In some enibodinents, the complement inhibitor can inhibit the. activity of a complement protein such as, but not limited to, complementcomponent Cis, cmplemen compontentr, the M owvertase, the CS eonertoaseer (5b-9. 15 in some embodiments of any of the methods described herein, the complement inhibitor inhibits the cleavage of human complement component C5 G4, C3, or C2. For example. a complement inhibitor can inhibit the cleavage of coniplemnent component C5 into fragments Ca and C5b In some embodiments, the complement inhibitor is an antibody or antigen 20 binding fragment thereof that binds to a human complement componet protein (e g, a CS protein), in some embodiments the antibody or atntigenbinding fragment thereof binds to the alpha chain of C5 protein" in some embodiments the antibody or antigen-biding fragment thereof binds to the beta ch.a in of CS. In some embodiments, the antibody or antigen-binding fAgmen.tthereot binds to the alpha 25 chain of human complement component C5 and wherein the antibody (i) inhibits comp ernent activation in a human body fluid, (ii) inhibits the finding of puified human complement component CS to either human complement component C3b or human complement component C4b, and (iii) does not bind to thm human complement activation product free C5a, In some emnodiments, the antibody binds to the human 30 conlement component C5 protein compising or consisning of the amino acd sequence depicted in any one of SEQ ID NOs: 1-26. In some enbodiments the 4 inhibitor is an antibody or antigenlbinding fragnent thereof that binds to complement comiponeWnIt CS fragment C b. :n some embodiments the antibody can be a monoclonal antibody In some embodiments, the antibody or antgendng fragmnt thereof can be one selected 5 trom the group consisting of a hnmanized antibody a reconbinant antibody a diabody a ehimerized or ch metric antibody, a deimnmnzed human antibody a lfly human atbody a single chain antbody an Fv fragment, an Fd frament, an Fab fragment, an Fa' fragment, and an Ftabb fragment In some embodients of any of the methods described herein the complement 10 inhibitor is eculizumab or pexelizumab, In yet another aspect, the disclosure features an article of mantacture. which contains a container composing a labeL and a composition comprising a complement inhibitor, wherein the label indicates that the composition is to be administered to a humn. avng ssperdof avngorat rsk for dcdping , egs' disease.. The 15 inhibitor can be, e g.. an antibody or antigen-binding fragment thereof that binds to a human complement comionent C5 protein The inhibitor can be e an antibody or antigen-bnding fragment thereof that binds to a fragment of human complement component C5 protein such as C5a or CCb In some embodiments the article of manufacttire inchides one or more 20 additional active agents such as, but not limited to, one or more anti-inflammatory agent, anti coaglants. or antitrombotic agents, The inventor also discovered that the Degos' patient described herein had elevated levels of inteffmn alpha vels in semrn as wcil as withinthe biopsied shin tissue While not being bound by any particular theory or mechanism of action, as 25 interferon alpha upregulates adaptive and innate immunlityotentiating the effects of any antigenic trigger, and administration of exogenous interferon alpha has been reported as a cause of cutaneous thrombosis and ulceration, the inventor believes that inhibiting interferon alpha is a useful strategy for treating Degtos' disease. Accordingly, in another aspect, the disclosure features a method for treating a 30 paient afflicted with Degos disease, the method comprisingadministering to a patient afflicted with Dego disease an inhibitor of interferon alpha in an amount sufficient to treat the disease. 5 In another aspect', the disclosure fea t ures a method o trat patient affected with Degos disease, the method compnsing chronically adrnistetug to a patient afflicted with Degos disease an inhibitor of interferon alpha in an amount and with. a frequency sufficient to maintain a reduced level of' interferon alpha activity in. 5 the patient to thereby treat the disease In another aspect, the disclosure features a method for treating Degos disease, which method incl udes: identifying a patient as being, or likely to be, afflicted with Deos disease:and administering to the patient an inhibitor of interfron alpha in an amount sufncient to treat the disease. 10 in another aspect, the dislostre features a method for treating or preventing (e.g,, preventing the occurrence of Degos' disease or preventing the progression of the benign cutaneous form of Degos disease to a more advanced, rnmitiorgan and/br systemic form of the disease) The method icludes admniszedng to a patient in need thereof an inhibitor of interferon alpha in an amount sufficient to treat or prevent the 15 disease. In some enibodimmnsthe inhibitor can be chronically administered in an amount and with a frequency to maintain a reduced levelof interferon alpha expression or activity in the blood of the patient for the. duration of the treatment. In some embodiments, the inhibitor of interferon alpha can be, e.g., one selected from the group consisting of a polypeptide, a polypeptide analog, a nuceie 20 acid, a nucleic acid analogand a small molecule, The inhibitor can.eg inhibit the expression of interferon alpha or an nterferon alpha receptor by a cell, The inh I bitor can. e, inhibit the activity of interferon alpha or an interferon alpha receptor protein. In some embodiments the irnhibi tor of nterferon alpha binds to interferon alpha In some embodiment, the inhibitor of interferon alpha binds to an interferon 25 al pha receptor. For example. in soen embodiments, the inhibitor of interferon alpha is an antibody (or an antigen-binding fragment thereof) that binds to interferon alpha or to an. interferon alpha receptor. Th.e antibody can be a monoclonal antibody, The antibody or antigen-binding fragment thereof can be.eg. one selected from the group consisting of a huanized antibody, a recombinant antibody, a diabody, a chirnerized 30 or chimeric antibody, a deimmsunized human antibody, a fully human antibody, a single chain antibody, ai Fv fragrnent, a d fragunent, an Fab fragment, an Fab tragment, and an Ftab )frarnent 6 In yet another aspect; the disclosure features an articde of nufacture containing a container c rpnu a abel; and a composition composing inhibitor of interferon alpha. wherein the label indicates that the comostion is to be adminisered to a human havingsuspected of having, or at risk tor developing 5 Degos disease, The inhibitor of interferon alpha can bee, g, any inhibitor ot interteron alpha described herein such as an antibody or antigen-binding fragment thereof that binds to interferon alpha or to an interferon rector In some embodiments, the article of manufacture incudes one or more addiona active agents such as/ but not umted to, an niuinianaatory agent, an 10 anticoagulant or an antithrombotic agent In some emabodmient the methods described herein can include admniistration (either as a 0sngle agent or in combination with a complement irdibitor and/or an interferon lpha inh ibi tori of a B cell-targeted therapy, For example the disclosure fatures a metod for treating or revn Degos disease, themethod 15 comprising admnistering to a patient having, suspected of having, or at rik fbr developing, Degos' diseaa therapeuniaily effective amount of a B celltargeted therapy The B3 cell4argeted therapy can be, eg an anti4D20 binding agent such as, but not limited to, antiCD20 antibodies. Exemlary therapeutic anti-D20 antibodieswhich are approved for clinical use or are in cynical development, that can 20 be used in the methods described herein include, without limitation, rituxima6 (Biogen [dec), tY-ibritumomab tuxeta(n e 1cc), 14losihuinoinab (CiaxoSmithKirne) ofatumrnumab (Genmab), TRU 015 (Trubion), veitrzumab (IMMU06; Ihmunomedics, ocrelizuiab (Rohe) and ANIME, I33v (Applied Molecutar Evolution) Se, e~g, Levene et at (2005) supra; Burge et A (2008) Olin 25 Th-n AQ(:180 6-1816; Kausar et at (2009 ) Expe't f Opn Biol Thet 998894895; Morschauser et aL (2009) J C/in Oncni 27{20L33463353 and Mvilani and Castillo (2009) CUr7 Opin Mo ThAer i):200207. In another example. any of the methods described hereineg, methods in which a complement inhibitor and/or an interferon apha inhibitor is administered to a 30 Degos' disease patient, the methods can also include administering a B cellbtargeted therapy such as an anti-CD20 antibody "Polypeptidej "peptide) and ',protein" are used interchangeably and .mean any peptide-linked chain of amino acids regardless of length or postetranslaional modification, The complement component proteins described herein (e ig compemeincomponent (2, C3, C4, or C5 rotens) can contain or be ldype proteins or can be variants thahve not more than 50 (e.g., not more than one, two. three, four five six seven, eight, nine, ten, 12, 15, 20, 25, 30, 35, 40, or 50) 5 conservative anino acid substitutions. Conservative e substitutions typically include substitutions within the following groups: glycine and alanine; vaNlne, isoleucine, and leucine; aspartie acid and glutamic acid; asparagine; glutamine, shrine, and tireonine; lysine, histidine and arginine; and phenylaanine and tyrosine The human complement componern proteins described herein aiso include 10 "antigenic peptide fugments" of the proteins, which are shorter than fulllength, immature (procpro) proteins, ut retain at least 10% (e. at least I0% at least 15%, at least N% at least 25%, at least 30%. at least 35%, at least 40 at least 50%, at least 55% at least 60% at least70% at least 80% at least 90% at least 95% at teas, 90% at least 9%, at least 99.50" or 100% or more) of the abili y of the full-length 15 protein to induce an antigenic response in a mammal. For example an anttigenic peptide fagment of C5 protein can be any Ragment of the protenwi is less than the fUll- length innmature protein and retains at least 10% of the ability of the fSll length protein to induce an antigenic response in a mammal . Antigenic peptide fragments of a complement component proteinchide terminal as weli internal 20 deletion variants of the protein. Deletion variants can lack one, two, three, fotur five. six, seven eight. nine, ten, 1, 1, 13, 14, 15, 16, 17, 18, 19. or 20 amino acid segments (of two or more amino acids) or non-contiguous single amino acids. Aneigiee peptide fragments can be at least 6 (e g.. at least 7, 8, 9 10, 1 12 3, 14, 15, 6, 17, 18 19,20, 21 22, 23 24, 26,27,28,29,30;31,32,33,34,35,37, 25 38 39,40, 41 42, 43, 44,45, 46, 47,48, 49 50, 55, 60 65, 70, 75,80, 85 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450500, or 6001' more) amino acid residues in length (eg, at least 6 contiguous amino acid residues in any one of SEQ ID NOQS~ I I n some emsbodiments, an antigenic peptide fragment of a huanm complement component protein is less than 500(egg, 30 less than 450, 400, 350, 325, 300, 275. 250, 225, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 655 60, 50, 49;, 4 4 46, 45, 44; 43 42 41, 409; 938, 37, 36, 35 34, 33 32, 31 30, 2, 28 226, 25 24,222 21 20 19, 18 17, 16, 15, 14, 13 12, 11, 10, 9, 8. or 7) anino acid residues in length (eg, less 8 than 500 contigiuous amino acid residues in any one of SEQ ID NOs- 1,n some emdbodirrients, an antigenic peptide fragrnent of a ftlengthiniaature huMi complement component protein (prepro-C5 protein)is at least 6, but less than 500; amino acid residues in length. 5 In sme embodiments, the human complem.ent component C5 protein can have an amino acid sequence that isor is greater than, 70e.g 7172, 73, 74.,7576, 77, 78, 79, 80, 81,,83, 84, 85, 86,S7, 8, 89, 90, 91.9293 94, 95 96, 9, 98, 99, or 100)% identical to the human C5 protein having the amino acid sequence depicted in SEQ ID NO, t0 Percent (%) amino acid sequence identity is defined as the percentage of arminoacids in a candidate sequence that are identical to the amino acids in a reference sequence after aligning the sequences and introducing gaps, if necessary to achieve the m n percent sequence identity. Alignment for purposes of determining percent sequence identity can be achieved in various ways that are within 15 the skill in the art or instance, usingpubhdy available compuer software such as BLAST, BLA T2, AG IN, AIGIN-2 or Megalign (DNASTAR) software. Appropriate parameters for measuring alignment including any algorithms needed to achieve maximal anment over the fUlength of the sequences being compared can be determined by known retiods, 20 Amino acid sequences for exemplary human C5 proteins as well as antigenie peptide fragments thareof are known in tle ait and ire set forth below As used throughout the present disclosure, the term "antibody" refers to a whole or iact antbodv(e. , IgM ,lgC. IgA 1gbor gI) molecule that's generated by any one of a variety of methods that are known in the art and described herein. 25 The term "antibodfincludes a poiyclonal antibody, a monoclonal anybody, a chimerized or chimeric antibody, a deimmnized human antibody: and a faily human anybody, The antibody can be made in or derived fmm any of a variety of Species, e mammalss such as humans, non-human primates (e.g, monkeys, baboons, or chimpanzees), horses, cattle, pigs, sheep, goats, dogs, cats. 30 rabbits, guinea igs gerbils, hamstersrats, and mice. The antibody can be a purified or a recombinant antibody As used herein, the term "antibody fragmenta "anti gen g m or similar terms refer to fragment of an antibody that retains the ability to bind to an 9 antigen fe g a complement component (5 potein). eg. a single chain antibody, a single chain Fv fragment (scFvan Fd fragment, an Fab fragment, an Fabt frgnent, or an F(ab) fragment. An scFv fragment is a single polypeptide chain that includes both the heavy and light chain variable regions of the antibody from which the sci is 5 derived. In addition, diabodies (Poljak 1994)Struaure 12121 1123; Hudon et a (1999)1 inmumni :Vehds 23(i 2:177-W9 the discosures of both of which are incorporated herein b reference in their entirety) and intrabodies (Huston et ai (2001) antibodies A0nt-4:1 l27-142 ; Wheeler ct al (2003 AM Ther 8(3 r355 366; stocks (2004) Dru N hreo v Toda q22f 9 66 the disclosures of each of 10 which are incorporated, herein by reference in their entirety) that bind to a counplernent component protein (egtg complement component C'5) ca be incorporated into the conpositiorns, and used in the methods, described herein., Unless otherwise defined, all technical and scientific terms used herein have 15 the sane meaning as comimoly understood by one of ordinary skill in the art to which this disclosure pertains. In case of conflict, the present document, inciting definitions, will control. Preferred methods and materials are described below. although methods and materials similar or equivalent to those described herein can also be used hi the practi cc or testing of the presently disclosed methods and 20 compositions. All publications, patent applications patents, and other references mentioned herein are incorporated by reference in their entity: Other features and advantages of the present discosure, eg, methods for treating or preventing Degoss disease vill be apparent frnn the flowing description the examples, and from the claims. Detailed Description The present disclosure provides compositions containing an inhibitor of human complement (eg. an antibody that binds to a human complement component C5 protein) and methods for using the compositions to treat or prevent Degos' 30 disease Whiein no yway intended to he initing exemplary compositions e.g pharmaceutical compositions and formulations) and Tmethods for using the compositions are elaborated on below and exemplified in the working Examples, 10 The Comalement Pathway The COamp ent systen acts in' conjunction with othemmunolo2cai systems of the body to defend against intrusion of eel Iar and viral pathogens. There are at east 25 complement proteins, which are Found as a complex collection of 5 plasma proteins and membrane cofactors. The plasma proteins make up about 10% of tne globulins in vertebrate seum, Complement components achieve their mnmune defensive functions by interacting in a series of intricate but precise enzymatic cleavage and membrane binding events, 1he resulting complement cascade leads to the production of products with opsonic, ind lytic A 10 concise summary of the biologic activities associated with complement activation is provided, for example, in The Merck Manual, 6 t Edion. The compenIent cascade progresses via he classical pathw a,,,-the alternative pathway, or the leetin pathway. These pathways share many components, and while they differ in their initial steps they converge and share the same "-teminali 15 conplement" components(C5 through C9) responsible for the activation and destrmction of target cells. The classical complement pathway is typically initiated by antibody recognition of, and binding to, an antuenic size on a target. cel The alternative pathway can be antibody independent, and can be initiated by certain molecules on 20 pathogen surfaces Additionally, the lectin pathway is typically initiated with binding of nmannosebinding lectin (MIBL) to high rnannose substrates These pathways converge at the point where complement component C3 is cleaved by an active protease (which is different in each pathway) to yield C3a and C3b Other pathways activating complement attack can act later in the sequence o'f events lea ding to various 25 aspects compienent function C3a is an anaplyatoxin Cb binds to bacterial and other cells, as well as to cetain viruses and imtntme complexes, and tags theni. for reinoval frormi the circulation. (C3b in this 'role is known as opsonin.) The opsonic function of C3b is generally considered to be the most inporiant antinfective action of the conplement 30 system. Patients with genetic sons that block C3b function are pone to infection by a broad variety of pathogenic organismswhile patients with lesions later in the complement cascade sequence 'ie. patients with lesions that block C5 functions, are 'I 'I found to be more prone only to iAfsseria infection, and then only somewhat more prone, C3b also fbrns a complex with other components unique to each pathway to form classical or alternative CS convertase, which cleaves C5 into C5a and C5b C3 5 is thus regarded as the central protein in the complement reaction sequence since it is essential to both the alternative and clssical pathways, This property of (b is regulated by the serum protease Factor i which acts on (13b to produce iC' \hi Ihc still functional as opsonin iC3b cannot form an active CS convertase. CS is a 190 kDa beta giobuhlin found in normal serum at a concentration of 10 approximately 75 pgIhL0.4 D ) C5 is glycoslated, with about 1.5 to 3 percent of its mass attributed to carbohydrate, Mature CS is a heeodner ofa 999~ ain acid 11 5 k),a apha chain that is ultide linked to a 655 amino acid 75 Wa beta chain. C5 is synthesized as a single chain precursor protein pmdu ct of a single copy gene (H aviland et a. 991) / !}nw! ! :3j62- 68 The eDNA sequence of the 15 transcript of this gene predicts a secreted pro -C precursor of 658 amino acids a1oJg with an 1,8 amino acid leader sequence (s e gUS, Patent No. 6355,245) The pro-5 precursor is cleaved after amino acids 655 and 659, to yield the beta chain as an amino ternnal fragmnt (amino acid residues +1 to 655 of the above sequence) and the alpha chain. as a carboxyl termiml fragment (amino acid residues 20 660 to 1658 of the above sequence) with four amino acids (amino acid residues 65k 659 of the above sequence) deleted b etwen the two, CSa is cleaved fkm the alpha chain of C5 by either alternative or classical C convertase as an ano teninal fragrment comprising the first 74 amino acids of the alpha chain (ie amino acid residues 664733 of the above sequence). 25 A pproxinately 20 percent of the I I kDa nass of 5a is attributed to carbohydrate. The cleavage site for convertase action is at, or unmediately adjacent to. amino acid residue 733 of the above sequence. i compound that would bind actor adjacent, to this cleavage site would have the potential to block access of the C5 convertase ezymes to the cleavage. site and thereby act as a complement inhibitor. 30 C5 can also be activated by means other than C5 convertase activity. Limited trypsin digestion (see egg, Minta and Man (1997). JImnnnu 1.119,15971602 and Wetsel and Kolb (1.98-2)FhwxnnumoI 128=20942216) and acid treatment (Yarnamoto 12 and Gewurz (1978) immunoI 1202008 and Damerau eat A(1989)Molimmuno! 2Q 1331142) can also cleave C5 and produce active C5b, Cleavage of C releases C5a, a potent anaphylatoxin and chemotactic factor, and leads to the formation of the iytic terminal complement complexC5b-9, (Oa and 5 (15$9 also have pleiotropic cell activating properties, b amplifying the release of downstream. inflammatory factors such as h enzymes, reacive oxygen spe at chidonic acid metabolites and various cvtoknes. Cb combines with C6 Ch. and C8 to form the Cib-8 complex at the surface of the target cell, Upon binding of several C79 moleculesthe membrane attack 10 complexMAC, C5b9 terminal complement complex-T CC is formed When sufficient nurnbers of M ACs insert into target cell mrenranes the openings they create ( MAC pores) mediate rapid osmotic lysis of the target ceIs Lower nonlytic concentrations of MAC can produce other ef'fbcts n particular membrane insertion of small numbers of the CSbd-9 complexes into endotheial cells and platelets can 15 cause deleterous eell activation. In some cases acuvation may precede cel lysis. As mentioned above(a and CSa are anaphylatoxins. These actva ted complement components can trigger mast cell degranulation, which releases histamine from hasophils and mast cells, and other mediators of inflammation, resulting in smooth muscle contraction, increased vascular permeability leukocyte 20 activatio, and otherinlmaoypeoeaicuigellrpoifatn resulting n hyper.eularity. Ca also functions as a chenotactic pepde that serves to attract proinflammatory granulocytes to the site of complement activation. C(A receptors are found on the surfaces of bronchial and alveolar epithehal cells and bronchial smooth muscle cells, C5a receptors have also been found on 25 cosinophiIs mast clls .onocytes, neutropils and aeivated lymphocytes The composiions described herein can contain an inhibitor of human complmenwnt. Any compound which binds to or otherwise blocks the generation and/or 30 activity of any of the humnif ompIement components may be utilized in accordance with the present disclosure. For example an inhibitor of complenient can be, eg, a small molecule a nueleic acid or nucleic acid analog, a peptidomnetic.or a macromolecule that is not a nuclei acid or a protein These agents include, but are 13 not limited to, small orgaiae molecules RNA aptamers, LRNA aptanmers. Spiegerners, antiserse compounds double stranded RNA, smallinterfeng RNA, locked n uclei c acid inhibitors, and peptide mieleic acid inhibitors. in some embodimentsacomplement inhibitor may be a protein or protein fragment, 5 .some embodiments, the composition contain antibodies specific to a human complement component. Some compounds include antibodies directed against complement components C L C2, (C3,4 (Ci(5 (or a fragment thereof; see below), C (2, C8, C9) Factor D; Factor Bs Factor , MDL. MASt 1, or MAStN2, thuns preventing the generation of tie anaphylatoxic activity assocated with C5a and/or 0 p ting sembly of the membrane attack complex (MAC) associated with (b. In some emd i bodiments, the nhibitor of cornpleTe inhibits the activity anior assembly of the (15-9 complex; For example; in soni embodiments. the inhibitor is an antibody or an antigenbins ing fragieut thereof that binds to one of C6,C? C8. 49,or C5b to thus prevent the assembly and/or activity of the MAC. 15 The compositions can also contain naturally occurring or soluble forms of compnlernent inhibitory compounds such as CRIE, LLXCR l, MCP, DAF, CD59, Factor H. cobra venon factor, F O[ 15. complestatin, and K76 COO-1 Other conpounds which may be utilized to bind to or otherwise block the generation and/or aciity ofay of the human complement components include, but are not Iimited to. 20 proteins, protein fragments peptides, small molecules, RNA aptaners including ARC 17 (vhich is commercially available from. Archernix Corporaion, Cambridge. 4AY ,.-RNA aptamers, spiegelmers, antisense compounds serine protease inhibitors. moleules which may be uilized in R NA interference (RNAi) such as double stranded RNA including small interfering RNA (si KNA). locked nuclei acid LNA) 25 inhibitors, peptide nucleic acid (PNA) inhibitors, etc, In some embodiments, the complement inhibitor inhibits the activation of compleneot, For example, the complement inhibitor can bid to and inhibit the complement activation activity of Ci e C qg C 1r or C2 ) or the complement inhibitor can bind to and inhibit (e g., inhibit cleavagw of) ( ' C3s or C4 In some 30 embodiments, the inhibitor inhibits formation or assenbl of the C3 convertase and/or C5 convertase of the alternative and/or classical pathways of complement In some embodiments, the conplcinent inhibitor inhibits terminal complement fornationeg, formation of the C5b-9 membrane attack complex. For examp an antibody 14 complement inhibitor may include an anti CS antibody, Such anti-C5 antibodies may directly interact with Cs and/or ib o as to inbibit the formation of aid/or physiologic function of (5b, In some embodnients, the compositions described herein can contain an 5 inhibitor of human compleent component C5 (e g an antibody or antigen-binding fragment thereof, that binds to a human complement component CSprotein or a biologicadlyactive fragment thereof such as GWa or (514 As used herein, an -inhibitor of complement component CS" is any agent that inhibits: (i) the expression, or proper itracellular trafficking or secretion by a cell, of a complement component 10 CS protein i) the activity of C5 cleavage fragments M~a or C5b (eg, the binding of CSa to its cognate cellularreceptors or the b nof C5b to C6 and/or other components of the terminal complement couple; see above); i the cleavage 0f a human C5 protein to frn Ca and C b or (iv) te proper intracelllar trafficking of; or secretion by a cell of a complement component C5 protein. Inhibition of 15 coiplenent comnponcnt C5 protein expression includes: inhibition of transcription of a gene encodng a human C5 protein; increased degradation of an nRNA encoding a human CS protein; inhibition of translation of an mRNA encoding a human CS increased degradation of a huMan CS protein; inhibiion of proper processing of a J), prepro human C5 protein; or inhibition of proper trafficking or secretion by a 20 celW of a human C5 protein, Methods for determining whether a candidates agent is an inhibitor of human complement component C5 are known ir the art and described herein An ihibitor of human complement component CS can beg, a small molecule, a polypeptide, a polypeptide analog, a nucleic acid, or a nucleic 25 acid analog. "Smal-molecule" as used herein is meant to refer to an agent. which has a molecular weight of less than about 6 .kDa and most preferably less than about 2,5 IkDa, Many pharmaceutical companies have extensive libraries of chemical and/or biological mixtures comnprising array ofsmall molecules, ofen fungal, bcter' or 30 algal extracts, which can be sreened with any of the assays of the application This application contemplates usingni, anong other things, small chemical ibraries, peptide libraries, or collections of natural products. Tan et at described a library with. over two million synthetic compounds that is compatible with miniaturized celbi-ased 15 assays Q~n C hem Soc (1998) 12:85654566, [t is within the scope of this appotr that such library may be used to screen br ihibitors of hman complement component C5. There are numerous commercaloy avaibe compound libraii.es, such as the Chembridge DIVERSet. Libraries are also available from academic investigators, such as the Dixersity set from the N( developmental therapeutics program, Rational drug design may also beeiployed. For examnl, rational drug design Can employ the use of crystal or sol uIon structural inforaation on the human complment componentC5 protein, See, e g, the structures described in Btageman al (2008)J BiOCeIn 2 2):763-75 and Zuiderweg et al. 0 989) It) Bith nmisti' 28( 172--85. Rational drug design can also be achieved based on known corn pounds- e,., a known inhibitor of CS (e.g. an antibody, or antigen bindng fragment thereof that binds to a human complement component (15 protein). Peptidomimetics can be cornpounds in which at least a portion ofa subject polypeptide is modifed, and the three dimensional struttirc of the peptidomimetie 15 remains substantially the same as that of the subject polyeptide, Peptidoniimetics may be analogues of a subject polypeptide of the di scosure that are, thmevs polypeptidcs containing one or more sustitutions or other modifications within the subjet pyppTide sequence. ternaively at let abortion of the subject polypeptide sequence may be replaced with a non-peptide structuresuch that the 20 three-dimensional structure of the subject polypeptide is substantially retained. In other words, one, two or three amino acid residues within the subject poiypeptide sequence may be replaced by a non-peptide structure, in addition, other peptide portions of the subject polypepideny but need no'b repice vt a non-peptde structure. Peptidomimeties (both peptide and nonpeptidyl analogues may have 25 improved properties (e.g, decreased poteolysis increased retention or increased bioavailability) Peptidommetics generally have improved oral availability, which makes them especially suited to treatment of disorders in a human or animal. It should be noted that peptidomimeties may or may not have similar two-di.mensional ciem ical stracttues, but share cormon three-dimensional structural features and 30 geometry, Each peptidomimetil may further have one or more unique additional binding elements. Nucleic acid inhibitors can be used to decrease expression of an endogenous gene, e g a gene encoding hunan complement component C5. The nucleic acid 16 antagonist can be. e~. an siRNA. a dsRNA. a ribozytme, a trip leheix former an aiptaine. or an antisensucei acid, siRNAs arc small double stranded PRNAs (dsRNAs) that optionally include overhangs, For example, the duplex region of an. siRNA is about 18 to 25 nucleoides in length eg, about 19, 2 2. 223, or 24 5 nudeotid.s in length The siRNA sequences can bein soin embodints exacty comnplenentary to the target rRNA. daRN s and siRNAs in pardculr can be used to science gene ecpreo in mamnahan eeS (g, human e Seg Clemens et a (2000) Pre na Acadi USYS 0490 3; lfly et afl,4(200 re1 N atd ,pad Sc'i / 5 $ y 442814433; Elbashiyr et a1C(2001) Nature 41 1:494-8; Yang et al. 10 (2002) Pime Ad ACadSci USA 99:9942-0i47 and S Paten t Application Publication Nos. 20030166282, 20030143204, 20040038278 and 20030224432. Anti-setnse agents can include, for example, farm about 8 to about $0 nucleobases (ie front about 8 to about 80 nucleotides) e g, abo to about 50 nucleobasesor about 12 to about 30 nucibases. Antisense compounds incide ribozymes, cxterna. guide 15 sequence (EOS) oigonuceotides (oligozynies, and other short catalytic RNAs or catalytic oh gonucleotides which hybridize to the target nucleic acid and modulate its expression. Anti-sense compounds can include a stretch of at least eight consecutive nucleobases that are complementary to a sequence in the target gienes An oligonucleotide need not be 100% complementary to its target acid sequence 20 to be specifically hybridizable. An oligonueleotide isspecifically hybridizable when binding of the oligonucleotide to the target interferes wth te normal function ot the target molecule to cause a loss of utility. and there is a suficient degree of cornplemnentarity to avoid0 non-specifh i bildilig of the oligonudieotide to nonstarget sequence under conditions in which specific binding is desired. i.e. under 25 physiological conditions in the case of in wivo assays or therapeutic treatment 0, in the case of in vitro assays, under conditions in which the assays are conducted, Hybridization of antisense oligonucleotides with mrnRNA (e.g- ain RNA encoding a human C5 protein can inteffere with one or more of the nonnal functions ofniRNA. The functions of inRNA to be interfered with include all key functions such as, for 30 example. translocation of the RNA to the site of protein translation, tanslation of protein from the RNA, splicing of the RNA to yield one or nore mRNA species, and Latalytic activity which may' be engaged in by the RN A Binding of specific protein(s) to the RNA may also be interfered with by antisense oligonucleotide 17 hybridization to the RNvA. Exemplary anisense compounds include DNA or RNA sequences that speciicaly hybridize to the target nuclei acid, e.g- the niRNA encoding a hw.nan complement component 5 protein, The complementary region can extend for between about 8 to about 80 nucleobases, Tlhe compounds can include 5 one or more modined nucleobases Modified nucleobases may include e.g., 5-substituted pyrinidines such as 5 iodouracil, iodocytosine, and Cpropynyi pyrimidines such as Cypropvnylcytosine and Cpropyniuracil, Other suitable modified nucleobases include. eg g sudbst d-stieddearapurines such as, for i0 example, 7-iodo-7- deazapunines cio deazapurines7-aminoearbonyl-7 deazapurines, Examples o n these include 6~amirio-iodo-7deaznprins 6-asninou cyano-deazapurines. 6- amino~- aminocarbony V-deazapuri 2a\ muinod hyvdroxy-7-iodo-7deaza putiines. 2- amijno-6~hydroxy 7Ycyano diazaipurines. and 2~. arnn-o~hvdrox v. arninocarbon yl-7-.deazapurines. See egg. U SPatent Nos, 15 4,987,071; 511 IC741 and 5093)246;"Antisense RNA and DNA DA. Mehon, Ed. Cold Spring Elarbor Labotaory, Cold Spring Harbor. N.Y. (4988) Haselhof and Gerlach (1988)aM ;45559 Helene. C. (199 I) AnticancerLrng D 6:569-84; Helene C1992) Ann NY Acad S 6602716; and Maher ,992) Bbwssai 807.IS Aptamers are short oligonucleotide sequences that can be used to recogize 20 and specifically bind almost any molecule, including cell surface proteins, The Systematic evolution of Iigands by exponential eT.nichnt (ELEX) process is powerful and can be used to readily identity such aptanerms Aptamers can be made for a wide range of proteins of importance for therapy and diagnostics uch as growth factors and cell surface antigens. These olionudeotides bind their targets with 25 similar affinities and specificities asantibodies do, See e. Urich (2006) Hanidh Exp Pharnacol 473:305 -326, in sone ernbodimirents the inhibitor of huma. (1C5 is an antibody or antgen binding fragment thereof which binds to a human complement component C5 protein (Hereinafler, the antibody rnay sometimes be referred to as an "anti-C5 30 antibody") i some embodiments, the anti-CS antibody binds to an epitope in the human pro-E: precursor protein.. For example, the anti-C5 antibody cai bind to an epitope in the human complement component C5 protein comprising, or consisting of, the amino 18 acid sentence depicted in SEQ ID NO:d (NCBI Accession No, AAA51925 and Flaviland et A, lypr), An "epitOpe" refes to thite 01 a protein eg a hnman compement component C5 protein) that is bound bn antibody 'veapping epitopes include 5 at least one (eg, two, three, four, fv eor six) common amino acid residue(s) in some enbodinents, the anti ( antibody binds to an epitope in the human pro&$ precusoprorotein iackng the leaderr sequence. For example theantiC5 antibody can bind to an epitope in the human complement component C5 protein comprising, or eonslsting ofthe amino aid sequence epicted in SEQ 11) NO:2, 10 which is a human C5 protein lacking the amino terminal leader sequence, In som embodiment the antxC antibody can bind to an epitope in the alpha chain of the human complement component CS protein [or example, the a ntiC5 antibody can bind to an epitope within, or ovedapping with, a protein having the amino aidJsequence depicted in SEQ ID N0 O hich is the hunan complement 15 component C5 alpha chain protein. Antibodies that bind to the alpha chain of1 ar e described in, for example. Ames et al.(994)Jhnanuno/I52458LjS in some embodiments, the anti-CS antibody can bind to an epitopc in the beta chain of the human complemen component C5 protein. For example the anti-C S antibody can bind to an epitope wthin, or overlapping with a protein having the 20 amino acid sequence depicted in SEQ ID N0:4, which is the human complement cononent CS beta chain proton Antibodies that bind to the C5 beta chain are described in....g..ongkarndi et al (1982) Tmmuncabiol 162:397; Moongkarndi et al. (1983) Jwnmamobioi 165323; and Molnes et at. (1988) Scand !hnumo! 2307 3~12,. 25 in some embodiments, the anti-C5 antibody can bnd to an epitope within or overlapping with, an antigenic peptide fragment of a human complement component CS pmtein. For example he anti45 antibody can bind to an. epitope within, or overapping with, an antigen peptide fragment of a human complement component C5 protein, the fragment containing, consisting of, the flowing amino acid sequence: 30 V DHQGT.KSSKCVRQKVEGSS (SEQ ID NO5 or KSSKC (SEQ ID NOW. in some emibodiments, the anti-C5 antibody can bind to an epitope within, or ovedapping with, a fragment of a human complement Component (7 protein, the fragment containing, or consistng of, any one of the following amino acid sequences 19 (which are exemplary antigenic fragments of SEQ ID NO: : NFSETWFOKEH WVKT L sVVPEGVKR ESY SGVT LDPRC YGTI SRRKEF PYRUP LDLV PKT Ei KRILS VKOL V GEl LSA VESQEGIN I[ LI!PKG. ROSA EA ELMSV VP VF YVFHYI ETONH WNIFHSD (SEQ ID NO:?); 5 SESPVI DHQGTKSSK KVRQKV EG0SSSHLVT'FTVLPLEIGJlHNINFSLETWFGKEII LVKTL..RVVPEGVKR ESYSGVTLDPRIYTISRRKEPYRIP LDLVPKTEIKR.IL SVKOLL VG EISA VLSQ EIN IIHLPKSAEAELMSVVP VFYVFHVELETGNH WN FliSDPtEKQKLKKKLKECML SMSYRNADYVSYS (SEQ ID ND:8); SHKDM IQLGilMETiLPVSKPEIRSYFPES (SEQ ID NO% 10 SHKDM QLGRL HM[KTLLPVSKPEI RSY FES WLWEVHLVPRRKQLQFALPDSL TTWEQI I SNTIC(VADTVKAKVFKDVFLE MNIPYSYVRGEQQLKCTVYN YRTS GMQ I KMSAV[C. CTSESlVI lDHQCTKSSKC VRQ KVEOSSSHILTFL VTTV LPLEIGLHNINFSLET WFC KEILVKTI. RVVPECKRESYSOVT[ )PRC]YG'IISR RKEFPY R.I LDLVPKTEI KR I [S VKCLL VGE ILSA VLSQEG IN ILTiFHi. PKCSAEA.E 15 LM\VVPVFYVFHlL ETGNHWNIFHSDPUEKQKLKKKIKEM SI MSYRN A D YSYS (SEQ ID NO: 1)and I)HQGTKSSKCVRQKVEG (S EQ IT) NO Ili Additional exemplay antigenic fragments of human complement component CS are disclosed in e g., U S Patnt No. 6,355,245, the disclosure of which is incorporated herein by reterene. 20 In some embodimets, the ant i<5 antibody specially binds to a human comnplement component C5 protein (eag, the human C5 protein having the arno acid sequence depicted in SEQ D NO: 0V The terms "specific binding" or "specifically binds" refer to two molecules foning a complex(egacomplea between an antibody and a complement component C5 protein) that is relatively stable under 25 phyoloc is ordered specific when the association constant (K is high than I0* M Thus, an antibody can specifically bind to a C5 protein with a K, of at least (or greater thar) IV(, (e.g. at least or greater than 10i 10 A 10, 1w 10 104 l0or W>or higher) M Examples of arnibodies that specifically bind to a human complement components protein are 30 describedin. eg. 1S Latent No. 6355 145 the disclose of which is incorporated herein by reference in its entirety, Methods for deternmirngy whether an antibody binds to a protein antigen and/or the affinity for an antibody to a protein antigen are known in the art, For 20 example the binding of an antibody to a protein antigen can be detected and/or quantified g a arety of techques such as, b.t not I nted to. Wester blot, dot blot, plasman surface resonance method (eRg BIAcore system; Pharmacia Biosensor Aaa Upps~a Wedon and Piscataway, N.II or enzymie inked immunosorbenz assays 5 (EUSA) See cg Harlow and Lane (1988) "Antibodies A Laboratory Manual" Cold Spring Harbor Laboratory Press, Cold Spring Harbor N.Y. Benny K. C. Lo (2004) "Antibody Engineering: M4 methods and Protocols' Humana Press (ISBN: 158829092 1) Borrebaek (1992) "Antibody Engineering, A Practical Guide? Wii Freeman and Co N; Borrcbaek (1995) "Anntibody Eng.neringu'2Edi tionL 10 Oxford University Pres NY Gxfbrd; Jobne et al (1993)Jhpmc o Mesh 160:191 198: JonssontL(nsson et al. (1991) Biotechniques II2 -2/ See aM S Patent No.i,355245 In some embodimets the anti-(5 antibody can crosblock binding of another antibody that binds to an epitoe within, or overlapping with a human complement 15 cononentC5 protein. In some embodiments, the antiC5 antibody can crossblock binding of an antibody that binds to an epitope within,or overapping with, a peptide fra gment of a human complement Component C5 protein. The peptide fragment can be a fragment of a human complement component CS protein having the amino acid sequence depited in any one of SEQ ID) NOS:-I For example the peptide 20 fragment can contain, or consist of. the following amino acid sequence: 'IDHIQGTKSSKCVRQKVEGSS (SEQ ID NO:5). As used herein the term "erossblocking antibody" refers to an antibody that lowers the amount of bindinn of an ti-C antibody to an epitope on a complement component C5 protein relative to the aniount of binding of the anti-C5 antibody to the 25 epitope in the absence of the antibody: Suitable methods br determining whether a frst antibody crosblocks binding of a second antibody to an epieare known in the art. For example, erossbiocki.ng antibodies can. be identified by comparing the binding of the 51L 1 anti -C5 mornoclonal antibody (produced by the hybridoma cell ine ATCC designation HB-i 1625;ce US. Patent No, 6,355245) in the present and 30 absence of a test antibody, Decreased bindingofthe 5G 1 antibody in the presence of the test antibody as compared to binding of the 5G1C antibody in the absence of tnetest antibody indicates the test antibody is a crossblocking anybody, 21 Methods for identifying the epitope to which a particular antibody (eg.an anti-C5 antibody) binds are also known in theat.Fo example tbe bndmg epitope of an anti-C5 antibody can be ide-ntified by measuring the binding of the antibody to ever'a (e.g., three, four, five, six, seven, eight, nine, 10, 15, 20, or 30 or more) 5 overapping peptidle fragments of a complement component C5 protein (cetg several overlapping fragntcs of a protein having the amino acid sequence depicted in any one of SEQ ID NOs:M 11) Each of the different ovedapping peptides is then bound to a unique address on a solid support, eg. separate wells of a multi-webl assay plate Next the anti-CS antibody is interogated by contact it to each of the peptides in 10 the assay plate tor an namounit of time and under conditions that allow for the antibody to bind to its epitope. Unbound anti-Ct antibody is removed by Washing each of the wells. Next. a detectably~1abeied secondary antibody that binds to the anti-CS antibody if present in a well of the pate, is contacted to each of thewells and unbound secondary antibody is removed by washing steps he presence or amoutt 15 of the detectable signal produced by the detectablydabeled secondary anybody in a well is an indication that the anti-CS antibody binds to the particular peptide fragment associated iith the well Se, egd.. oarow andLane (supra) Benny K, C, Lo (supra), and US. Patent Application Publication No. 20060153836, the disclosure of whicl is incorporate by refene in its ire A particular op to which an antibody 20 binds can also be identified using BlAcore chromatographie techniques (se. oeg. Pharnacia BiAtechnology Handbook, "Epitope Mapping'Section 6.32 (May 1994); and Jolme et aL (1993).,J"nd Ad/hods I60 Y2)190 -8) The anti-C5 antibodies described herein can have activity in blocking the generation or activity of the CSa and/or Cb active fragments of a complement 25 component CS protein (eg. a human C5 protein), Through this blocking effet; the anti-C5 antibodies inhibit, e g., the proinhaminatory effects of CSa and the generation of the CSb-9 membrane attack complex (MAC) at the surface of a celfI Anti-C5 aibodies that have the ability to block the generation of C5a are described in, edg.. Moongkandi et a (1982) hnamunub 162397 and Moongkarni et a (1983 30 Tmninobind 165:323, In some enbodinents, an anti-C5 antibody, or antigen-binding fragment thereofcan reduce the abilty of a C5 protein to bind to hunnan complement component C3b (eig, C3b present in an AP or CP C5 convertase complex) by greater 22 than 50 (esg, greater than 550, 65 70, 75, 80, 85. 90. or 95 or more) % in some enaibodirnent, uponbindig to a C5 protein the aTnti-C antibody or anteigmi-biiding fragment thereof can reduce the ability of the CS protein to bind to complement component oCb (e g, C4b present in a CP CS converted) by greater than 50 (eg 5 greater than 55. 60, 65, 70 75. 80. 85 90, or 95 or more) %. Methods for determining hviet her an antibody can block the geneation or activity of the C5a and/or CSb active fragments of a complement component C5 prote o ing complement component C4b or C3b are known in the art and described in. eg US, Putpnt No6 6355a45 and Wurzner Ct a. (1991) cmemnu n 2 340 to In some embodiments an antiC5 antibody binds to an amino-terminal region of the alpha chain of a complement component C5 protein. but does not bind to free C5a Epitopes tor an antiC5 antibody within the amino-tenninalregion of the alpha chain inchdee 'g eNites Wthin the human sequence VIDHQT(KSSKC VRQK VEG SS (SEQ ID NO:5 15 In some embodiments, the composition comprises, and/or the antibody is, eculizunab (Soliris@; Alexion PharmaceticaisInc, Ches.i re, (CT). Sie a Kaplan (2002,) Curr Gm p hvesfig Drugs 37:101>23; Hill (2005) Cin A Henadto Oncol 3(1 1849-50; and Rother et at, (200/ vature Blienology 25f 11:1256 148&) 20 In some embodiments, the eompo\ition compises, and/or the antibody is, pexelizumab Al n Pharmaceuticalsnc, hic shie CT), See e,g Whiss (2002) Curr wp /nvesig [)rugs 268707; Patel et al 200) Dg ody /HC Bare 44(31 165-70; and Thomas et (1996) Moi1mmuno!31-81389-40 1 In some embodiments, the C5 inhibitor is an antibody that binds to C5a 25 (sometimes referred to herein as "an ani CS a an tbody In some embodiments, the antibody binds to Ca, but not to fuliength C5, As discussed above, the profomi of CS, a 1676 amino acid residue precursor protem, is processed by a series of proteolytic cleavage events, The first 1.8 peytides (numtbere.d - 18 to -1 constitute a signal peptide that is cleaved from the precursor protein The remaining 658 amino 30 acid protein is cleaved in two places to form the alpha and beta chains, The first cleavage event occurs between amino acid residues 655 and 656 The seco-nd cleavage occurs between amino acid residues 659 to 660. The two cleavage events result in the formation of three distinct polypeptide fragments (i) a fragment 23 comprising amino acids I to 655 which is refetred to as the beta chain; (ii) a fragment cOmpusing ammo acids 660 to 1658, which is rTefrred to as the alpha chain; and (iii) a tetrapeptide fragment consisting of amiiino acids 656 to 659, The alpha chain and the beta chain polypeptide fiagnents are con nected to each other via diside bond and 5 constitute chnatue C5 protein. The CP or AP C5 eonvertase activates mate C'5 by cleaving the alpha chain between residues 733 and 734 which results in the libuation of C5a fragment (amino acids 660 to 733), The remaining portion of mature C5 is fragment C 'b which contains the residues 734 to 1658 of the alpha chaindisufide bonded to the beta chain. 10 I v1vo u5a is rapidly metabolized by a semrm enzyme.arboxypeptidase B to a 73 aino acid form teried "C.3a deArg which has lost the carboxyteminai arginne residue, Acconngly in some embodimentsan antibody that binds to C5a also binds to desarginated C a some embodimnents, an antibody that binds to C5a does not bind to desarginated C5a, 15 In some embodimenta the C5 inhibitor is an antibody that binds to a neceptope present in C5a Le, an epitope that becomes exposed upon the iberation of 5a from the alpha chain fragment of mature C5, Antibodies that bind to C5a ( .aneo-eptope present in CSa) are known in he art as are methods for producing such antibodies. For example. an antibody that binds to (lIa can have the binding 20 specificity of a C5a neoepitope specific antibody described in any one of. eigPCT Publication No, WO () !5 73 I Ames et a (1994} / amnunol :52(9)45724581 Inoue (1 989) pleienncntflkamn 6 3)2 92Z; ad U.S, Patent No. 6,661845 in another example, an antibody that binds to CSa can have the binding specificity of a commercial C5a neoepitope-specific antibody such as, but not limited to. sc-5263 25 (Santa Cri Biozecnology, Inc Sant Cru Calfomia)152-1486 (BD Pharmingen/BiD Biosciences). ab 11877 (Abcam, Cambridge, Massachusetts), and 1M2079 (clone 2952; HyCul Biotechnology, the Netherlands), ha some embodiments, an antibody that binds to C5a can crossblock the binding of any of the atoremienoned C5a neoepitopespecific antibodies. 30 In some embodiments the CS inhibitor can be an antibody that binds to a mamman g e human) (a protei. For example, the antibody can bind to a human C5a protein having the following amino acid sequence: 24 'TLQKKIEEIAAKY KHSVYVKKCCY DGAC VN NDETCEQRAARISLGPRCIKAFTE (CVVASQR VANISHIK.DMQI.G R (S EQ ID NO: 12). The antibody can bind to human C'a at an epltope wihn or ovedapping with the amino acid sequences CCYDOACVNNDETCEQRAAR (S EQ FINO:13); KCCYDGACNNDET CEQR 5 (SEQ ID 0:4); NND ETCEQR (SEQ ID NO:15) VNNDEf(SEQ D NO: 16); AARISLOPR (SEQ ID NO;17) (tYDGACVNNDETCEQRAA (SEQ ID NO:'d1); CCYDOACVNNDER EQRA (SEQ I D NO:'9; "'Y DGACVN NDETCEQR (SEQ D0NO:20); CCV DOACYVNNDET[CE.Q (SEQ :lD ND:21; CCYDGACVN;NDETCE (SEQ D NO:22)'; CYDGACVNNDETCEQRAAR (SEQ ) N 10 YDGACVNNDETCEQRAAR (SEQ ID NO:24); or CYDGACVNNDEfCEQRAAR (SEQ ID NOd25). In some embodimentsan antibody can hind to a hunan C5a protein or fragment thereof containing an amino acid sequence that contains, or consists of at least fotur (e"a. lease tour fivc six, seven, eight nine, 11, 12, 13, 14 15 16 or I7or more) consecutive amino acids depicted in any one of SEQ ID 15 N Os1, 2-5 Additional C5a protein fragments to which a natibody described hereiT can bind and rnethods tor generating suitable C75&specine antigen combining sites are .set forth in, e g. U.S. Patent No. 1466100. the disclosure of which is incorporated herein by reerene nits entirety Insonic enmbodiments, the binding of an antibody to (Ia can inhibit the 20 biological activity of C5a. Methods for measuring C5a activity indude eg. chemotaxis assays, RiAs, or ELISAs (see, e g., Ward and ZAiler (1971) J Ci Invest 50(3}60616 and Wurzner et aL(1991) Complmnt Jnflann 8:328440). in somie einbodinmerts, the binding of an antibody to C5a can inhibit the irnteracton between Cia and C0aR1 Suitable methods for detccting and/or measuring the 25 interaction between 75a and C5aRl (in the presenceand absence of an tibod are known in the art and described in, e.g, Mary and Boulay (1993) Eur Hlaexmatol 5c'22~287 Kaneko etGat (1995) hwmunalogy 61:49 154; (iannini et al, (995) /Biol Che 220(2:191 66 191 72; and US, Peatant.A pplication Publication No, 20060160726, For example, the binding of detectably labeled (e.g, radioactively 30 labeled) C0a to C5aR 1 expressing peripheral blood mononuc ear eel1 can be evaluated in the presence and absence of an antibody; A decrease in the amount of dtectably-labeled CSa that binds to C1a1A I in the presence of the antibody, as compared to the amount of binding in the absence of the antibody is an indication that the antibody inhibits the interaction between C5a and CaR L In some en ibodirnents, the bitdng of an ant ibody to CSa can inhibit the interaction between C'5a and C5-2(see below); Methods for detecting and/or measuring the interaction between C5a and C5L2 are known in the art and described in, eg. Ward (2009) I.Moi 5 Med 874:375378 and Cfhen et aL (2007) Natre 4471 -32;203207(see below In some embodiments, the C5 inhibitor is an antibody that binds to C'% (sometimes referred to herein as "an anCi.O5b antibody In some embodiments, the antibody binds to Cb, but does not bind to fulength C5. The structure of CSb is described above and also detailed, MilIer~Eberhard %5) Bio<hem Soc Sym 10 10:235246, Yamiamoto and Ge wurz (17) /inuno! 1206:2008-2015; and Hlaviland et al~ (1991 ) supra. As described above. Cb combines with C76. C'7 and (8 tiform the C'sb S complex at the surface of the target cell. Protein complex intermediates formed during the series of combinations include Ctb-6l (including C~b and ('6), (10 (including b C6, and C71 and 5b8 (including ('5b. C6 (7, and 15 CY Upon binding of several C9 molecdes, the membrane attack complex (M1 AC, COb-9 terminal complement conpex (TCC) ) is fored. When sutcient numbers of MACs insert into target cell membranes the openings they create (MAC pores) mediate rapid osmotic lysis of the targetcells. lh some embodiments the binding of an antibody to C(5b can inhibit the 20 interaction between C5b and C6. In some embodiments, the binding of the antibody to COb can nhibit the assembly or active of the CS b-9 MAC-TCC Insome embodiments, the binding of an antibody to Cb can inhibit complement-dependent cell lysis (eigin viMt and/or in iva) Suitable methods for evaluating whether an a dy inhibits complement-dependent lysis include ego. hemolytic assays or other 25 functional assays or detectig theactivity ofsohible C5b-9, For example, a reduction in the cellysing ability of complement in the presence of an antibody can be measured by a hemolysis assay described by Kabat and Miayereds ) "Experimemntal 1munoehemistry 2 Edition," 135-240, Springfield, IL, CC Thomas (1961> pages 135-139 or a conventional variation of that assay such as the chicken 30 erythrocyte hemolysis method as described in. eg. Eillmen et al, (2004)N Eagl Med 350%6:552. Antibodies that bind to C(b as well as methods for making such antibodies are known in the art. Sec. eg, LIS, Patent No. 6355245. Commercially available anti 26 C:5b ae -,,ailabt f'4na tnulmer ot vendors inchtdig og., F lycult r~~v~(calalogue nter: JIM,208(X, cioai 568) and Abcwnm'hY (a 46 1 5 I or in sone enboninents, the C5(iS ttr I'S anl ant''ibody that. binds: to a 5 Namana (e,. humai Eowm of C D%, For examinple. thec armhodv can bidto a porticm of' ai liman nm poteini having th oiwgaim no acid sequence: (1OSPDKISNPR1 MX.I IKAKY KLD-,[FST,-I-'(I'AY FIX KIYVLPHESMSIEP"EY NE I CY K NE" ('N H TII K A RY F'YNK A,9.TfHlA DV YI'POITI R E',D 1 K 1) DQ K IMQN IV1TA M QNTM UN(Ii IAYT F DSVIA VKEL S 7XS [FDLNNK ML Y A-%VTVI'S'OSFF I PC KY ESYKUEMAI SEPGIYP KMQKDSLDQLA- VOGY PVILNKNQTID MN,\QET'rSDLWFISKS VTRI>VD.DC VASE VI'.. ' 1 ',N.LJF56 VT,"lV 1--F LENY K-ID-'-[AB.D[I EE NQA, L.S K'K4CI ii] fl ;-k-';'R ; LFS D ASYQS IN IF VTQ1'"'NMV P35 L>'S.', [MYRIIEQITAF IMSD S VEN'IL .KCNQQVFLSPA DYSPQIVSLNMA( %,AIDS WV AAVDS .AI)DSQE NF DE POKEALF(SEQINr4.I.oeemotnsheaiod can NitICYAIMMKAVFK ME LM IP'S V EQIQ KO' N YRIS ,MQFCV .22 5 I N.KTIEl I RI IESVK-G(WE VO El ESAMLSOCI N I F'iLPSAAEMSVVIZ X QYQI KE;QOT U L>"V 'EAR'EN ,SE VET'A.FT VICGIRKAFF)ICPl'LV tD KA 11ThI FEL NTEf..P.AQSTETL-A ISAVYA [,SFDTPFSIVA[ EAFKNPYFK 30 NIEQHKI~i-)SSV[ N'IOTIARIMV E'.I'I'AYAFE.-I'S LLKlADN> VNFVIKW.S ESEEQRYOC SH RC VGNSUOY KRIVACAS PKPSREESSSGSSINM L IGSANEE DLKA I..VEGVDQILFTDYQIK DGHFl Q. FNS IPSS DFLCV RERIWFEL FEV I FLS P AT FTVY EYB R PD KQCT MFYSTSNIKIQKVCEGAA CKCVEADCOQ 'QF LDLTISAEFTRKQTA-CKPE I AYAYKVSIISITi VENVFVKY 5 KATL LD YKTOEAVAEKDS FIKKVTCTNAELVKGRQYLMGKEALQIKYN FSFRAYPLDSLTW EYWPRDTTCSSCQAFLANLD EFAED I FINCH (SEQ ]D NO,26) in some embodiments, the antibody can bznd to human C5b prtein or fragment thereof contain an amino acid sequence that contains, or consists of; at leS or (egatleast tour five siseven; eight, nine. 10 11, 12, 13 14 15, 16, 17 10 18. 19 or 20 or more) consecutive amino acids depicted in SEQ ID NO:4 or SEQ 1D NO26 Additional exemplary sub4ragments of human Ch or Cla to which a. C5 inhibitor antibody can bind are disclosed in, e.g,, U.S Patent No 6 55,245, the disclosure of whicb is incorporated hereinby refeece 15 In some embodiments, the inhibitors an antibody that specifically binds to a (7a polypeptide (eg. the human C5a polypeptide having the amino acmid sequence depictd. inl SEQ ID NO: 12). in some embodiments, the inhibitor is an antibody that peci ficav hinds to a CSb polypeptide. Methods fr determining whether a particular agent is aninhibitor of human 20 complement component C5 are de ascribed herein and are known in the art, For example, the concentration and/Or physiologic activity of Ca and CSb in, a body fluid can be measured by methods well known in the art: Methods fbr measuring CSa concentration or activity inchuoe. eg. chemotaxis assays, R I s, or EISAs (se eg 5 Ward and vaffer (1971) J~n Invest 0V606-i6 andl Wurzner et atl (1991) 25 Commenxtnh wn:28 340). For C5b, hemolytic assays or assays for soluble C56-9 as discussed herein can be used Other assays known in the art can also be used Using assays of these or other suitable types, candidate agents capable of inhibiting human complement conIponent C5 sueh as an anti C'5 antibody, can be screened in order to. eug identify compounds that are useful in the methods described 30 herein and determine the appropriate dosage levels of such compounds. Methods for detecting inhibition of expression of mnRINA or prOtein (e~g.. inhibition of human CS protein expression or expression. of an rmRNA encoding human C5 protein) are well known in the art of molecular biology and include, e.g, 28 Northern blot and Re-PCR (or quantitativeI RJCI) techniques for rRNAand for protein deection Western blot, dot blot, or EISA techniques Se eg Sambrook et al (1989"Molecular Coning: A Laboratory Manual 2 Edition," ColId Spring. Harbor Laboratory Press, Cold Spring Harbor, N). 5 Methods for deteraminina whether a candidate compound inhibithe cleavage of hunan C5 into forms Cla and C51b are known in the art and described in. e gv, Moongkandi et at (1982) !anmunobIl 162 397; Moongkarndi et at (1983) immuns/io 165:323; Isenman et al. (1980)J/)nmuno 124(: 326-3i; Thomas et at (1996) Ml lmtunol 7 8): 1389-401; and Evans et a (1995) Mo/ Ibnu 10 32(I6)118395 'hib.iton of human complement com poen C.5 can aso reduce the cell lysing abilty of complement in a subjects body fluds, Such reductions of the cell lysing ability of complement present can he measured b methods well known in the art such as, for example; by a conventional hemolytic assay such as the henolysis 15 assay described by Kabat and Mayer (edsyxperimental hmnochemistry2x Edition) S 135240, Springfield, L, CC Thomas (1961 pages 135-39.or a conventional variation of that assay sMh as the chicken crythrocyte hemolysis method as described in, e.g lAlmen et at (2004) iVEngl/Med3S0(6)552. Insome embodiments, he compositions described herein can contain an 20 inhibitor of interferon alpha- Any compound which binds to or otherwise blocks the generaton and/or activity of interfron alpha may be utilized in accordance with the present disclosure. For example, an inhibitor of interferon alpha can be. e.g.. a. small moleculea nucleic acid or nucleic acid analog (e.g, an siRNA, a dlsRNgA a ribozyme. a triple-helix former, an aptamer) a peptidomimetic or a macromolecule 25 that is not a nucleic acid or a protein. These agents include but are notlnited to, small organic molecules, RNA aptamers. LRNA aptamers Spiegemers. antisense compounds, double stranded RNA, small interfering RNA, locked nucleic acid inhibitorsand peptide nucleic aid inhibitors. I sonic embodimeas. an inhibitor of nierten alpha may be a protein or protein fragment. in some embodiments, the 30 inhibitor of intcrferon alpha is an inhibtor of the receptor (interferon alpha receptor) to which interteron alpha binds. The humn interferon alpha receptor is described in, Sg Novick et al (1994) d/e/ =3)39 1-400; CI.'l]let al.. (2003) Structre .1(791 802 and UzP et al (2007) Culop MIb 1 uo/3;71-95, In some 29 emnbodiments. the inhibitor of interferon alpha binds to interfron alpha or its receptor and inhibits the interaction between iiterteinn adpha and its receptor. In some embodiments, the inhibitor of interferon alphais an antibody, or antigen-binding fragment thereof, which binds to an interferon alpha protein. 5 (Hereinafter, the antibody may soretines be refierred to as an "anti-itterferon alpha antibody;") Exemplary anti-interron a]pha antibodies are known. the art and described ine g. S; patent application publication nos. 20090324605, 20070059309, and 20080160030; U.S, patent nos. 708726 and 4;42314 the disclosures of each of which are incorporated herein by rektrence in their entirely. 10 Additional exemplary anti-interferon alpha antibodies that can be used in the cognipositions and methods described herein include, eg MEDI$45 (MDX-1 103, AstraZenecaMedinmane) 15 Suitable methods for producing an antibody (e.g., an anti-C5 antibody or an antiinterferon alpha antibody), or antigen-binding iragments thtereof, in accordance with the disclosure are known in the art (see e g S Patent No. 6,355,245) and described herein. For example. monoconal anti-CS antibodies may begeneated usng complement component CS-expressing ceIls, a CS p or an antigenie 20 fragment of C5 polypeptide, as an imrunogen, thus raising an immune response in animalIs vom which ant body-producingcels and in tun monoclonal antibodies may be isolated. The sequence of such antibodies may be determined and the antibodies or variants thereof produced by recornbiat techniques. Recombinant techniques may be used to produce chimeric, CDR-grafted, humanized and fidly human antibodies 25 based on the sequence of tihe monoclonal antibodies as well as polypeptides capable of binding to human complement component CS. Similarly, monoelonal anti in terferon alpha antibodies may be generated using an inerferon alpha polypeptide. or an antigenie fragment of interferon alpha polypeptide, as an inmunogen thus raising an immune response in animals from which antibody-producing cells and in tun 30 nionoelonalantibodies may be isolated. Moreover, antibodies derived from recombinant libraries ("phage an tibodies") may be selected using antigenic polypeptides such as a complement component protein or interferon alpha as bait to isolate the antibodies or polypeptides on the 30 basis of target speciTc. The production and isolation of nonhuman and chimeric arnbodIies are well within the purview of the skilled artisan Recombinant DNA technology can be vised to modify one or more characteristics of the antibodies produced in non-human cells. Thus, chinmeric 5 antibodies can be constructed in order to decrease the inmnnogenity thereof in diagnostic or therapeutic applications. Moreover, immunogenicity can be minimized by humatOizing the antibodies by CDR grafng atid, optionally. framework modication, See, S. Patent Nos. 225§39 and 7,393,648 the contents of each of which are incorporated herein by reference. 10 Antibodies can be obtained from animal serum or. in the case of monoclonal antibodies or fragments thereot produced in cell culture, Recombinant DNA technology can be used to produce the antbodies according to established procedure including procedures in bacterial or preferably namma an cell cuHure The selected ell culture system preferably secretes the antibody product. 15 In another embodiment a process for the production of an antibody disclosed herein includes culturing a host, e E, coli or a rarmalian cell, which has been transformed with a hybrid vector. The vector includes one or more expression cassettes containing a promoter operabiy linked to a first DNA sequence encodig a signal peptide linked in the proper reading frame to a second DNA sequence encoding 20 the antibody protein. The antibody protein is then collected and isolated, Optionaly the expression cassettemnay include a promoter operably linked to polycisonic (e g bicistronic) DNA sequences encoding antibody proteins each individually operable linked to a signal peptide in the proper reading frame Multipliation of hybridonm cells or mammalian host cells in vro is carried 25 out in suiable culture nedia, which mel ude the customary standard cuitare media (such as, for example Duibecco's Modified Eagle Medium (DME or RPMI 1640 .medium), optionally replenished by a mammalian serum (getal calf serum). or trace elements and growd sustaining supplements (eg. feeder cells such as normal mouse penitoncal exudate cels, spleen cells, bone marrow nacrophages, 2 30 aminoethanol. insulin, transferrin, low density lipopmttein, oleic acid, or the like). Multiplication of host cells which are bacterial ells or yeast cells is likewise carried out in suitable culture media known in the art, For example, For bacteria suitable cuure media include medium LE, NZCYM, NZYM. NZM, Terrific Broth. SOB 31 SOC.2 . or M9) Minimal Medium. For yeast. suitable cuture media include medium Y n D YPD, YEPD, Nininial Mediumr orn plete NIi irnal Dropout Medh.n in vitro production provides relatively pure atbody preparations and alows scale-up production to give large amounts ofthe desired antibodies Techniques for 5 bacterial cell, yeast, plant, or mamnaltan cclieultivation are kaown in the art and incude suspense cultre (g in airlift reactor or in a continuous stirrer reactor), and i.mrmobilizcd osr entrapped celi culture (e g in hiol low fibers. microcapsules, on agarose microbeads or ceramic cartridges Laie quantities ofhe desired antibodies can also be obtained by multiplying 10 mammalian cells in vivm, For this purpose, hybridoma cells producing the desired antibodies are injected into histoeompatible mammals to cause growth of antibody produnng tuniors. Optional, the animals are primed with a hydrocarbon, espcia 1y mineral oils such as pristine (tetramethykentadecane) prior to the injection. After one to three weeks, the antibodies are isolated frnm the body fluids of those 15 mammals, For example, hybridoma ces obtained by fason of suitable myeloma celis with antibodyproducing spleen cellsfkom Balb mice, or transfected cells derived from hybridoma ell line Sp2/O that produce the desired antibodies are injected itraperitoncally into Bal b/c mice olptionally pretreaited with pistane. After onetwo weeks. asitchi id i, a h-orn- the~c animals.. 20 The foregoing and other techniques arc discussed in, for example, Kohler and M stein, (1975) Murew 25:495497; f S. Patent No 4376,0; Harlow and Lane. Antibodies: a Laboratory Manual, (I (198) Cold Spring Harbor, the disclosures of which are all incorporated hein by eference, Techniques fbr the preparation of recombinant antibody molecules are described in the above references and also in, 25 e.g. W097/08320; U.S, Patent No. 5,427,908; U.S. Paent No, 5,508,717; Smith (1985) Science 225:1315-131i; Pamiley and Smith (1988) Gene 73:305 18; De La Cru et al. (1988) /unrwal/Biogica Chemistir 26:4318-4322; .S. Patent No. 5x403484; US. Patent No. 5 223A409 W88/06630; WO9215679; U.S. Patent No. 580;279; U.S. Patent No 5,571498; U.S. Patent No. 6,040,136; Davis et al. (1999) 30 Cnce Metastasis Rev 18L41421-5; and Taylor t al. (1 992) Nucleic Acids Research 20: 6287-6295; mTonizuka et al, (2000) Pe N'Vaui Acad Sci UISA 9?( 722-727 the contents of each of which are incorporated herein by reference in their entirety. 32 The cell euLire supernatants are screened for the desired antibodies by, e g.. rruno blotting, by an enzyme .n"munoassay e g a sandwich assay or a dot-assay, or a radioimunoassay For isolation of the antibodies, the inmunoglobulins in the culture 5 suppematats or in the ascitic fluid nay be concentrated, g by precipitation with armonium sudfate; dialysis agaitnby groscopic material such as polyethylneQ glycol, fitration through seleetiv membranes or the like I necessary and/or desired the antibodies are purified by the customay chromatography methods, for example gel fitration, ion-exchange ChiroiatographY chroiratography over DEAE-celhdose 10 and/or (immuno-) affinity chromatography e g. affinity chromatography with one or more surface poiypeptides derived fmm a complement component CSexpressing cel ine, or with Protein-A or -C. Another embodiment provides a process for the preparation of a bacterial cell ine secreting antibodies directed against a protein(eg. a complement protein or 15 interteron Ipha) in a suitable mmnnmal, A phage display library produced from the immunized rabbit is constructed and panned for the desired antibodies in accordance with methods well known in the at (such as etg. the methods disclosed in the various references incorporated herein by retbrence) llybridoma cells secreting the monoclonal antibodies are also disclosed The 2( preferred hybridoma cells are genetically stable, secrete monoclonal antibodies described herein of the desired specicity, and can be expanded from deep-frozen cutures by thawing and propagation in vitr or as ascites in vh'o. In another embodiment, a process is provided for the preparation of a hybridona cell line secreting monoclonal antibodies against a protein of interest (e'g, 25 ("5 poeni or interfemn alpha). Inthat process% a suitable mammal, fbr exanple a Balb/c mouse is inmunized with one or more polypeptide antigens of interest or antigenic fragments thereof Antibody-producing eelIs of the immunized mammal are grown briefly in culture or fused with cells of a suitable myeloma cell line The hybrid ells obtained in the fusion are cloned, and cl clones secreting the desired 30 antibodies are selected. Methods for preparing a hybridoma cell line include immunizing Balb/c mice by injecting subcutanously and/or nitraperuoneally an imnmnogenic composition coataining the proton of interest (or an immunogenic fragment thereof) several times eg, four to six times, over several months. eg. 33 between two and four months. Spleen cells from the immunized mice are taken two to four days after the last injection and ised with cells of the ryeloma ce line PAT in the presence of a fusion promoter, preferably polyethylene glycol, Prefembly, the myeloma cel are fused with at three to zwentvdfld excess of spleen cells from the 5 irnmnzed mice in a solution contaning about 30%." to about 50% polyethylene glycolof a molecular weight around 4000. After the fusion, the eells are expanded in suitable culture media as described qgra supplemented with a seleeton medium tor example HAT medium, at regular intervals in order to prevent normal myeloma cells trorm ov'ergrowing the desired hybridoma cells, 10 The antibodies and fragments thereof can be "chimeriei Chimeric antibodies and antigen-binding frame.nts thereof comprise portions Ifrorn to or more different species (eg, mouse and human), Chiimeric antibodies can be produced with mouse variable regions of desired speciicity spliced into human constant domain gene segme ntsfor example, U.S. Patent No 4 8156 5), In this manner, nonrhuman 15 antbocies can be modified to make tbem noi table for human clinical application (e.g, methods for treating or prevenmig Dos disease in a human subject 1. The monoetonal antibodies of the present disclosure include "lhumanized" foIms of the non-human (eag, mouse) antibodies. Humanized or CDR-grafted mAbs are particulardy use faas therapeutic agents for humans because they are not cleared 20 from the circulation as rapidly as mouse antibodies and do not typicaly provoke an adverse immne reaction. Methods of preparing hunmanized antibodies are generally well known in the art For example, humanization can be essentially performed tollowing the method of Witer and co-workers (see. e g Jones et al(!986)Ndrc 321522-52 Riechmnann et al 19$8) Nature 3_2323-32"; and Verhoeyen et a 25 (1 988)&Sence 23:1 534-1536). by substituting rodent C.DRs or CDR sequenc-esfor the corresponding sequences of a human antibody, Also see e,.g, Staelens et al. (2006) Mo hnnwro 4 I i243-1257 In some embodiments unanzed forms ofnon human (e.u. mouse ) antibodies are human antibodies(ecipient antibody) in which hypervariable (CDR,\) region residues of the recipient antibody are replaced by 30 hypervariable region residues from a non-nhman species (donor antibody) such as a mouse, rat, rabbit, or non -human primate having the desired specificity, affinity. and binding capacity, In some instances framework region residues of the hmnan immunoglobulin are also replaced by corresponding non-human residues (so called 34 back mutation") In addition. phage display libraries can be used to vary amino acids atchosen positions wthin the antibody sequence, Thepoperties of a hennanized antibody are also affeted by the choice of the human framework. Furtherriore, humanized and chimeized antibodies can be noodied to comprise 5 residues that are not found in thl recipient antibody or in the donor antibody in order to further improve antibody properties, such as, for example, afiity or effector function. Fully human antibodies are also provided in the disclosure. The term "human antibody' in des anibodies haintg variable and constant regions if present) 10 derived from human ermline inmunoglobulin sequences Human antibodies can cicude arino acid residues not encoded by hunan gernlne nninunogiobulin sequences (e g. mutations introduced by randomor sitespecifie nutagenesis in 1tro or by somaic mnutation in vivn However, the term "human antibody" does not include antbodies in which C'DR sequences dried from the gemiline of another 15 manmalian species, such as a mouse' hae been grafted onto hunmn framework sequences (.e. hmnazed antibodies), Fuly human or human anibodies may be delved from transgenic mice carrying human antibody genes (carrying the variable (V, diversity (M. joining () and constant (C exons) or from human cells For example, it is now possible to produce transgenic animals "g mice) that are 2( capable, upon immunization, of producing a full repertoire of human antibodies in the absence of endogenotus inmmnoglobul in production. See, e g. Jakobovits it a. (1993) Prov aladSci UM 90:2551; Jakobovits et al (1993)Naure 362:255-258; Bruggemann et a (1993) Year in mtnunnal7:33; and Duchosal et al. (1992)Nture 1 258, Transgenic mice strains can be engineered to omain gensequences from 25 unmereanged human unnangobulin genes Ihe human sequences may code for both the heavy and Iight chains of human antibodies and would function correctly in the miceundergoing rearrangement to provide a wide antibody reperoire similar to that in humans. The transgenic nice can be innunized with the target protein to create a diverse array of specific antibodies and their encoding RNA Nucleic acids 30 encoding the antibody chain components of such antibodies may then beconed from the animal into a display vector, Typically, separate popuations of nucleic acids encoding heavy and tight chain sequences are coned.and the separate populations then reconibined on insertion into the vector, such that any given copy of the vector 35 receives a random combination of a heavy and a light chain, The vector is designed to express antibody chains so that they cai be assembled and displayed on the outer surface of a display package containing the vector. For example, antibody chains can be expressed as fusion proteins wh a phage coat. protein from the outer surface of the 5 phage. Thereafter, display packages can be screened for display of antibodies binding to a target In addition human antibodies can be derived from phage-display libraries (Hoogenboom et al. 1991) j MoAoBA 227:381, Marks et al (1991) J Mo/Bof 258 597; and Vaughan et at, (1996i AN r Biowech 4309 (1996) Synthetic 10 phage libraries can be created which use randomized combinations of synthetic human antibody y V-regions. By selection on antigen fully human antibodies car be made in which the Vregions are very human-iike in nature Seeg, U. Patent Nos. 6,794;132, 6,680,209, 4,634666, and Osfberg et al (983) Jhridama 2361 362. the contents of each of which are incorporated herein byreference in their 15 entirety FIorU tNhegeetion of human antibOdies, aso see Mendez et alg.99A Cre Genetic' LI 46 56 and Green and Jakobovits (198) > Med 188483-495, the discksures> of which are hereby incorporated by reference in their entirety ulman antibodies '~arefurther discussed and delineated in U. Patent Nos,: 5,939598; 2( 6 673S86; 6 14,598; 6075,18L:6 16296 63 650,584; 6;713.610; and 6 657103 as well as U.S PatentPublication Nos 2003-0229905 A. 2004-0 010810 Al, US 2004 O093622 Al, 2006-0040363 Al, 2005-0054055 Al 20O5-006395 Al, 2005 0287630Al, See also WIternational Pubication Nos, W() 94/02602, \V) 964096; and WO 98:2489 and European Patent No, EP 0 463 151 B1 The disclosuresot 25 each of the above-cited patents. applications, and references are hereby incorporated by reference in their entirety. In an alternative approach. others, including GlenPharm International, Inc, have utilized m a nilocus" approach, in the minilocuts approach, an exogenous Ig locus is mimicked through the inclusin of pieces (individual genes) from the Ig 30 locus. Thus, one or moreV g enes, one or more DR genes. one or more J genes, a mu constant region, and a second constant region (preferably a gamma constant region) are trned into a construct for insertion into an animal This approach is described in; eg. US. Patent Nos,: 5,4 5,807; 5,545 806; 5425825; 625126; 5,633,425; 36 R;661 016; 770,429; 178965; and 5 81431S; 5,591,669; 57612,205; 5.21.367; 5;789215; 643763 6 2 587397; 6300,129,874299;6255,458; and 704 1 87 1 the disclosures of which are hereby incorporate by reference, See also Luropean Patent No. 0 546 073 BI, International Patent Application Publication Nos. 5 WO 92/03918, W( 92/22645 WO 92/22647. WO 92--2)2670 W() 93/12227. WO 94/00569,WO 94/25585. W) 96/144365 NVO 97/35, ind NW) 9/24884 the disclosures of each of which are hereby incorporated by reference in their entirety See further Taylor et aL (1992)NuceieAids Res 20; 6287; Chen eta L (1993) ht Mn not 647Tuaillon et ' '(1993)P cd S 3720~4; Choi et 10 al (1993) Ahr- Gencest - 117; Lonberg e al (1994) Natre 368: 856-859; Taglor et a (1994) Interninal nn: 75 Tuilior et al (1995)Jhnund E54; 6453~6 5 Fishxx5 et a (1996) Natre Bictaecdog i 4; 845; and Tiaillon ct al (2000) E' bnmuno' 10: 2998-3005. the disclosures of each of which are hereby incorporated by referece. in their entirety, 15 In certain embodinents, deAimmunied antibodies or antigenbinding ragments thereof are provided Deimized antbodies or antgendbnding fragments thereof are antibodies that have been modified so as to render the antibody or ai treof non-immmmogenie or less .mmunogenic, to a given specis (Cg to a humar De-imrunization can be achieved by modifying the 20 anybody or antigen-binding fragment thereof utilizing any of a variety of techniques known to those sklled in the art (see eg, PCT Publication Nos, WO 04108158 and WO 00/34317) For example, an antibody or antigen hinding fragment thereof may be dlme-irununized by identifying potential 7 cell epitopes and/or 13 celepitopes within the amino acid sequence of the antibody or antigen- binding fragment thereof and 25 removing one or more of the otential I' cell epitopes and/or B celi epitopcs from the antibody or antigen-binding fragment thereof, for example, using recombinant techniques, The modined antibody or an tigen-binding fragment thereof may then optionally be produced and tested to identify antibodies or antigenbnding fragments thereof that have retained one or more desired biological activities, such as, for 30 example. binding affinity, but have reduced immunogenicity Methods for identifying potential T cell epitopes and/or B Cll epitopes may be carried out using techniques known in the art, such as, for example computational methods (see e g, PCT Publication No-'WO 02/069232) M ino or in silico techniques, and biological assays 37 or physic al methods (such as, for example,determination of the binding of peptides to M I-IC rnolecues denomination of the binding of peptidc.MHC complexes to the T cell receptors from the species to receive thie antibody or antigenvbinding fragment thereof testing of the protein or peptide parts thereof using transgenic animalswith 5 the MHC nioleteIs of the species to receive the antibody or antigeebinding fragment thereof or testing n i tnsgeni animals reconstituted wth immune system cells front the spadei to receive the antibody or aingenginding fragment thereof, etel in various embodiments, the de-immunized antibodies described herein inside deimunized antigen Fab, Fv. sfr.mv;t F[by and Fab 10 monoclonal antibodies urine antibodiesengineered antibodies (such as for example, bimeric, single chain. CDR-grafted, humanized, fhdly huran antibodies and arificially selected antibodies synthetic antibodies and semisynthetic antibodies, :in sonc embodiments a recombinant DNA comprising an insert coding for a 15 heay chain yA<lW domain andor for a light chan variable domin of an antibody (eg, an anti-CS antibody or an aantilterteronalpha antibody) is produced and transfected into a. host cell for expression of the antibody. The term DNA includes coding single stranded DNAs, double stranded DNAs consisting of said coding DNAs and of complimentary DNAs thereto or these complementary (single stranded) 20 uNAs themselves; Furthermore, a DNA encoding a heavy chain variable domain and/or a light chain variable domain of anti-5 antibodies can be enzymatically or chemically synthesized to contain the authen tic DNA sequence codig fora heavy chain variable domain and/or for the light chain variable domain, or a mutant thereof A mutant of 25 the authentic DNA is a DNA encoding a heavy chain variable donain and/or a light chain variable domain of the above-mentioned antibodies in which one or more anino acids are deleted, inserted. or exchanged with one or more other amino acids. Preferably said modifications) are outside the CDRs of the heavy chain variable domain and/or of the l ight chain variable domain of the antibody in humanization and 30 expression optimization applications. The term mutant DNA also embraces silent inutants wherein one or nore nuleotides are replaced by other nucleotides with the new codons coding for the same anino acids} The term. mnutatt sequence also includes a degenerate sequence. Degenerate sequences are degenerate within the 38 meaning of the genetic code in that an unlimited number of nucleotides are replaced by other nruciotides without rsaiung in a change of the amino acid sequence origmally encodedSuch degenerate seqnences may be useful due to their different restriction sites and/or frequency of particular codons which are preferred by the 5 specific host. particularly E col to obtain an optimal expression of the heavchain murine variable domain and/or a light chain murine variable domain. The termi mtant intended to inchide a DN.A mutant obtained by in mutagenesis of the authentic DNA according to methods known in the art For the assemnbly of completetrameric inumoglobAlin molecules and the 10 expression of chinerie antibodies, thecombinant DNA inserts coding for heavy and lightchin variable donins are fused with the corresponding DNAs coding for heavy and light cbain constant doma ins, then transferred into appropriate host cells, for example after incorporation intohybrid vectors. Another embodiment pertains to recombinant DNAs coding fir a recombi nant 15 polypeptide wherein the heavy chain variable domain and the tight chain variable domain arelinked by way of a spacer group optionally comprising a signal sequence macilitating the processing of the antibody in the host cell and/or a, DNA sequence encoding a peptide facilitating the purification of the antibody and/or a cleavage site and/or a peptide spacer and/or an agent, The DNA codin for an agent is intended to 20 be a DiN A coding for the agent useful in diagnostic or therapeutic applications Thu, agent moleculs which are toxins or enzymes.especially enzymes capable of catalyzing the activation of prodrugs- are particularly indicated. The DNA encoding such an agent has the sequence of a naturally occurring enzyme or toxin encoding DNA. or a mutant thereof and can be prepared by methods well known in the art. 25 Accordingly, the monoclonal andbodies or antigentinding fragments of the disclosure can be naked antibodies or antige-binding fragments that are not coniugated to other agents for example a therapeutic agent or detect.able label Alternatively the innoclonal antibody o antigen-binding fragment can be conjugated to an agentsuch ai fOr example. a cytotoxic agent a mall molecule a 30 hormone. an enzyme, a gwth actor a cylokine, a ribozyme, a peptidomimetic a chemical a prodrug, a nucleic acid molecule including coding sequence (such as antisense. RNAigenetargeting constructs, etej or a detectable label feg., an. NtMR. or X-ray contrasting agent, fluorescent molecule, etc.). In certain -mbodiments, an 39 anti-C5 antibody or antigenbinding fragment (eg Fab. Fv, sile-chain se0 Fab and FabaV}) is linked to a molele that increases the halt-ie of the antibody or antigentinding fragment (see abovc) Several possible vector systems are available tor the expression of cloned 5 heavy chain and Light chain genes in nannualian cells, One class of vectors relies upon the integration of the desired gene sequences into the host el geome. Cells which have stable integrated DNA can be selected by simultaneously introducing dug resistance genes such as E3 cou gpt (Mulligan and Berg (1981) Procatl Acc Si SA 72072) or T neuo (Southem and Berg (1 982A App! Oenei :327). 10 The selectable marker gene can be either linked to the DNA gene sequene to be expressedor introduced into the same cell by co-transfection (Wigler c al. (1979) Cel 1§:7) A second class of vectors utilizes DNA elementswhich coife autonomously replicating capabilities to an extrachromosomnal plasmid These vectors c.an be derived from animal iruses, such as bovine papilnmavirus (Sarver et a 15 (1982) Proc Nat! -cad Sc! USA 79:7147y, polyoma virus (Deans et ali 1984) Proc a>! Ac i S USt 292'), or SV4O virus (1Lusky and Bote han 98 aue 29-99 1 Sin ce an imunogiobulin eDNA is comprised only of sequences representing the mature mNA \encoding an antibody proteinadditional gene expression elements 20 regulating transcription of the gene and processing of the RNA are required for the syntesis of imin iobalin mRNA, These elenmtents may include splice signals, transcription promoters. including inducible promot ers5 enhancers, and termination signals. DNA expression vectors incorporating such elements include those described by Okayamna and Berg (1983)4 CMl Bioi:20; Cepko et al. (1984) CelH 25 al1053 and Kaunan (1985)roc ad Acad Sci USA 689 In the therapeutic embodiments of the present disclosure, bispecific antibodies are contemplated, Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specifiies for at least two different ant igens. In the present case, one of the binding specificiiies is for a human 30 complI emien t protein or interfe-nin alpha protein, and the other one is for any other antigen, Methods for making bispeci tic antibodies arc within the purvew of those skilled in the art Traditionally, the recombinant production of bispecific antibodies is 40 based on the expression cf two immunoglobulin h evy-chainight-chain pairs, where the two heavy chains have difMerent specificities (Nistein and Cueo (1983) tre- 305:537539) Antibody variable domains with the desired binding specificities (atbodyantigen conAining sites) can. be fused to zmmunogjobulin 5 constant domain sequences. he fusion preferably is ith an inminioglobulin heavy Chain constant doman' including at feast part of the hinge. Cu2, and Q3 regions, DNAs encoding the mimmnogibuin heavy-chain fusions and, if desired, the imm1runoglobulin light chain. are inserted into separate expression vectors, and are co transtected into a suitable host organism For further details of illustrate currently 10 known methods for generating bispecific antibodies see, egg Suresh t A (1986) WhodhchEtin Enzuymology 12120; PCT Publication No, WO 96/270!.1; Brennan et al, (1985) Sence 22!8; Shalaby et al J tg Med (1 992) j 217-225; Kostelny et at 1992) j nnunoli Q15(1547-1553; Hollinger et a (1993) Prwc ad AdS ScTiUS 90:6444-6448 Guniber et al (1994) nml 12:538; and utt et a!, (1991 )J 15 Imnimol 14760. Bispeci (I antibodies als~o include cross-linked or hieteroconjugate antibodies. Heteroeongate antibodies inay be made usirig any convenient cross linking method. Suitable cross-linking agents are well known in the art, and are disclosed in U S P No, 4476980, along with a number of cmss-linking techiqes Various techniques for i.king and isolating bispecific antibody fragments 20 directly from recombinant cell culture have also been described, For example bispecihc antibodies have been produced us;in lencin zippers See' e, Kostelnv et al (0 992,) J Jmmumo 18(S:1547-553, The !eu-cine zipper peptides from the Fos andJu proteins may be nked to the Fab' portions of two different aatibodiesby gne fusion, The antibody homodimers may be reduced at the hinge region to form 25 monomers and then re-oxidtzed to form the antibody hetemdiniers This method can also be utilized for the production of antibody homodiners. Th- "diabody" technology described by Holinger et a! (1993) Proc Ad Acad &I M4 9S06444 6448 has provided an aItemati e mco han isifi mr i aking bi specific antibody fragments, The fragments comprise a heav-chain variable domain (VE) connected 30 to a light-chain variable domain (V) by alinker which is too short to allow pairing be en the two domains on the sane chain Accordingly, the Vli and Vt donmia ins of one agent are forced to pair ith the cornpeneritary VL and V domairns of another fragment, thereby forming two antigen-binding sites. Another strategy for 41 making bispecific antibody fragments by the use of single-chain v (scFv dimers has also been reported. See g. Grube et a).d(994) 3 Jmmnol 53~i68. Alternatively the anibodies can belinear antibodies"as described in, eg Zapata et ali 1995) ro: Eng. §1Q1105102. Briefly, these antibodies comprise a pair of tandem 5 Fd segments u A I VC ul) which tormn a pai of anigen binding regions, Linear antibodies can be bispecific or monospecific. The dicosure also embraces variant forms of bispecific antibodies such as the tetravalent dual variable domain immunoglobulin (DVD-g) molecules described in Wu et aL (2007) Nr Biotwno! 25 1j290-1297. The DVD~g molecules are i0 designed such that two different ligt chain variable domains (VL) from two different parent antibodies are linked in tandem directly or via a short linker by reconbinant DNA techniques followed by the light chain constant domain. Methods for generating .DVDIg molecules from two parent antibodies are further descrbed in, g PC Publication Nos. WO 08/024188 and WO 07/024715, dhe disclosures of 15 each of which are incorporated herein byreference in their entirety: Pharmaceugical Compositions and Formulations The compositions containing a complement inhibitor (eg an inhibitor of hnran complenent co.mponent C5 such as an anti antibody or antiuenmbinding 20 fragment thereof or an inhibitor of interferon alpha) can be formulated as a pharmacetical composition e. g, [or admnistraion to a subjectto treat Degos disease. The pharmaceutical compositions will generally include a pharmaceutically acceptable carrier. As used herein a pharmaceuically acceptable earTer refers to, and includes any and all solvents, dispenion media, coatings, antibacterial and 25 .antifungal agents, isotonic and absorption delaying agent, and the lke that are physiologically compatible. The composions can include a pharmaceutically acceptable salt, e.g, an acid addition salt or a base addition sal (seeeBerge et ah (19y7) JPharn Sci 6:19). The compositions can be formulated according to standard methods 30 Pharnmceutical formulation is a well-established art and is further describedin e.g, Gennaro (2000) "Remington: The Science and Practice of Pharmacy, 20 Edition, ILippincott, Williams & Wilkins (ISBN: 0683306472); Ansel et aL (1999) 'Pharmacettical Dosage Forms and Drug Delivery Systems," 7" Edition, Lippincott 42 Williams & Wilkins Publishers (SBN:68330527); and Kibbe (2000) "Handbook of Pharmaceutical Exci pion ts erican Pharmaceutical Associatiofn) 3 EditIOn (ISBN 091733096X) In some embodenents, a composition can be formuiated, for example, as a Wffred solution at a suitabe concentration and suitable for sorage at 5 2-8*C In some en a composion can be ftornulated for storage at a temperature below 0*0 (e '( 2 or 40Ck) The pharnaceutcal compositions can be in a varety of forms These forms include, eg, liquid, semisolid and solid dosage forms, such as liquid solutions (eg, injectabl and infusible solutions), dispersions or spions5tabets pils powders. 10 liposomes and suppositories. The preferred forn depends. in part, on ,h0intendd mode of adnnistration and therapeutic application. For example. compositions Containing an a.".tktJadc A spcior lou dehvcir' can be in. the forrn of injectable or inftusibc solutions. Accordingly the compositions can be formulated for adinistration by a parenteral mode (e g, intravenous, subcutaneous 15 iraperitoneal or unranmuscular Icin), 'Parentera administratio" "adnnistered parenterali and other grammaicaly equivalent phrases, as used herein, refer to modes of administration other than enter and topical administration, usually by injection, and includeithout imitaon, intravenous, intranasal intraocular, pulmonary, intramuslar, intraarterial, intrathecal intracapisular, 20 intraorbital, intracardiac inrad ermal intrapuimonary intraperioneal transtracheal, subcutaneous, subecuticul ar, in traarticular, subcapsular, subarachnoid, intmaspina I epidural, intracerebral, intracranial, intracarotid and intrasternal injection and infusion (see below). The cornposinions can be formulated as a solution,microemuisiondispersion. 25 Iposome or other ordered structure suitable for stable storage at high concentration. Sterile injectable solutions can be prepared by incorporating an antibody described herein in. the required amount in an apprpriate solvent with one or a combination of ingredients enumerated above, as required followed by filter sterilizaton. Generally dispersions are prepared by incorporating an inhibitor of human complement (e.g, an 30 anti&5 antibody) and/or an inhibitor of interferon alpha described herein into a sterile vehicle that contains a basic dispersion medium and the retiuired other ingredients fronm. those enumerated above In. the case of sterile powders for the preparation. of sterile iniectabie solutionsmethods for preparation include vacuum drying and 43 treezedryng that yield a powder of the antibody desrnbed herein plus any additional desired ngredient from a previously sterlicltered soutjon thereof The proper idity of a solution can be maintainedfor example, by the use of a coating such as lecihind, by the maintenance of the required particle size in the case of dispersion and 5 by the use of suractants Prolonged absorption of ijeqctable compositions can be brought about by including in the composition a reagent that delays absorption, for example, monostearate salts and gelatin; in certain emobodiments the complement inhibitor (e, an antiC5 antibody or antigen-bindig A thereof or inhibitor of interferon alpha can be prepared 10 with a carrier that will protect the compound against rapid release, such as a controlled release fbmulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyi acetate, poanhd polyglycolic ad collagen, polorthoestersand polylactic acid. Many methods for the preparation of such foraulations are known in the art, 15 SeigJR Robinson (1978) "Sustained and Controlled Release Dug Delivery Systems, Marcel Dekkeric, New York. In some embodiments, an inhibitor described herein can be fbrm ated in a com position suitable f intra pulmonary administration (eg fr administration via nebuliztrito a manmal such as a. fau-nanti, Methods for preparing such compositions 20 are well known in the art and described in, eg< S US. Patent Application Publication N 20080202513; IS. Patent Nos 11 21341 and 6.019,968 and PCT Publication NoS. WYO 001061 178 arid W 06 122257 the disclosures of each of which are incorporated herein by reference in their entirely ry powder and suitable systems for administration of the formulations are described in e g US 25 Patent Application Publication No 20070235029 .PCTi Publicadon No, WO 00/69887; and US. Patent No. 5,991848, i some emnbodinents, an inhibitor of human complement (eg, an anti-C5 anybody or antigen-binding fragment thereof) or nihibitor of iterferon alpha described herein can be modified, e,g., with a moiety that improves its stabilization 30 and/or retention in circulation, eg. in blood serum, or other tissues. The stabilization moiety can improve the stability, or retention ot the antibody by at least IS(e g. at least 2, 5 1 5, 20, 25, 30, 40, or 50or inore) fbld 44 The nuclei acid inhibiors of human coplmntecried herein (ei. gan anti-seruse nie ec acid or siRNA) can be incorporated into a gene construct to be used as a pat of a gene therapy protocol to deliver nucleic acids that can be used to express and produce agents within cells. Expression constructs of suct components may be 5 administered in any biologically effectkie carrier e.gang formulation or composition capable of effbctively delivering the component gene to cells in n'o; Approaches include insertion of the subject gene in viral vectors hcluding recombinant retroviruses, adenovirus. adenorassociated virus, lentivirus, and herpes simplex virus 1 (Hi-I) or reconunant bacterial or eukarvotic plasrnids. Viral vectors can 10 transfect eells directly; plasmid DNA can be delivered with the help of, for example cationic liposomes (lipofecin) or derivatized (e g antibody coiugated), polylysine conjugates, granicidin S. artificial vira envelopes or other such intracelluar careers, as well as direct injection of the gene construct or CaPO precipiation carried out in Wiwi (See a0o, "x tivo Approaches) below.) Exanple.s of suitable retrovimses 15 include pLJ, pZIP, pWE and pEM which are known to those skiled in the art (see, e.g, Eglitis et al. (1985) Science d :395~1398; Danos and Mulligan (1988) Proc at. Acad SIM UA 85:64600464; Wison et al (1988) ProcNad Acad Si US 853014-3018; Armentano et al (1990) Proc Nad A1ad Si US $06141 6 5 Huber et al ( 1991)1o- -Na Lcad Si USA 8880398043 e Lrry et a 1991) Th 0' 20 Nad Acad Sci 11 88 8377 8381; Chowdhury et al (99i) Scence 2j4, 802 1805; van Beusechem et at 9 9) Proc Na Acad Ai U 4 SQ 640- 644; Kay et a 1992) 1zinan Gene Therapy " I64 17; Dai et al. (1992) Pror Natt ca !i US 8910892 -10895; Ilwu et al (1993) J Inuo 4 I 50:4104- 4115: .S. Patent Nos 4,868,116 and 4,80286; PCT Publication Nos. W08907i36 W089/02468 25 WO9/05345, and WO92. 075731 Another iral gere deliverv system utilizes adenovirUs-derived vectors (see eg., Berkner et al (1988) BioTechniques 6'616; Rosenflbd et al (1991 Sciene '43l-434; and Rosenfeld et a. 1992) MI 68l 143 155), Suitable adenoviral vectors derived -fom the adenovirus strain Ad ype 5 d1324 or other strains of adenovirus gg Agd2,Ad d d, etc.) are known to ose skilled in 30 the art. Yet another viral vector systun usfld for delivery of the subject gene is the adeno-associated virus (AAV). Sec e.g,5 Flotte et l (1992) lm , Respir Cel Mo16 B6!o1349356; Sanulski et al. (1.989) JMI 633822828; and MeLaughlin et al, (1989)1 Viro 6: 1963-1973, 45 in some embodiments, more than one (e-g.. two three. fours five sixseven, eightine, 10 or more) ih.bitor(s) (eg one or rnoe inh.bitors of human C5) can be co"ormulated. For example, a CS-specifi siRNA and an anti-C5 antibody can be formulated together. 5 onine embodimentsan inhibitor of human complement (eig., an inhibitor of human complement such as an antiC5a or g n fam tereof) or inhibitor of interferon alpha descrbed herein can be fornulated wi t one or more additional active agents useful fo treating Degos disease or amelorating a symptom thiereof F-or example, an anti-C5 antibody can be fobrnulated with an 10 immunosuppressive agent. Immunosuppressive agents include e., corticosteroids phenylbutazone, azathioprine methotrexate, cyclosporine tacroimus, and nyeophenolate mofetil eycophosphamide and anti &D20 agent such as rituximab (Rituxan"';liogen ide, Cambridge, M- A). In some embodiments, the inhibitor human. complement can be tornulated for administration to a subject along with 15 iravenous imnunoglobuin therapy (WIG), red eell Iransfusionp iasmnapheresi, or with p lasma exchange See, eg., Dyrsen ct a.2008) upra and Zhu et al. (2007 In some embodiments, the inhibitor of human complement can be formulated for joint therapy (eg. simultaneous or concurrent) wI th an antthromboic agent 20 and/or an anticoagutant such as, but not limited to. clopidogrel aspirin, dipyridamole, warfarin (Coumadin), heparin phenindione fondapanrix idraparimx, and thrombin inhibitors (e.g argatroban, lepirudin. bivalirudin, or dabigatran). An inhibitor of human complement (eg an anti-C5 antibody)can also be fbrnated for use with a fbrinolgtic agent(e.g an.rd aaminoeaproic a atplasnin-anprostylin.and 25 delbroti-') for the treatment of Degos' disease. In sone ernbodmrnents, g, wnere the Degos' disease is associated with an. infection, the inhibitor human complement and/or inhibitor of interferon alpha can be ftorulated with one or more agents for use in treating an infection, For example. a C5 inhibitor can be formulated with an antibiotic or an anti-viral agent 30 When the inhibitor of human complement is to be used in combination with a second active agent, or when two or more inhibitors of human complement are to be used (eg., an anti-C5 antibody and an anti-factor B3 antibody), the agents can be formulated separately or together. For example the respective pharmnaceuica 46 compositions can be Amixed, e'g, just prior to administration and administered together or can be administered separatelye-g. at the sane or ditIrent times (see below) Ukewise, when the inhibitor of interferon alpha (e.g, an antiliterferon alpha 5 antibody) is to be used in combination with a second active agent, or when two or more inhibitors of interferon alpha are to be used, the agents can beformulated separately or together, As described above, a composition can be formulated such that it includes a therapeutical ly efectiv amount of an i nIbitor of human complement (eg., an ari 10 C5 antibody or antigei-binding fagient thereof) or the composition can be forrnuiated to include a sub-tnerapeut amount of the inhibitor and a sub-therapeutic amount of one or more. additional active agents such that the conmponits in total are therapeutically effective for treating Dcgos disease Insonc eibodirinents, a composition can be formulated to include two or more inhibitors of human 15 complenient each at sub-therapeutic doses, such that the inhibitors in tota are at a concentradon that is therapeutically effective for treating Degos' disease. A composition can be formulated such that it includes a therapeutically effective amount of' an inhibitor of interfern alpha (eg, an antiinterfemn alpha antibody or antigen binding fragment thereof) or the composition can be formulated to include a sub 20 therapeu tic amount of the inhibitor and a sub-therapeutie* amount of one or more additional active agents such that the components in total ar therapeutically effective for rating Degos' disa. In some embodiments a composition can be formiulated. to include two o7rmore inhibitors of interferon alpha' each at subtherapete doses, such that the inhibitors in total are at a concentration that is therapeutically effective 25 fr treating Degos disease in some embodiments the composition includes an inhibitor of human complement and an inhibitor of interferon alpha, Methods for detcrmin ig a therapeutically effective dose (er.g, a therapeutically effective dose of an anti-CS antibody or an anti-interferon antibody) are known in the art and described hereinO. 30 Methods oreatgert The above-described composhions are useful in, inter adia, methods for treating or prevention Degos disease in a sbiect (g. a human). The compositions 47 can be administered to a subject eg. a human subject, using a variety of methods that depend, n part, on the route of adominstrason. The route can be, e. intrabeeous injection or infusion (TV), subctaneous injcton ,intraperitoneal (IPX or intramuscular in jection. 5Admstratin can be achiced by, e g. local infusion injection. or by means of an implant, The implant can be of' a porous, noporous, or gelatinous material including membranes. such as sialastic membranes, or fibers, The implant cai be configured for sustained or periodic release of the composition to the subject. (See, e.g. S Patent Publiation No, 20080241223 U;S Patent Nos. 550L,856; 10 4,863457 and 3710795 EP488401; and EP 430539; the disclosures of each of which are ticorporaed herein by reference in their entirety. The coruposition can be delivered to the subject by way of an implantable device based on, eg. diffusive, erodile, or connective systems, emg osmotic pumps, biodegradable inplanst electrodiffusion sstemselectroosmosis systems, vapor pressure pumps electrolytic 15 pmmps eeffervescent umps piezoelectric pumps, erOSiobased systents or electronmechanical systems. A suitable dose of an inhibitor of human complement (eg. an anti-C5 anthbdy or fragment thereof) or an inhibitor of iterferon alpha (e, an anti interferon alpha antibodywhich dose is capable of treating or preventing Degos' 20 disease in a subject can depend on avariety of factors including. eg., the age, sex and of a subject to be treated and the particular inhibitor compound used. Fr example, a different dose of a siRNA specific for human CS may be required to treat a subject with Degos' disease as compared to the dose of an anti-C5 antibody required to treat the same patient Other factors affecting the dose administered to the subject 25 inudc eg. the type or severity of Degos' disease. For emrnple, a subjet having a cutaneous form of Degos' disease may require administration of a different dosage of tia inhibitor than a subjct with a systemic form of Degosdisease Other factors can include. eg. othemedical disoiders concurrently or previously affecting the subject, the general heath of the subject, the genetic disposition of the subject, diet, time of 30 administration, rate of excretion, drug combination, and any other additional therapeutics that are administered to the subject, It should also be understood that a specific dosage and treatment regimen to r any particular subject wil depend upon the judgment of the treating medical practitioner (eg.. doctor or nurse Y 48 The inhibitor can be administered as a fixed dose, or in a nilligram per kilogramit (n/kg) dose, in some eibodimtients, the dose can als he chosen to reduce or avoid production of antibodies or other host immune responses against one or more actve agents in the composition While in no way intended to be imiting, exenplary 5 dosages of a conple.ment inhibitor (e.g., an atii75 antibody)and/or an inhibitor of interferon alpha included g. 1100 pk 0 .550 g/kg, O1100 pg/kg 0 5 ggkg, 120 pgkg, and N10 1-pg 00ng U -E0 mgkg 0 100 rgkg 0,5 25 ing/he 20 ing/hg, and 1-10 mg/kg. Eemplary dosages of an antibody described herein include, without limitation, 0 j pgg i 5 p P pgkg,2.0 p kg; 4 10 pg/kg and 8gg/k k g,k 0.5 ngkg, 10 mg/kg 2,0 mgkg 4 mgk and1 8 mg/kg. In some embodiments, a human can be intraenously administered an anti-C5 antibody (e g eculiumnab) at a dose of about 900 mg about every 12 (e-g.about every 10, 1, 13 14. 15, 16, 17,18, 19,20,21.28,30, 42, or 49 or more) days, See 15 e g, Hill et al. (2005).Blood JQ:12559. in some embodiments. a human can be intravenously administered an anti-S5 antibody (eig ecuizumab) at a dose of about 600 (e.g, about 625, 650, 700, 725, 750, 800, 825, 850. 875, 900, 925 950. or 1,000 or more) mog every week, optionally, tor two or more (e g three, four, five, six evenor eight or more) weeks. Following 20 the initial treatment, the human can be administered the antibody at a dose of about 900 mg about every 14 (e.g., about every 15, 16, 17, 18, 19,20, 21,28 30. 42, or 49 or more) days, eg, as a maintenace dose. Se, eg., Hillmen et a. (2004) NEnglJ Med 250:6552 9 and Dmytriik et at (200k) The Oncohgisr 13 993 A pharmaceutical composition can include a therapeutically effective amount 25 of an inhibitor of human complement component c (eg, an anti-CS antibody or antigen-binding fragrenn t thereof) and/or a therapeutically effective amount of an inhibitor of interferon alpha- Such effective amounts can be readily determined by one of ordinary skill in the art based. in part, on the effect of the administered inhibitor or the cimbinatoriaeffect of the antibody and one or more additional active 30 agents, if more than one agent is used A therapeutically effective amount of an inhibitor ofhuman conplement (e. an ani5 an tibody) can. also vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability 49 of the antibody (and one or more additional active agents) to dicit a de.sired response in the individual, eg, melioraton of at least one condition pararriete, eg, amehamtion of at least one symptom of Dgos disease. For example. a therapeuticaly effective amount of an inhibitor of human complement (e.g., an anti 5 CS antibody) can inhibit (esen the severity of or eliminate the occurrence of) and/or prevent Dego discas i and/or any one of the symptomsof Degos disease known in the art or described herein. A therapeutically effective amount is also one in which any toxic or detrimental effects of the composition are outweighed by the therapeutically beneficial ffets. 10 The terms "therapeutically effective amount" or "therapeutically effective dose, or sirnilar terms used herein are intended to mean an an&uat of an agent (e an inhibitorof human complement) that will elicit the desired biological or medical response (e.g., an improvement in one or more symptoms of Degos disease. In some enmbodiments, a composition described herein contains a therapenticaliy 15 effective amount of an inhibitor of human complement component C5. In some eibodients, a composition described herein contains a therapeutically effective amount of an antibody, or antigenbinding fragment thereof, which bindsto a com plemen t component CS protein,. I some embodtnents, the composition contains two or more (e.g, three, four. fivesix seven, eight nine. 10. or I I or more) different 20 inhitbitors of human complement such that the Composition a whole is therapeuticaly elective, For example, a composion can contain an antibody that bnds to a human CS protein and a siRNA that binds to, and promotes the degradation of, an HRNA encoding a human CS protein, vheren the antibodyand siRNA are each at a concentration that when combined are therapeutically effective, In some 25 embodirients, the comnosition contains the Inhibitor and one or moresecond active agents such that the composition as a whole is therapeutically effective, For example. tGe cornpositio.n can contain an antibody that binds to a human C5 protein and another agent useful fo treating or preventing Degos' disease, In some embodiments, a composition described herein con tains a 30 therapeutically effective amount of an antminteferon alpha antibody or an antigen binding fragment thereof. Toxicity and therapeutic ef-fcacy of such compositions can be determined by known pharmaceutical procedures in cell cultures or experimental animals. These 50 procedures can be used, e.g., for determining the L0D(the dose lethal to 50% of the population) and the FD, (thed e therapeuticallyefletive in 50% of the population), Ih dose ratio between toxic and theuapeutic effets is the therapeutic index and Acan be expressed as the ratio L D 5 ;D Compositionsorcomplement 5 inhibitors (e anti(C5 antibodies) of the compositions, that exhibit high therapeutic indices are preferred. While compositions that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue and to minimize potential damage to normal cells and, thereby, reduce sideueffects. 10 The data obtained from the cell culuIre assays and animal studies can be used i .tormnuatig a range of dosage for use in humans. The dosage of such hbitors lies generally withina range of circuating concentrations of te inhibitors) (g an an ti.4C5 antibody, an anti interfbmne alpha antibodyr antigeinding fragments tereof) that include the EDo 0 with little or no toxicity The dosage may vary within 15 this range depending upon the dosage form employed and t route ot administration utilized. For an Wihibitor of human comnplement con'ponent C' (eg an anti.C antibody) used as described herein (e.g. for treating or preventing Degos' disease) the therpeutically effective dose can be estimated initially fin cell eiure assays. Levels of the complement inhibitor in, eg the plasma of treated humans or animals 20 may be measured. for emplby high performance liquid chromatography. In some embodiments. the required dose of an inhibor of hum an complement (eg. an anti-C5 antibody) can be determined based on the concentration in the subject's blood of the complement protein to which the inhibitor is directed. For examples, ubject having a higher concentration of circulating human C5 protein 25 levels may require a hgher dose of a human C5 inhibitor than a subject having lower levels of circulating human C5 Methods for determining the concentration of human complenrenti a blood-derived fluid sainple from a subject are known in the art, For example, a method for determining serum C5evels is described in, e g.. Rawal et at (1998) JBiol Chem 2 1(i82816835 30 A 'subet as used bere ca be any mamnIal For eample a subject can be a human, a nonh human primate (e monkey; baboon, or chimpanze)a horse, a cow, a pig, a sheep. a goat, a dog a cat a rabbit, a ginea pig a gerbil. a hamster, a rat or a mouse in some enibodimcnts the subject is an infant (,eg' a human infant). 51 in some embodiments, the subject is one who is refractory to one or more additional therapeutic agents that were admindstered to treat Dagos' disease, "Rcsistance" to a therapy, "refractory" to therapy, and like grammatcal phrases, as used herein refer to a patient's clinical state of being, in which there is a reduction in. 5 the effectiveness of a given therapy in treating or curing a given disorder (eg. Degos disease) or a reduction in the efliveness of the treatment in ameliorling one or more symptoms associated with the disorder For example, the therapeutic benefits of WIg to a patient afflicted with Degos disease may diminish over time such that the disease remains or progresses en itih Rg therapy, See ejg. De Breucker et al. 10 (2008). .pra As used heretn, a subject "tun nCed of prevention" "n need of treatment" or "in need thereof,"reters to one, who by the judg-me nt of' an appropriate medical practitioner (e g a doctor, a nurse, or a nurse practitioner i the case of humans; a veternnarian in the case otf non4human mammals). would reasonably benefit from a mven treatmen(sduh as treatment wh a composition comprisin an inhibitor of h unan corm plenaent or an Inhibitor of i nterteron alpha) As used herein, a subject "at risk for developing Degos' disease" is a subject having one or more (eg, two, hree, four, fie, sixseven, or eight or more) risk fauts or developing, the disorder. Risk factors for Degos' disease are wel known in 20 the art of medicine and include, e.gg. a predisposition to deyelop the condition. iie.. a Inuly history of the condition or a genetic status associated Vith Degos' disease such as e. ga Protein S deficiency, Se. ewg. Gilebene et al (2005) B, rDennai I§ 6&7. Risk factors for Degns disease also include those conditions that are associated with Degos' disease such as, but not limited to, viral infections (eg., IHlV 25 or B19 parvovirus infections a procoagulant state (C g.. Factor V Leiden) or an autoimmune disease such as LE, dermatonyositis, scleroderma, and antiphospholipid syndrome. Hereinafter.such manifestations of' Degos' disease maybe, where appopiiat referred to aseg. "infectionassociated Degos' disease" or autoimnune-associated Degos' disease, From the above it vi'UI be clear that 30 subjects "at risk Cor developing Degos' disease" are not all the subjectswithin a species of interest A subject "suspected of having iegos' disease" is one having one or more (eg two, three, four, five, six, seven, eight nine, or 10 or more) symptoms of the 52 conditon. Symptoms of this condtion are known to those of skill in the art of medicine and includgeet skin lemons (e, one or niore papules tha arraised and skin- or rose-colored, which papules progress to depressed scars with white centers and surrounding erythema and telangiectasias gastrointestinal bleeding, vormiing, 5 enteroctaneous fistua, neurological symptoms fcg faciatand acral paraesthesia, hieadahesdJizziness, aphagia, paplegia gaze palsy, epilepsy memory loss, or altered sensation strokes, dmpopia, ptosisvisual-field defects weakness. shortness of breath, and chest pain in some enibodiments. Degos' disease is associated with the presence i the patients of anticardiolin antibodies, the lupus anticoagulant, 10 antiphospholipid antibodies, or vascular IgA deposition, See eg Englert et at I 984N supra; Crowson et a. (2002). supra: and Grattan and Burton (199 1)Sn in Durmpwi ;4):1 52- 159. From the above it will be clear that subjects "suspected of having Degos disease" are not all the sulects wtha specie of interest In some embodiments, the methods can include identifying the subject as one 15 having suspected of having, or at isk for developing, Degos' disease. Sunable methods for identifying the subject are known ir he art For example, Ackerman decribes a histological method for positively identifying a Degos disease-associated cutaneous lesion. An1 L~encnatzoho0985) (2) 5 As described above, Degos disease can be associated w At the presence in the patients of anticardiolipin 20 antibodies, the lupus anticoagulant anchor antiphosphtulipid antibodies. Diagnostic histological methods are also exemplified in the working examples; Suitable methods for detecting the presence of these antibodies in the blood of a patient are known in the art and described ine.g., Caux et al (994) Ann Deruaz Wncreo 253-542. in some embodiments, Degos' disease can be associated with IgA deposition within 25 the cutaneous vascuiatre t Mhods for detecting such deposition are known in the art, See, e g,, Crowson et al,200, supra In. addition., as described in the working examples, Degos' disease can. be associated with prominent vascuafr C5b-9 MA C deposition as wel as elevated serum C reactive protein and factor VITT levels, Methods for detecting each these 30 1 parameters are exemplified herein, In some embodiments, the composion can be administered to a subject prophylactically to prevent the progression of the benign fbrn of Degos' disease to the systemic, multiorgan form of the disease. For example, a subject who has a 53 e.utaneous frn of Degos disease can be administered a composition described herein to prevent or lessen the likelihood of development n the patient of the lethal, systemic form of Degos' disease. Simiady. a subject who has a Degos disease-associated B19 parvoviral infetionan H infection, or an autoimmune sdiease can be 5 administered a composition described herein to prevent or lessen the likelihood of the development of Degos disease in the patient. The term "preventing" is art-recognized, and w hen used in relation to a condition, is well understood in the art, and includes administration of a eomposiion which reduces thiefrequency of, or dehys the onset of. symptoms of a medical 10 condition ina ,subject relative to a subject which does not receive the composition. Thus, prevention of Degos' disease includes, for example slowing the progression of the benign form of Degosdisease to the systmie muhiorgan form of the disease in a population of patients receiving a pmphylactc treatment relative to an untreated control population andcor reducing the seven it and/or delaying the onset of the one 15 or more symptoms of the disease in a treated population versusan untreated control populatione,g. by a statistics y and/or clinically signiticanamot In some enbodiments the inhibitor of human complement ea.n an anti-cS antibody or antigen -binding fragment thereof andtor the inhibitor of'interferon alha can be administered to a subject as a monotherapv Alernatively as described above, 20 the inhibitor can be administered to a subject as a combination therapy with another treatment, etg another treatment for Degos disease. For exaple, the combination therapy can include administering to the subject (e.g. a human patien) one or more additionalagents (eg., anti-coagulants or anti-inflammatory agts) taat prvidea therapeutic benefit to the subject who has, or is at risk of developing Degos disease. 25 In some embodiments, the inhibitor of hmnan complement ie an atOi-C5 antibody) or inhibitor of interferon alpha and the one or mue additional active agents are admninstered at the same time. li other embodiments, the inhibitor is admnnistered first in time and the one or more additional active agents are administered second in ine In some embodiment the one or nore additional active agents are 30 administered first in time and the inhibitor is administered second in time. The inhibitor of human comOleMent or inhibitor of interfeton alpha can replace or augmenta previously or curmtly administered therapy. For emple upon treating with an ant-C antibody or antigen-binding fragment thereof, 34 administration of the one or more additional active agents can cease or diminish, e g, be admistcred at lower levels .In some embodiments. administration of the previous therapy can be maintained. in some embodimentsa previous therapy ill be maintained until the level of inhibitor of human complement (e g an anti C5 5 antibody) or inhibitor of interiron alpha reaches a level suffiiet to provide a therapeutic efect. The two therapies can be administered in combination Monitorng a subject j. a human patient) for an improvement in Degos' disease. as defined herein, meat.s evaumting the subject for a change in a disease parameter e gc an improvementt in one or more symptorns of the disease, For 10 example, a medwil practitioner can examine the extent of vascular C5b-9 MAC deposition before and after treatment using a complement inhibitor described herein. Such symptoms include any of the symptoms of Degos' disease described herein. In some enbodimentsthe evaluation is performed at least hour, egg, at least 2, 4, 6, 8 12, 24. or 48 hours, or at least I day, 2 days, 4 days, 10 days, 13 days, 20 days or 15 more or at least I wee: 2 e eks, 4 weeks, 10 weeks; 13 weeks, 20 weeks or more, after an administration, Tie ubjct can be evaluated in one or more of the following periods: prior to beginning oftreatment; during the treatment; or after one or more elements of the treatment have been administered, Evaluating can include evaluating the need for further treatment, eg evaluating whether a dosage frequency of 20 administration, or duration of treatment should be altered, It can also include evaluating the need to add or dop a selected therapeuO, modalityecg addin or dropping any of the treatments for Degos' disease described herein. Ex vivO approaches, Where the inhibitor of human complement or inhibitor 25 of interferon al pha is a polypeptide (e g, an antibody or a nucleic acid (e~v, an siRNA or anti-sense nucleic acid) an ex vivo strategy for treating or preventing Degos disease can involve transfecting or transducing one or more cells obtained from a subject with a polynucleotide encoding the protein or nucleic acid. For example, the cells can be transfected wth a single vector encoding a heavy and light chain of an 30 antiC5 antibody or the cells can be trnsfected vith a first vector encoding a heavy chaiin and a second vector encoding a light chain of the antibody The transtected or transduced cells are then returned to the subject, The cells can be any of a wide range of types including, without limitation, hemnopoietic cells 55 (eg, bone marrow cells. macrophages, monocytes, dendritic cells, T cells, or B cells) fibrobiasts.epih ehal cells, endothelal cells keratinOcytes, Or usde cells. Such cells can act as a source (e g, sustained or periodic source) of the complement ih ibitor (eg. the anti-C5 antibody or antigen-binding fragment thereof, or antiC siRNA) or inhibitor of interferon alpha for as long as they strrvIe in the. subject In some embodennts. the vectors and/or cells can be configured for inducible or repressible expression of the antibody (see, e g. Schockett et al, (1996) Proc Nal Aca Sci USA 93 51735176 andUS Patent No.7056897. Preferably the cels are obtained fom the subject (autol[oglus but can 10 potentially be obtained from a subject of the same species other than the subject (al:ogeneic. S utable methods for obtaing cells from asubjgect and transdueng or transfecting the cells are known in the art of molecular biology. For example the transuCionl step can be accompi ished by any standard means used for ervivo gene 15 therapy. including calcium phosphae, ipofection eleetroponition virinfectionsee above anid biolistic gene transfer. See, eg.. Sambrook etA supa and Ausubel et al (1992') "Current Protocolsin Molecular Biology, Greene Publishing Associates Alteratively, iposomes or polymeric micronparticles can be used. Cells that have teen successftuly transduced can be selected for example. for eVxprssion of the 20 coding sequence or of a drug resistance gene Kits The disclosure also features articks of manufacture or its.hich include a container with a lahe and a composition containing one or niore (eg., one, two, 25 three four, ive, six seven, eight nine, or 10 or mone inhibitors) of human complement (e g. an antiaCT antibody or antigen/binding fragment thereof) and/or one or more (en.. one, two, three four, five, sigx seven, eight, nine, or 1.0 or more) inhibitors of interferon alpha (e.g., anamtilinterferon alpha antibod . The label indicates that the composition is to be adninistere to a subject (i.g, a human) 30 having suspected of having, or at risk fOr developing, Degos' disease. The kit can, optionally; include a means for e the composition to the subject. For example, the kits can include one or more syritges. 56 In some enabodiments, the kits can contain two or more (e g., three, four five, six, seven, eight. nine, or 10 or more) duieent types of inhibitors of Iuman complement. For example. a kit can contain an anti-C5 antibody (or antigen-binding fragment thereof and a siRNA that binds to an rnRNA that encodes a human C5 5 poteion in some embodiments, the kit can contain an antiC-5 antibody, a siRNA, and a small molecule inhibitor of complement. in some embodiments, the kits can further include one or more additional active agents such as any of those described herein. For example, the kits can include one' or more anti -coagulants, an- tthromboi ager or iiamrnatory agents. 10 The kits can also include one or more BF ec0targeted therapies such as an anti-CD20 antibody. The kits can optionallyinchude one or more means for detecting the presence of antihcardiohpin anti bod ies, the iupus antcoagulant; antiphosphol ipid antibodiesand/or vascular igA deposition 15 The following examples are intended to illustrate not imit he inyenticm. Examples Example Materials nd Methods Routine light microscopy Five-micron thicksections of paraffin embedded, 20 formain fixed tissue were stained with hrnafoxylin and cosi and examined by conventional light mtieroscospyv. Immenohistochemic assessmet for M.xA. The sides for use in detecing Mxi protein were placed inissue Tek Slide Holders and staining dishes (Miles 25 Elkhart, IL) and submersed in 200 mL of EDTA buffer. pH 8.0 (Zyned Laboratories, South San Francisco, CA), Folowing a 30-minute incitation with the primary antibodies, staining was performed using the commercially available Vision BioSystems Define Kit adhering to the protocol Incubation with the ptrirmary antibodies was conducted using the fol lowing dihiuons: anti-MxA antibody 1:1600, 30 A semi qluaiitative assessment was made in regards to the extent of staining based on an approximate percentage o celNs stained for a particular marker as wellas the distribution of staining across the slide, Slides were cover-slipped using the Shandon 57 ConsuMount Histology (Product No. 9990440) system on a Consul automated coverSipper (ThermoShandon, Pittsburgh, PA), See Magro et a. (2009) Ju/n Paxhol (November 4, electronic publication ahead of pn at; PMID: 19891658), 5manofuorescence studies on tissue. The following. 4mmunoiuorescence studies (as described in Crowson and Magro (1996) Ihanan Pathol ':149) were performed on skin biopsy material obtained in Michael's tranpot mdiun and subsequently stored at40*C Direct imnmunofluorescence (DIF) studies for immunoglobulin G (igG), A IgM. fibrin, and complement conponent (3 (DAKO. 10 Parpteria, CA USA were perfbmed on AionKl skit by the oveday of fhiorescein conjugated primary antibodies upon individual biopsy sections An indirect nnmmofi oresoence IF) rethodoiogy with a fluoresceincongugated rabbit anti mouse antibody was used to detect the presence of Cabe MAC DAKO) by way of its binding to a primary anti-Cb-9 antibody initidly contacted to a biopsy section. Electron microscopy Skin biopsy tissue was placed in glutaraldehyde fixatve for uhtrastructural exanmation Cell culture for indirect imimunofluorescence and Western blot studies. 20 Neonatal human dermal blood microvascular endothelial cells, IM EC-dBINeo (Iouza, Walkersville, MD) were cultured at 37 in complete medium (EGM Basal Medium supplemented with FIGM-2 MVBulletKit reagents and 5% Premium FfS) (Lonza) witis 5% C. Ihe cells were cultured for a time sufficient to reach 75% to 80% confluency in the culture flasks. Te cells were then washed with warm 25 phosphate-bufired saline (PBS) and harvested using a IN trypsi.n-F DTA solution ISignaAldrich, St, Louis, MO). After an additional wash with. PBS, the cells were re-plated in prevarmed complete medium onto tissue culture chamber slides (Nunc Lab/fek 1 Chamber Slide System 2 wells on Permanoxl, SigmaAldrich) at a density of 2 x 104 cellsn"mLI The chamber slides were cultuO d for 24 hours at 37*C 30 with 5% CO after which time the media was discarded, Foliowing removal of the media, the slides of each chamber were removed rinsed in PBS. and then air dried in combination with papertowels to wick away excess PBS The dried slides were then 58 stored at 80*C in an airtight container until examined using immunofluorescene Western blot studies he cultured IMVE(>dBlNeo eells were lysed using a 5 lysis buffer consisting of 0,05M sodium fluoride, 1% Trton X100. 50mMTris-H(l (pH 80),. 150mM NaC, 1 mM sodium orthovanadate, IM phenyhnthylsulfnyl an a 1 L00 tIo of Calbiochem Protease Inhibitor Cock.tail >et IJI (EMiD Chemicals, Inc Gibbstown, NJ) for 30 minutes at 4'C with occasional vortexing, The lysates were thenceared of nu.l and otherinsoible material by 10 niemeentfation Next, sodium dodecy sulfatepolyaerylamide gel (SDS-AGE) loading butler containing' mercaptoethanol ( m5% al concentration) was added to the cell tg0ate (1: 4 dikjtion of the X oadIng buft;r into tsate) Prior to boiling for two mines. Lsates were then resolvedby clectrophorsis through an. 8% to i6% gradient Tris-HlCl SDSPAGE gels (Biokad Hercules, CA) d transferred to 15 Whatnan ProtraniT nitroceiltlose menmbrancs (SigmaIrich) Membranes were incubated for sixhurs at room temperature with a blocking solutionof 3% nond-at milk in Tris-tuffered saline vith 0. 1% Twee~20 (TBSJf) on an orbital shaker, and then fitted into a Miniblotter 25 blotting maifold (Ilmmnnetics, Catibridge. MAY Miniblotter wells were filled with either patient or healthy control serm diluted 12.50 20 in TBS' entainin 02 bovinc seam albrAnin and the Miniblotter rocked gently overnight a 4C on in orbit shaker Thesera were then removed, the wells washed twice with TlBS 1 and the mn'ebranes removed from the apparatus. FollowingU additional extenswe washing with TBS-T, the membranes were stained for two hours at room tempeiatur w.ith a I:20O000 dilution of horseradish peroxidase-conjugated 2.5 goat ani urnan lg(heavy and light chain) secondary amibody (SouthemiBiotech, Birmingham, Al"). After extensive washing of the membranes with TBSJ. antibody .onmpl exes were detected using Supersinal@I West Pico Chemiluninescent Substrate (Thermo Scientific, Rockford, IL with cemiilhmine-scent bands visualized on HyBlUot Cilautoradiography film (Denville Scientific, Inc, Metuchen, NJD 30 Indirect inmunoluorescence studies to detect the presence of anti endothelial cell antibodies. Serum samples were diluted to a dilution factor of 1 100 and incubated with human cutaneous endothelial cells. Antbodv biindng was detected using a fluoreseeinconjugated goat antihumnan IgG (diluted 1.100 in PBS; Caltag, Buringare. CA). Fluesorsen-antibody VistplCesere visualized using an Olympus microscope and images were recorded with a digital camera, 5 !izawgLeg2sAggdi CUnical history. Over a two-year period, a 43ear old previously healthy male developed asymptomatie snal cutaneous lesions initial defined by raised paiul1 lesions eventuating inko w scars On ( 2 3 y 29, the patient entered the emergency room with a three-day history of intermittent low grade fevers 10 accompanied by severe abdominal pain and green tiged vomiting, An exploratory laparotomy was performed a small segment of bowel was removed, Both the skin and bowel specimens showed classic changes associated with Degos' Disease No Sanicardilipin ai anti-beta 2 glycoprotein antibodiesor l upus anticoagulant was detected. Additonal laboratory tests confined abnormally elevated serum factor 15 V levels (199 above normal, elevated von Willebrand factor (IVWF) levels (217 above normal and increased vascular endothelial cell growth factor (VEGf levels. While the coiplemen tcomponent proteins C2, C3 and C4 were determined to be witin normal levels. C5 levels were elevated. A thoracocentesis was performed on the patient to relieve the pneumithorax 20 The patient was started on intravenous gamma globulin and Lovenox at 490 mg daily, During a follow up visit on 12 August 2009, the patient had lost 15 pounds due to decreased appetie attrbutable to persistent abdomiralpain- A exam of the patient demonstrated decreased breath sounds in the bibasilar regions. The patient's C reactive protein, VWFI and VEGiF levels remained elevated at 6,5 r, 77 25 and 971, respectively. After four treatments of I V10 there was some improvement in the patients skin lesions, alhough the patient continued to sufkr from abdominal pain, In October 2009, the patient developed chest pain and shortness of breath, Which necessitaed hospital admission. The patient quickly decomnpensated hemodynanicaly and was placed in the medical intensive care unit, The patient vas 30 noted to have an ejection fraction of 14% associated with a large pericardial and plural effusion, A pericardial biopsy was obtained that confirmed a severe thrombotic microangiopathy consistent with Degos' disease Vascular C5b-9 60 deposition was also observed, Eculizumab was then administered to the patient An a)rmost ignnediate irprovenient in the patient s condition occurred. Fr example the patients ejection fraction improved draanatical Witin 2-4 hours of receiving the eculizumab, the patient was extubated and transferred to te medical ward Over the 5 next several weeks, the patient was syntomatiealif better and there was an objective improvement in the appearance of his skin lksions, Pathology, Three sets of skin biopsies were obtained from the patient The tUe at which these biopsies were performed waistemporally associated with 10 variations in treatment intervention, The first set was obtained from the patient prior to the administration of either IVIG or eculizumab to the patient and included two evoltionary phases of his ski lesions, One biopsy was from a raised papular lesion revealing striking mesenchvmai mucin deposition morphologic. ending that ied to an initial erroneous diagnosis of tunid hFpus erythematosus two vearspreviously, 15 Exam mad on of the vascul a ture revealed abnormalities including endothe l e swelig, necrosisand detachment with focal mural and luminaifibrin depo A, biopsy of the classic Deg o' disease associated porcelain depressed scarred papule demonstrated prominent epidermal thinning and dermal fibrosis with vascdar drop out. Thevessels demonstrated an extensive occlusive thrombotie microangiopathy 20 with endothelial cell degenerationeeom'is and endothelial cell sloughing into the vascular lumen. All of the biopsies revealed a dearth of inflammatory cells. The bowel specimen showed an extensive obliterative. caseulopathy affecting larger caliber arteries of the submucosa. Several weeks after commeneing VIG, another skin biopsy was obtained, 25 analysis of whch revealed persistent cutaneous ischemic changes including ucin. tibrosis and epithelial thinning, [However there was a reduction in the extent of active vascular ininry. Vessels containing significant lunial and mural fibrin deposition were not observed. An additional set of biopsies (thetird set) was obtained from te patient two 30 weeks after administration of ceuizumab. Analysis of the biopsied tissue revealed superficial fibroplasias with vascular drop out The vessels were th sickened reflecting basement membrane zone redupieadon Only rare vessels exhibited endothelal cclen damage and thrombosis. 61 Interferon alpha assessment in tissue samples. There was extensive expression of MxA protein in endothl al cells' inflammatory cells, and epidermral kerati nocytes. C5ba9 imm runo fluoresenee~ studies. in direct inmmnoduorescence studies revealed extensive deposits of (I75b-9 within the cutaneous vasculature of the first set of biopsies prior to commencing WIG and or eculizumab, The deposition pattern was both ntr nalunal and mural The extent of deposition was very promnet i nvolxing 10 several vessels throughout the dermis Althougth WVIG reduced C5bN9 deposition to some degree. the extent of CIlb-9 deposition observed in biopsies obtinned from the patent fol lowi n ecd iumab thrapy was markedly diminished Oav, three vessels showed mural C5bi9 deposition. 15 Electron Microscopy, Ultrastructural analysis of the biopsied tissue obtained prc-ttitrnmant showed extensive tubular reticultar structures in the epiderma keratinoeytes and in endothelial celis throughout the dermis. The linng endothelial celis showed profound degenerative chan ges with detachment of the cc ls from the vesselumens. The vascular basement membrane zones were redupTicated and also 20 showed, by collagen deposition. Antiendothelial cel antibody assay. Patient serun obtained prior to ecu dizumab treatment and serum obtaied two weeks following eculizumab treatment were incubated with cutaneous endothelial cells and fluoresceinwconjugated human 25 anti IgG antibodies. A grana lar nuclear decoration was observed in most of the endothehial cells in the pre- and post-eculizumab treatment samples. No staining was observed when the patient seram was contacted to human unbi licaI vein endothelal cells. 30 Western blot studies using endothelial eel lysates. The pre- and post treatment patient serum was also used in a Westen blot analysis to identifV the pro tein or proteins to which the humain-anti-human antbodes in the patient serum bind, As described above, the pre and post-treatment serum was incubated with a membrane contaning the size-resolved andothelial cell proteins and any binding of antibodies to tohe proteins of the membrane was detected by way of a fuorescein con jugated secondary atibody A distinct band of immunoreactivity cOrresponding 5 to a rnolecudar weight of 92 kDa was observed, A similar band of reactive was not identified in normalcontrol cases or in Westem blots of ivsates of human umbilical vein endothelial cells Assessment of serom interferon alpha levels aiterferonalpha levels in the 10 peripheral blood of the patient were very high -measuring 20.6, which was comparable to patients having 1upus erythematosus and several fold higher than interferon. alpha levels in blood front healthy patients Discussion, The patient described herein developed nultifocal intestinaL 15 pericardial, myocardial and cutaneous ischemia, attributable to prominent endothelial cell mty. The patient's symptoms were consistent wih Degas Disease. Usig utaneouts endothelial cells as substrate, there was evidence of anti-endothelial cell antibodies ing indirect innumofluorescence and Western blot ichniques. A dominant antigenic epitope was isolated based on Westem lot analysis, although its 20 identity is unclear. In view of the finding that the anti-endothelial cell antibodies were not reactive with hmannumbilical vein cells.it is likely thatthe atiendothelial cell antibodies observed in l-s Patiet were organ selective, vhereby the inmunogenicity to the selected endothel ial el based epitope is site dependent The studies described herein imniplicate complement-nediated endothelial 25 injury as the hkely effctor miechanisrn in the Degos' disease patient treated with eculizumab. There was a. dramatic objective clinical and pathological response to the admi.sfration of the drug Interferon alpha expression was markedly increased in the patient's serum as well as within his tissue Interferon alpha is known to upregulate adaptive and innate 30 inurnty, potentiating the effects of any antigenic trigger The administration of exogenous interferon alpha has been reported as a cause of cutaneous thrombosis and uIceration. The patient's interferon alpha signature in the peripheral blood was remarkably similar to that observed in patients with SLEalthough he had no specific 63 clinical features of systemic lupus eryhematosus The findings described herein support a conclusion that anhbion of interferon alpha in patients with iDgosi disease can be use for treating the disease, In conclusion, ecudizumab definessan. important therapeutic modality to treat 5 Degos disease that is otherwise fatal, The exact trigger to the activation of the cornlenent cascade sequence is unclear. While anti-endothelial cele antibodies (e.g., autoantibodies that bd to a 92 kDa antigen present on endotheil cells) pro oking activation of the classic complement cascade sequence may be causative of C b) deposition, the role of pitope szpreading in the natural course of tissue ir'ury 10 precludes establishing a direc causal effect of these antibodies, Nonetheless at some point in the paticts cinicA course additional 3 cell targeted therapies to reduce the production of these antibodies would be useful for the treatnent of Degos disease provided that the autoantibodies persist. 15 While the present disclosure has been described vith reference to the specific ernbodincnts thereof it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the disclosure. In addition nany mod ifions may be made adapt particular situation, material, comostonofmttr prcspoessep 20 or steps to the objective spirit and scope of the pre-sent disclosure. All such modicatdons arc intended to be within the scope of the disclosure, 64