WO2012119989A2 - Procédés et anticorps pour le diagnostic et le traitement du cancer - Google Patents

Procédés et anticorps pour le diagnostic et le traitement du cancer Download PDF

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WO2012119989A2
WO2012119989A2 PCT/EP2012/053759 EP2012053759W WO2012119989A2 WO 2012119989 A2 WO2012119989 A2 WO 2012119989A2 EP 2012053759 W EP2012053759 W EP 2012053759W WO 2012119989 A2 WO2012119989 A2 WO 2012119989A2
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seq
antibody
variable
amino acid
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WO2012119989A3 (fr
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Maria Natividad LOBATO-CABALLERO
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Oryzon Genomics, S.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3069—Reproductive system, e.g. ovaria, uterus, testes, prostate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/77—Internalization into the cell
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70503—Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3

Definitions

  • the invention relates to antibodies/binding molecules that specifically bind to Cell Adhesion Moiecule-1 (CADM 1 ).
  • CAM 1 Cell Adhesion Moiecule-1
  • the use of these antibodies/binding molecules in human and veterinary medicine, for example in the treatment and diagnosis of melanoma, prostate cancer and other cancers is also subject of the present invention. Further, compositions comprising the antibodies are also provided herein.
  • PSA prostate-specific antigen
  • PSA has shown important limitations in the diagnosis of prostate cancer, especially a low specificity.
  • Several non-cancer conditions frequently lead to serum PSA elevations.
  • Benign prostate hyperplasia (BPH) is the most common cause of false positives due to the increasing prevalence with advancing age.
  • Prostatitis, prostatic manipulation and some medical interventions are other processes which lead to unspecific increased PSA (Nadler ei al. (1995) J. Urol. 1 54, 407-413).
  • 15% of prostate cancer cases occur in patients with low serum PSA levels (Thompson et al. (2004) N, Engl. J, Med. 350, 2239-2246).
  • PSA and free PSA are the only two assays approved by the FDA for the testing of prostate cancer.
  • the ratio of free to total PSA (%fPSA) lowers in men with prostate cancer (Christensson et al. (1 993) J. Urol. 105, 100-105).
  • %fPSA was able to predict a future diagnosis of aggressive cancer up to 1 0 years prior to diagnosis (Carter et al. (1 997) Urology 49, 379-384, Partin et al. (2003) J. Urol. 1 69, 384).
  • the performance of this biomarker is also affected by prostatic manipulation (Lilja ei al.
  • PSA density incorporates the prostate size of each individual and is associated with a greater risk of prostate cancer as compared to BPH (Catalona ei al. (2000) Urology 56, 255-260).
  • PSA velocity is defined as the change in PSA per year (ng/m!/year) and has been shown by several studies to be a good predictor of the presence of prostate cancer and aggressiveness (Carter et al. (1992) Cancer Res. 52, 3323-3328, D'Amico et al. (2004) N. Engl. J. Med. 351 , 125-135, Carter et al. (2006) J. Natl. Cancer Inst. 98, 1 521 -1 527).
  • PSADT PSA doubling time
  • prostate cancer biomarkers are under study for prostate cancer screening, detection and prognostication.
  • This group includes serum markers such as EPCA (Dhir et a!. (2004) J Urol. 171 , 1419-1423, Uetsuki et al (2005) J Urol. 1 74, 514-518) and EPCA-2 (Leman et al. (2007) Urology 69, 714-720); tissue markers such as AMACR (Luo et al (2002) Cancer Res. 62, 2220-2226, Rubin ei al. (2002) JAMA 287, 1 662-1670), methylated GSTP1 (Lee et al. (1994) PNAS 91 , 1 1733-1 1737, Harden et al. (2003) J Urol. 1 69 , 1 138-1 142), TMPRSS2-ETS gene rearrangement (Tomlms et al. (2005) Science 31 0, 644-648); and urine markers.
  • serum markers such as EPCA (Dhir
  • TIMP-2 (Ross et al (2003) Mod Pathol. 16, 198-205), some M MPs (Morgia ei al. (2005) Urol Res. 33, 44-50, Brehmer ef al. (2003) prostate Cancer Prostatic Dis. 6, 217-222) including MMP-7 (Hashimoto et al. (1 998) J Urol. 160, 1 872-1876), PSMA (Xiao et al. (2001 ) Cancer Res. 61 , 6029-6033, Chikkaveeraiah ei al. (2009) Anal Chem. 81 , 9129-9134) or CGA (Sciarra et al. (2009) Urol Int. 82 , 147-151 ).
  • MMP-7 Hamoto et al. (1 998) J Urol. 160, 1 872-1876
  • PSMA Xiao et al. (2001 ) Cancer Res. 61 , 6029-6033, Chikkaveeraiah ei al.
  • the prostate cancer urinary biomarkers identified are mainly DNA-, RNA- or protein-based biomarkers.
  • Methylated GSTP 1 can be detected in urine with methylation specific PCR and used to detect prostate cancer with a high specificity but low sensitivity (Goessl et al. (2000) Cancer Res. 60, 5941 - 5945, Jeronimo ei al. (2002) Urology 60, 1 131-1 1 35) that can be improved by previous prostate massage (Goessl ef al. (2001 ) Urology 58, 335-338).
  • Several RNA biomarkers can be detected by PCR on urine sediments obtained after prostatic massage with good sensitivity and specificity, mainly PCA3 (DD3) (Fradet et al. (2004) Urology 64, 31 1 -31 6, Deras et al. (2008) J Urol . 1 79, 1 587-1 592) and TMPRSS2: ERG fusion transcripts (Hessels et al.
  • the group of protein urinary biomarkers includes thymosin ⁇ 1 5 (TB- 5) (Hutchinson ef al. (2005) prostate 64, 16TM 1 27, Hutchinson ef ai (2005) Clin Biochem 38, 558-571 ), AMACR (Rogers et al. (2004) J Urol 1 72, 1 501 -1 503), mini-chromosome maintenance-5 (MCM- 5) (Stoeber et a!.(2002) J Natl Cancer Inst.
  • Today screening for prostate cancer usually includes PSA determination in serum and a DRE (digital rectal examination). Depending on the results, diagnosis of prostate cancer is confirmed or excluded by a prostate biopsy. 6-10 samples of different areas of the prostate are obtained and analyzed by an expert pathologist. Samples undergo microscopic examination and the clinical stage (TIM system) and Gieason grade are scored.
  • DRE digital rectal examination
  • TNM classification is as follows (European Association of Urology, Aus G , Abbou CC, Bolla M, Heidenreich A, Van Poppei H . , et al . EAU Guidelines on prostate Cancer. 2007):
  • T primary tumor extension. Subdivided in different categories from TO (no evidence of primary tumor) to T4.
  • N propagation to regional lymph nodes. NO (absence) or N1 (presence).
  • M propagation to distant lymph nodes or metastatic sites. May be M0 (absence) or M 1 (presence)
  • the grading system proposed by Gieason (Gieason et al (1974) J Urol. 1 1 1 ,58-64) is based on a pathological examination of prostate tissue obtained by a biopsy. The result is an average index of abnormality, for which values between 2 and 10 can be taken .
  • G 1 Well differentiated (weak anap!asia): Gieason 2-4.
  • G2 Moderately differentiated G2 (moderate anaplasia): Gieason 5-6.
  • patients diagnosed with prostate cancer are stratified into three risk groups (low, intermediate and high) based on ciinical and pathological variables: PSA at diagnosis, Gleason score and clin ical tumor stage (prostate. In; AJCC Cancer Staging Manual. Eth ed. New Your, Springer, 2002, pp 309-316, Montie (1 995) Cancer 75 (7 Suppl), 1814-1 818).
  • CADM 1 Cell adhesion molecule-1 or CADM 1 , also known as tumor suppressor in lung cancer 1 (TSLC 1 ), immunoglobulin superfamily member 4(I GSF4), synaptic celi adhesion molecule (synCAM) and other aliases, is thought to mediate cell-cell adhesion in a Ca ⁇ + independent manner and in some cancers is thought to act as a tumor suppressor, CADM1 is a member of the immunoglobulin super family of proteins.
  • CADM 1 has tumor suppressor activity with loss of expression associated with poor prognosis in some lung cancers (Goto et al. (2005) Cancer Sci. 96:480-486), colorectal cancer (Chen et al. (201 0) Int J. Cancer 128(2), 266-73), melanoma (You et al, Melanoma Research 2010, 20: 1 79-83) and prostate cancers (Fukuhara et al. ((2002) Jpn J. Cancer Res. 93(6), 605-9)) amongst others.
  • CAD 1 is a therapeutic and diagnostic target; in particular, CADM 1 has been proposed as a therapeutic target for some types of lung cancer (Kitamura et al, Biochem.
  • CADM1 Antibodies to CADM 1 are described in e.g. , US pub. no. 2009/0053243 to Kurosawa et al. and WO 2010/1021 75 to Terret et al. Characteristics of CADM1 include (see e.g., Ito et al. ((2008) J. Smooth Muscle Res 44:83-93); Watabe et al. (2003) Histol. Histopathol. 1 8: 1321 -1 329; and Kawano ei al. (2009) J. Biol. Cfrem.284(35)23793-805j; - interaction with CRTAM and promotes natural killer (NK) eel! cytotoxicity and interferon-gamma (I FN-gamma) secretion by CD8 ⁇ cells in vitro as wei! as NK cell-mediated rejection of tumors expressing CADM3 in vivo;
  • NK natural killer
  • CADM1 the extracellular region of CADM1 directly interacts in cis with that of ErbB3 and reduces the H RG-induced signalling pathways of the ErbB3/Erb82 heterodimer for cell movement and survival;
  • CADM1 Fukuhara et at. ⁇ (2002) Jpn J, Cancer Res, 93(6), 605-9) report that CADM1 is absent or markedly reduced in 3 out of 4 prostate cancer cell lines. In PPC-1 cells the CADM 1 promoter was heavily methylated and significant methylation was found in primary prostate cancers also. Lastly restoration of CADM1 in PPC-1 cells in nude mice suppressed tumor formation.
  • Murakami Cancer Sci 2005 96(9):543-552
  • TSLC 1 is inactivated in numerous cancers including 44% of non-smali ceil lung cancers and 30- 60% of other cancers including liver, pancreatic and prostate cancers, more prominently in those with invasion or metastasis.
  • CADM 1 (TSLC1 ) was lost in 84 of 120 cutaneous melanoma samples, and further that CADM1 promoter was methylated in 58 of 1 20 samples.
  • the incidence of the loss of CADM1 expression and methylation of CADM 1 significantly increased as the tumor stage advanced. CADM1 was accordingly speculated as a tumor suppressor in cutaneous melanoma.
  • the invention relates to the finding that CADM1 is overexpressed in prostate cancer tissue as compared to normal tissue in biological samples at the RNA and protein level.
  • the studies described herein show that CADM1 was overexpressed in prostate cancer tissues as compared to control values obtained from matched non- affected tissue using expression microarray data in two independent sample sets.
  • CADM1 was also overexpressed at the protein level in prostate tumor tissue in a new set of samples on a tissue microarray.
  • the inventors have shown that CADM1 is upreguiated in a statistically significant manner in prostate cancer at the mRNA and upregulation at protein level is also observed.
  • the overexpression of CAD 1 was found in prostate cancers having diverse histologies and stages.
  • CADM1 is a tumor, blood, serum, plasma, and/or urine based biomarker for the detection of prostate cancer.
  • a CAD 1 biomarker may be a protein or nucleic acid biomarker which correlates to the levels of CADM1 protein or mRNA.
  • the invention also provides experimental data showing that CAD 1 is expressed in melanoma and colon cancer and that melanoma and colon and/or colorectal cancer can be addressed via targetting CAD 1 .
  • CADM1 is a target for a cancer therapeutic target.
  • the invention therefore provides a method for treating cancer comprising administering to an individual in need of treatment a therapeutic agent that modulates CADM1 levels or activity, in a more specific aspect, the invention provides a method for treating melanoma, colon and/or colorectal cancer or prostate cancer comprising administering to an individual in need of treatment a therapeutic agent that modulates CADM1 levels or activity.
  • the therapeutic agent that modulates CAD 1 is chosen from an antisense molecule, an interfering RNA molecule, a small organic molecule, and a therapeutic antibody or fragment thereof.
  • the therapeutic agent is an antibody or fragment thereof that binds CADM1 protein.
  • CADM1 is a diagnostic cancer biomarker. In one aspect of this embodiment, CADM1 is a diagnostic marker for prostate cancer.
  • the invention provides a method for diagnosis of cancer by determining the level of a CADM1 biomarker in a biological sample from an individual wherein an altered level of CADM1 biomarker in the biological sample is diagnostic of cancer or an increased likelihood of cancer.
  • the invention provides a method for diagnosis of prostate cancer by determining the level of a CAD 1 biomarker in a biological sample from an individual wherein an altered level of CADM1 biomarker in the biological sample is diagnostic of prostate cancer or an increased likelihood of prostate cancer.
  • an increased or elevated level of CADM1 biomarker in the biological sample is diagnostic of prostate cancer or an increased likelihood of prostate cancer.
  • the biological sample is chosen from tissue, tumor, blood, serum, plasma and urine.
  • the CADM1 biomarker can be a nucleic acid or protein biomarker.
  • PCR quantitative PCR
  • muitipiex PCR nucleic acid microarray
  • RNase protection assays serial analysis of gene expression (SAGE)
  • SAGE serial analysis of gene expression
  • immunohistochemistry western blot
  • ELISA radioimmunoassay.
  • protein levels of CADM1 are determined using an antibody or fragment thereof that binds CADMI protein.
  • the invention provides an antibody or fragment thereof to CADM1 protein or a CADM1 fragment or epitope, !n one aspect of this embodiment, the invention provides an antibody or fragment thereof that binds to CADM1 or a CADM1 epitope.
  • the CADM1 epitope is chosen from one or more of the peptide sequences of CADM1 as described in more detail below, in one aspect of this embodiment, the CADM1 epitope is an extracellular epitope. In one aspect of this embodiment, the CADM1 epitope is an intracellular epitope.
  • the antibody or fragment thereof is chosen from a monoclonal antibody or a recombinant antibody, or a fragment thereof that binds to CADM1 or a CADM1 epitope
  • the antibody or fragment thereof is a recombinant antibody chosen from a chimeric antibody, a humanized antibody, a fully human antibody, or a fragment thereof, that binds to CADM1 or a CADM1 epitope.
  • the antibody or fragment thereof is a monoclonal antibody or fragment thereof that binds to CADM1 or a CADM1 epitope.
  • the antibody or fragment thereof is a recombinant antibody or fragment thereof that binds to CADM1 or a CADM1 epitope. In one aspect of this embodiment, the antibody or fragment thereof is a chimeric antibody or fragment thereof that binds to CADM1 or a CADM1 epitope. In one aspect of this embodiment, the antibody or fragment thereof is a humanized antibody or fragment thereof that binds to CAD 1 or a CADM1 epitope. In one aspect of this embodiment, the antibody or fragment thereof is a fully human antibody or fragment thereof that binds to CADM1 or a CADM1 epitope. In one aspect of this embodiment, the antibody or fragment thereof binds selectively to CADM1 or a CADM1 epitope.
  • the antibody or fragment thereof binds specifically to CADM1 or a CADSV11 epitope.
  • the antibody to CADM1 is conjugated to another agent.
  • the antibody or fragment thereof is conjugated to a toxin, a therapeutic agent, or a detectable label.
  • the antibody or fragment thereof blocks an active site or a binding site on CADM1 or inhibits the activity of CAD 1 or a CADM1 fragment or epitope, in one aspect of this embodiment, the antibody is a therapeutic antibody or a diagnostic antibody.
  • the antibody is a therapeutic antibody.
  • the antibody is a diagnostic antibody.
  • the present invention relates to antibodies, antibody fragments or binding molecules specifically binding to CADM1 .
  • binding moiecu!e in accordance with this invention relates to functional fragments or functional derivatives of the herein disclosed and the herein defined antibodies. I n one embodiment, these antibodies, antibody fragments or binding molecules comprise the variable regions and/or CDRs as provided herein .
  • the invention also provides for antibodies/binding molecules that comprise CDRs and/or variable regions that are at least 75% identica! in their protein sequence (amino acid identity) to one or more of the CDRs and variable regions as provided herein.
  • the present invention also provides for antibodies that bind to/recognize the same epitope as any of the antibodies as disclosed herein.
  • Preferred antibodies of the invention as disclosed below exhibit remarkable functionai properties, which make them particularly suitable for use in the therapy or diagnosis of CAD 1 -mediated disorders, including cancer, in particular, said antibodies exhibit one or more of the following properties:
  • CADM 1 -expressing cells including CADSVS1 -expressing cancer ceil lines, resulting in very potent cancer cell-killing effects when administered conjugated with another agent such as a toxin .
  • They are thus very effective carriers for targeted delivery of cancer-ceil killing agents into cancer cells. Particularly good results have been obtained against melanoma, colon cancer and prostate cancer cell lines;
  • the invention further provides nucleic acids encoding the antibodies/antibody fragments or binding molecules according to the invention.
  • vectors such as expression vectors, comprising said nucleic acids, and host ceils comprising said nucleic acids or said vectors.
  • the invention further provides a process for the production of an antibody/antibody fragment/binding molecule as disclosed herein , said process comprising culturing a host comprising a nucleic acid or vector encoding said antibody/antibody fragment/binding molecule under conditions allowing the expression of the antibody/antibody fragment/binding molecule and recovering the produced antibody/antibody fragment/binding molecule from the culture.
  • a method for identifying an antibody or fragment thereof that binds to a CADM1 protein or a CADM1 epitope comprising: (a) providing a CADM1 protein or CADM1 epitope; (b) contacting said CADM1 protein or CADM1 epitope with an antibody or fragment thereof; and (c) identifying an antibody or fragment thereof that binds to a CADM1 protein or CADMI epitope.
  • a monoclonal antibody that binds to a CADM1 protein or CADM1 epitope prepared by a process comprising: (a) providing a hybridoma capable of producing the monoclona!
  • the invention further includes a hybridoma that produces the monoclonal antibody described herein.
  • a recombinant antibody that binds to CADM1 or a CADM1 epitope prepared by a process comprising: (a) providing a cell line capable of producing a recombinant antibody; and (b) culturing the celi Sine under conditions that provide for the production of the recombinant antibody by the ceil Sine.
  • the invention further includes a celi line that produces a recombinant antibody described herein.
  • the invention provides nucleic acid based cancer diagnostic reagents for detecting the levels of a CADM1 biomarker.
  • the invention provides nucleic acid based cancer therapeutic agents for modulating the level or activity of CADM1.
  • FIG. 1 illustrates results of cell viability studies with severai antibodies of the invention (squares indicate Antibody-8 and triangles indicate Antibody-10).
  • the upper panel is with LNCaP cells and the bottom panel is with DU145 cells. See Example 8 for description.
  • FIG. 2 illustrates results of cell adhesion studies with Antibody-10 of the invention using DU145 cells and Fibronectin as indicated. See Example 8 for description.
  • FIG. 3 illustrates results of cell migration studies with Antibody-10 of the invention using BxPC3 cells. See Example 8 for description.
  • Figures 4, 5 and 6 illustrate the results of the specificity study disclosed in Example 19 with AB2 (Fig 4), AB3 (Fig 5) and AB10 (Fig 6), respectiveiy.
  • the graphs show the signal detected on CHO cells, negative for CADM1 expression (grey), no transfected Clon 139 (dotted grey line), C!on 139 transfected with an siRNA control (grey line), and Clon 139 transfected with siRNA s24325 selected to reduce CADM1 expression (black line).
  • Figures 7, 8 and 9 show the signal detected on CHO transfected with each CADM family member (A: CADM1 ; B:CADM2; C: CADM3; D:CADM4) after incubation with AB2 (Fig 7), AB3 (Fig 8) and AB10 (Fig 9) and anti-human fluorescence secondary antibody. See example 20 for description.
  • Figures 10 and 1 1 Fig 10 illustrates the results of affinity studies to CADM1 by cytometry with AB10 using A375 ceils, and Fig 11 shows the results obtained with AB3 using SKOV3 cells. See example 21 for description.
  • the graphs show a representation of concentration of the antibody versus value of FACS Geometric mean .
  • Figure 12 and 13 illustrate the effect on cell viability of the antibody- saporin conjugates AB3-SAP (Fig 12) and AB10-SAP (Fig 13) in the assay disclosed in Example 24 using A375 cells.
  • the graphs show a representation of % cell viability versus concentration of the antibody.
  • the invention relates to the finding that CADM1 is overexpressed in prostate cancer tissue as compared to normal tissue at the RNA and protein level.
  • the studies described herein show that CADM1 was overexpressed in a first set of samples having 27 primary prostate cancer tumor tissues as compared to matched non- affected tissue.
  • a second study with 7 prostate cancer tumor samples compared to non-affected matched tissue confirmed the first study showing that CADMI was overexpressed in these samples.
  • CAD 1 it was found that it was also overexpressed at the protein level in tumors in another set of samples which included high grade PINs, low-grade and high-grade prostate adenocarcinomas on a tissue microarray.
  • CADM1 is upregulated in a statistically significant manner in prostate cancer at the mRNA. Furthermore, the overexpression of CADM1 is observed at the protein Ievel. The overexpression of CAD 1 was found in prostate cancers having diverse histologies and stages. Without wishing to be bound by any particular theory, the inventors believe that given the above results, and with knowledge of the properties of CADM1 , CADM1 is a biomarker as well as a therapeutic and/or diagnostic target for prostate cancer. In particular, the inventors have found a group of antibodies that bind CADM1 and have surprising therapeutic or diagnostic benefits.
  • CADM1 is a tissue, tumor, blood, serum, plasma, and/or urine based biomarker for the detection of cancer, including prostate cancer, melanoma and colon and/or colorectal cancer.
  • the CADM1 biomarker can be a protein or nucleic acid biomarker.
  • CADM1 is expressed in melanoma and colon cancer ceil lines and that melanoma and colon and/or colorectal cancer can be addressed via targeting CADM1 expressed in said cancers.
  • the inventors have identified a group of antibodies or binding agents against CADM1 that exhibit high affinity and specificity for CADM1 and are particularly suitable for use as therapeutic or diagnostic agents for disorders or diseases wherein CADM1 is expressed or involved.
  • These antiCADMI antibodies are particularly suited for use in the field of cancer, particularly in melanoma, colon and/or colorectal cancer and prostate cancer.
  • Therapeutic Antibodies to CADM1 protein and CAD 1 epitopes are particularly suited for use in the field of cancer, particularly in melanoma, colon and/or colorectal cancer and prostate cancer.
  • the invention provides a therapeutic antibody or fragment thereof that binds to a CADM1 protein or a CADM1 epitope.
  • the therapeutic antibody or fragment thereof is a monoclonal antibody or fragment thereof or a recombinant antibody or fragment thereof that binds to CADM1 or a CADM1 epitope.
  • the therapeutic antibody or fragment thereof is a monoclonal antibody or fragment thereof that binds to CADM1 or a CADM 1 epitope.
  • the therapeutic antibody or fragment thereof is a recombinant antibody or fragment thereof that binds to CAD 1 or a CAD 1 epitope
  • the recombinant antibody or fragment thereof that binds to CADM1 or a CADM1 epitope is chosen from a chimeric, humanized, or fully human antibody or a fragment thereof.
  • the therapeutic antibody or fragment thereof is a chimeric antibody or fragment thereof that binds to CADM1 or a CADM1 epitope.
  • the therapeutic antibody or fragment thereof is a humanized antibody or fragment thereof that binds to CADM1 or a CADM1 epitope.
  • the therapeutic antibody or fragment thereof is a fully human antibody or fragment thereof that binds to CADM1 or a CADIV11 epitope.
  • the therapeutic antibody or fragment thereof to CAD 1 or a CADM1 epitope is conjugated to a toxin and/or therapeutic agent.
  • the therapeutic antibody (or fragment thereof) as described above in this paragraph can be provided as a pharmaceutical composition comprising the antibody (or fragment thereof) and a pharmaceutically acceptable carrier.
  • the therapeutic antibody or fragment thereof as described above in this paragraph binds selectively to CAD 1 or a CADM1 epitope.
  • the therapeutic antibody or fragment thereof binds specifically to a CADM1 protein or a CADM1 epitope.
  • the therapeutic antibody of the present invention can be generated against a CADM1 protein or an epitope of a CADM1 protein.
  • the therapeutic antibody of the present invention binds to a CADM1 protein or an epitope of a CAD 1 protein, in one embodiment, the therapeutic antibody binds to or can be generated against a polypeptide having the full length sequence of a CADM1 protein as in SEQ ID NO;1- 3 ⁇ See Example 4).
  • the binding site or epitope for therapeutic antibody is located on an extracellular domain of the protein as defined by the amino acid sequence as in SEQ ID NO:4.
  • the therapeutic antibody binds or can be generated against a epitope having the amino acid sequence of one or more of SEQ ID NOs:5-16, below which represent preferred epitopes of the extracellular domain of CADM1.
  • SEQ ID NO: 7 SRFQLLNFSSSEL VSLTIMVSISDEGRYFCQLYTDPPQESYTTITVLVPPRN
  • a preferred epitope is chosen from the amino acid sequences as in SEQ ID NO:4- 16.
  • the epitope is the amino acid sequences as in SEQ ID NO:4.
  • the inventors have identified a number of antibodies raised against a CAD 1 epitope.
  • the CDR sequences as deduced from their corresponding nucleic acid sequences from the light and heavy chains were determined for these antibodies and are listed below.
  • AB1 is Antibody- 1 of the invention; AB2 is Antibody-2 of the invention; VL_CDR1 AB3 is the first CDR of the light chain of Antibody-3 of the invention. See Tabie 7 and Table 8 in Example 7.
  • VL_CDR1 AB 1 SEQ ID NO: 17 QGDTFRTYYAS
  • VL_CDR1 AB3 SEQ ID NO: 19 QGDSLRTYYAS
  • VL_CDR1 AB4 SEQ ID NO:20 SGDRLGETYVS
  • VL_CDR1 AB5 SEQ ID NO:21 SGDKLGD YAS
  • VL_CDR1 AB6 SEQ ID NO:22 SGDRLGETYVS
  • VL_CDR2 ABI VL_CDR2 ABI ; SEQ ID NO: 29 GEN RPS
  • VL_ CDR3 ABI SEQ ID NO:41 HSRDNSGHLHV
  • VL _CDR3 AB6 SEQ ID NO:46 QAWVGSTPFV VL_CDR3 AB7; SEQ ID NO:47 CQQSNSMPPS VL CDR3 AB8; SEQ ID NO:48 QAWVGSTPFV
  • VH_ CDR1 AB3 VH_ CDR1 AB3 ; SEQ ID NO:55 RYPMY
  • VH_CDR1 AB4 SEQ ID NO:56 SYKMN
  • VH_CDR1 AB6 SEQ ID NO:58 KYEMV
  • VH_CDR1 AB8 SEQ ID NO:60 SYKMN
  • VH_CDR2 AB l SEQ ID NO:65 SIGSSGGYTKYADSVKG VH_CDR2 AB2; SEQ ID NO:66 YIVPSGGATLYADSVKG VH_CDR2 AB3; SEQ ID NO:67 SISSSGGLTHYADSVKG VH_CDR2 AB4; SEQ ID NO:68 GIGSSGDWTFYADSVKG VH CDR2 AB5; SEQ ID NO:69 WIVPWWQYTKYADSVK VH_CDR2 AB6; SEQ ID NO:70 YIVPSGGATLYADSVKG VH_CDR2 AB7; SEQ ID N0:71 LYLSGGMTHYADSVKG VH ⁇ CDR2 AB8; SEQ ID NO:72 GIGSSGDWTFYADSVKG VH CDR2 AB9; SEQ ID NO:73 YIYSSGGPTPYADSVKG VH_CDR2 AB I O; SEQ ID NO: 74
  • each of these antibodies can bind to CADM1 , their CDRs can be combined to create other antiCADMI antibodies/binding molecules of the invention.
  • CADMI binding of said antibodies generated by combination of the above described CDRs can be tested using the binding assays described in the Examples.
  • therapeutic antibodies of the invention comprise one or more of the CDR sequences above or a sequence at least 75% identical, preferably at least 80% identical thereto.
  • the therapeutic antibody of the invention comprises one or more of the CDR sequences above or a sequence at least 90% identical thereto (e.g. 90%, 95%,96%,97%,98%,99% or more).
  • the invention thus provides an isolated antibody that specif ica!iy binds CADM1 wherein said antibody has one or more CDRs, preferably 2 or more CDRs, more preferably 3 or more CDRs, and still more preferably 6 CDRs, each CDR corresponding to a CDR chosen from the CDRs of Antibody-1 , Antibody-2, Antibody-3, Antibody-4, Antibody-5, Antibody-6, Antibody-7, Antibody-8, Antibody-9, Antibody-10, Antibody-1 1 , or Antibody- 2 as defined herein, or a CDR sequence having 75% or more (e.g . 80%, 85%, 90%,95% ,96%,97% ,98%,99% or more) amino acid identity to said CDR.
  • CDR sequence having 75% or more (e.g . 80%, 85%, 90%,95% ,96%,97% ,98%,99% or more) amino acid identity to said CDR.
  • the invention a!so is a nucleic acid encoding one or more of the above listed CDR sequences or a CDR sequence at least 75% identical, preferably at least 80% identical thereto.
  • the nucleic acid encodes one or more of the above listed CDR sequences or a CDR sequence at least 90% identical thereto.
  • the invention also involves one or more of the CDR sequences above or a CDR sequence at least 75% identical, preferably at least 80% identical, more preferably at least 90% identical thereto wherein said CDR sequences is in the context of an antibody framework.
  • the antibody framework is a human antibody framework.
  • CDR as empioyed herein relates to "complementary determining region", which is well known in the art.
  • the CDRs are parts of immunoglobulins and T cell receptors that determine the specificity of said molecules and make contact with specific ligand.
  • the CDRs are the most variable part of the molecule and contribute to the diversity of these molecules .
  • CDR-H depicts a CDR region of a variable heavy chain and CDR-L relates to a CDR region of a variable light chain.
  • H means the variable heavy chain and L means the variable light chain.
  • the CDR regions of an Ig- derived region may be determined as described in Kabat ( 1991 ), Sequences of Proteins of Immunological I nterest, 5th edit., N I H Publication no. 91 -3242 U .S. Department of Health and Human Services; Chothia (1 987), J . Mo I . Biol . 196, 901 -917; and Chothia (1 989) Nature, 342, 877-883.
  • Each CDR region of a variable heavy chain is herein interchangeably designated as CDR-H1 or VH-CDR1 , CDR-H2 or VH-CDR2, and CDR-H3 or VH-CDR3, respectively.
  • each CDR region of a variable light chain is designated herein CDR-L1 or VL-CDR1 , CDR-L2 or VL-CDR2, and CDR- L3 or VL-CDR3, respectively.
  • the invention provides an isolated antibody that specifically binds to CADM1 , wherein the variable region of the heavy chain of said antibody comprises a VH_CDR3 region having an amino acid sequence as depicted in SEQ ID NO. : 79, SEQ I D NO.: 86, SEQ ID NO. 78, SEQ ID NO.: 77 or SEQ ID NO.: 84.
  • the antibodies may also comprise a CDR sequence having at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95% , at least 96%, at least 97%, at least 98%, or at least 99% amino acid identity to one of said CDRs.
  • variable region of the heavy chain of the antibody of this invention comprises a VH_CDR1 region having an amino acid sequence as depicted in SEQ I D NO: 55, SEQ ID NO: 62, SEQ I D NO: 54, SEQ ID NO: 53 or SEQ !D NO:60 , or a CDR sequence having 75% or more (e.g. 80%, 85%, 90%,91 %,92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) amino acid identity to one of said CDRs.
  • variable region of the heavy chain of the antibody of this invention comprises a VH_CDR2 region having an amino acid sequence as depicted in SEQ ID NO: 67, SEQ ID NO: 74, SEQ I D NO: 66, SEQ I D NO: 65 or SEQ ID NO:72, or a CDR sequence having 75% or more (e.g. 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) amino acid identity to one of said CDRs.
  • the variable region of the heavy chain of said antibody comprises:
  • VH_CDR1 region having an amino acid sequence as depicted in SEQ ID NO: 55
  • VH_CDR2 region having an amino acid sequence as depicted in SEQ ID NO: 67
  • VH_CDR3 region having an amino acid sequence as depicted in SEQ ID NO.: 79;
  • VH_CDR1 region having an amino acid sequence as depicted in SEQ ID NO; 62
  • VH_CDR2 region having an amino acid sequence as depicted in SEQ ID NO: 74
  • VH_CDR3 region having an amino acid sequence as depicted in SEQ ID NO.: 86;
  • VH_CDR2 region having an amino acid sequence as depicted in SEQ ID NO:
  • VH_CDR3 region having an amino acid sequence as depicted in SEQ ID NO.: 78;
  • VH_CDR1 region having an amino acid sequence as depicted in SEQ ID NO: 53
  • VH_CDR2 region having an amino acid sequence as depicted in SEQ ID NO: 65
  • VH_CDR3 region having an amino acid sequence as depicted in SEQ ID NO.: 77 or
  • the antibodies may also comprise a CDR sequence having 75% or more (e.g. 80%, 85%, 90% , 91 %, 92%, 93%, 94%, 95%, 96% , 97% , 98%, 99% or more) amino acid identity to one of said CDRs.
  • variable region of the heavy chain of said antibody comprises:
  • VH_CDR1 region having an amino acid sequence as depicted in SEQ ID NO:
  • VH_CDR2 region having an amino acid sequence as depicted in SEQ ID NO:
  • VH_CDR3 region having an amino acid sequence as depicted in SEQ ID NO.: 79; ( ⁇ ) a VH_CDR1 region having an amino acid sequence as depicted in SEQ I D NO: 62 , a VH_CDR2 region having an amino acid sequence as depicted in SEQ ID NO: 74 , and a VH_CDR3 region having an amino acid sequence as depicted in SEQ !D NO.: 86; or
  • the antibodies may aiso comprise a CDR sequence having 75% or more ⁇ e.g. 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95%,96%,97%,98%,99% or more) amino acid identity to one of said CDRs.
  • variable region of the light chain of said antibody comprises a VL_CDR3 region having an amino acid sequence as depicted in SEQ I D NO . : 43, SEQ I D NO.: 50, SEQ ID NO. 42, SEQ I D NO . : 41 or SEQ I D NO. : 48, or a CDR sequence having 75% or more (e.g. 80% , 85%, 90%, 95%, 96%, 97% , 98%, 99% or more) amino acid identity to one of said CDRs.
  • variable region of the light chain of said antibody comprises a VL_CDR1 region having an amino acid sequence as depicted in SEQ I D NO: 19, SEQ I D NO: 26, SEQ I D NO: 18, SEQ I D NO: 17 or SEQ I D NO:24, or a CDR sequence having 75% or more ⁇ e.g. 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more) amino acid identity to one of said CDRs.
  • variable region of the light chain of said antibody comprises a VL_CDR2 region having an amino acid sequence as depicted in SEQ ID NO: 31 , SEQ ID NO: 38, SEQ ID NO: 30, SEQ !D NO: 29 or SEQ ID NO:36, or a CDR sequence having 75% or more (e.g. 80%, 85%, 90%, 91 % , 92%, 93%, 94%, 95% ,96%,97%,98%,99% or more) amino acid identity to one of said CDRs.
  • variable region of the light chain of the antibody of this invention comprises:
  • VL_CDR1 region having an amino acid sequence as depicted in SEQ ID NO: 19
  • VL_CDR2 region having an amino acid sequence as depicted in SEQ ID NO: 31
  • VL_CDR3 region having an amino acid sequence as depicted in SEQ !D NO.: 43;
  • VL_CDR2 region having an amino acid sequence as depicted in SEQ !D NO:
  • VL_CDR3 region having an amino acid sequence as depicted in SEQ ID NO.: 42;
  • VL_CDR1 region having an amino acid sequence as depicted in SEQ ID NO: 17
  • VL_CDR2 region having an amino acid sequence as depicted in SEQ iD NO: 29
  • VL_CDR3 region having an amino acid sequence as depicted in SEQ ID NO.: 41 ;
  • the antibodies may also comprise a CDR sequence having 75% or more (e.g. 80%, 85% , 90%, 91 % , 92%, 93% , 94% , 95%,96%,97% ,98% ! 99% or more) amino acid identity to one of said CDRs.
  • variable region of the light chain of the antibody of this invention comprises:
  • VL_CDR1 region having an amino acid sequence as depicted in SEQ ID NO:
  • VL_CDR2 region having an amino acid sequence as depicted in SEQ ID NO:
  • VL_CDR3 region having an amino acid sequence as depicted in SEQ ID NO.: 43;
  • VL_CDR1 region having an amino acid sequence as depicted in SEQ ID NO: 26
  • VL_CDR2 region having an amino acid sequence as depicted in SEQ ID NO: 38
  • VL_CDR3 region having an amino acid sequence as depicted in SEQ ID NO.: 50;
  • the antibodies may also comprise a CDR sequence having 75% or more (e.g. 80%, 85% , 90%,91 %,92%, 93% , 94%, 95%,96%,97%,98% I 99% or more) amino acid identity to one of said CDRs.
  • the antibodies/binding molecules etc. of the present invention may be characterized by at least one CDR sequence as described above.
  • the antibody comprises 2 or more CDRs. More preferably, the antibody comprises 3, 4, 5 or more CDRs. Still even more preferably, said antibody comprises 6 CDRs. Yet, even more preferably the antibody comprises a set of 6 CDRs: 3 CDRs in the variabie region of the Iight chain of the antibody and 3 CDRs in the variable region of the heavy chain of the antibody.
  • the invention provides the antibodies as follows:
  • an isolated antibody comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ ID NO: 17, SEQ ID NO:29, SEQ ID NO:41 , SEQ ID NO:53, SEQ ID NO:65, SEQ ID NO:77 or a CDR having an amino acid sequence at least 75%, more preferably at least 90% identical to any of said CDRs.
  • the one or more CDRs are at least 95% identical to said amino acid sequences.
  • said antibody comprises 2 or more CDRs. Even more preferably, said antibody comprises 3 or more CDRs. Still even more preferably, said antibody comprises 4 or more CDRs. Yet even more preferably said antibody comprises 5 or more CDRs.
  • said antibody comprises 6 CDR sequences.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer. Even more preferably, the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • an isolated antibody comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ ID NO: 18, SEQ ID NO:30, SEQ ID NO:42, SEQ ID NO:54, SEQ ID NO:66, SEQ ID NO:78 or a CDR having an amino acid sequence at least 75%, more preferably at least 90% identical to any of said CDRs.
  • the one or more CDRs are at least 95% identical to said amino acid sequences.
  • said antibody comprises 2 or more CDRs. Even more preferably, said antibody comprises 3 or more CDRs. Still even more preferably, said antibody comprises 4 or more CDRs. Yet even more preferably said antibody comprises 5 or more CDRs.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer.
  • the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • an isolated antibody comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ ID NO: 19, SEQ ID NO:31 , SEQ ID NO:43, SEQ ID NO:55, SEQ ID NO:67, SEQ ID NO:79 or a CDR having an amino acid sequence at least 75%, more preferably at least 90% identical to any of said CDRs.
  • the one or more CDRs are at least 95% identical to said amino acid sequences.
  • said antibody comprises 2 or more CDRs. Even more preferably, said antibody comprises 3 or more CDRs. Still even more preferably, said antibody comprises 4 or more CDRs, Yet even more preferably said antibody comprises 5 or more CDRs.
  • said antibody comprises 6 CDR sequences.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer. Even more preferably, the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • an isolated antibody comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ ID NO:20, SEQ ID NO:32, SEQ ID NO:44, SEQ ID NO:56, SEQ ID NO:68, SEQ ID NO:80 or a CDR having an amino acid sequence at least 75%, more preferably at least 90% identical to any of said CDRs.
  • the one or more CDRs are at least 95% identical to said amino acid sequences.
  • said antibody comprises 2 or more CDRs. Even more preferably, said antibody comprises 3 or more CDRs. Still even more preferably, said antibody comprises 4 or more CDRs. Yet even more preferably said antibody comprises 5 or more CDRs.
  • said antibody comprises 6 CDR sequences.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer. Even more preferably, the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • An isolated antibody comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ ID NO:21 , SEQ ID NO:33, SEQ ID NO:45, SEQ ID NO:57, SEQ ID NO:69, SEQ ID NO: 81 or a CDR having an amino acid sequence at least 75%, more preferably at least 90% identical to any of said CDRs.
  • the one or more CDRs are at least 95% identical to said amino acid sequences.
  • said antibody comprises 2 or more CDRs. Even more preferably, said antibody comprises 3 or more CDRs. Still even more preferably, said antibody comprises 4 or more CDRs. Yet even more preferably said antibody comprises 5 or more CDRs.
  • said antibody comprises 6 CDR sequences.
  • the invention is one or more nucieic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer. Even more preferably, the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • an isolated antibody comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ ID NO:22, SEQ ID NO:34, SEQ ID NO:46 5 SEQ ID NO:58, SEQ ID NO:70, SEQ ID NO:82 or a CDR having an amino acid sequence at least 75%, more preferably at (east 90% identical to any of said CDRs.
  • the one or more CDRs are at least 95% identical to said amino acid sequences.
  • said antibody comprises 2 or more CDRs. Even more preferably, said antibody comprises 3 or more CDRs. Still even more preferably, said antibody comprises 4 or more CDRs. Yet even more preferably said antibody comprises 5 or more CDRs.
  • Stili yet more preferably said antibody comprises 6 CDR sequences.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer. Even more preferably, the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • An isolated antibody comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ ID NO:23, SEQ ID NO:35, SEQ ID NO:47, SEQ ID NO:59, SEQ ID NO:71 , SEQ ID NO:83 or a CDR having an amino acid sequence at least 75%, more preferably at least 90% identical to any of said CDRs.
  • the one or more CDRs are at least 95% identical to said amino acid sequences.
  • said antibody comprises 2 or more CDRs. Even more preferably, said antibody comprises 3 or more CDRs. Still even more preferably, said antibody comprises 4 or more CDRs. Yet even more preferably said antibody comprises 5 or more CDRs.
  • said antibody comprises 6 CDR sequences.
  • the invention is one or more nucleic acids encoding said antibody, fn another related aspect, the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer. Even more preferably, the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • An isolated antibody comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ ID NO:24, SEQ ID NO:36, SEQ ID NO:48, SEQ ID NO:60, SEQ ID NO:72, SEQ ID NO:84 or a CDR having an amino acid sequence at least 75%, more preferably at least 90% identical to any of said CDRs.
  • the one or more CDRs are at least 95% identical to said amino acid sequences.
  • said antibody comprises 2 or more CDRs. Even more preferably, said antibody comprises 3 or more CDRs. Still even more preferably, said antibody comprises 4 or more CDRs. Yet even more preferably said antibody comprises 5 or more CDRs.
  • said antibody comprises 6 CDR sequences.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer. Even more preferably, the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer,
  • An isolated antibody comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ ID NO:25, SEQ ID NO:37, SEQ ID NO:49, SEQ ID NO:61 , SEQ ID NO:73, SEQ ID NO:85 or a CDR having an amino acid sequence at least 75%, more preferably at least 90% identical to any of said CDRs.
  • the one or more CDRs are at least 95% identical to said amino acid sequences.
  • said antibody comprises 2 or more CDRs. Even more preferably, said antibody comprises 3 or more CDRs. Still even more preferably, said antibody comprises 4 or more CDRs. Yet even more preferably said antibody comprises 5 or more CDRs. Stil!
  • the invention comprises 6 CDR sequences.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer. Even more preferably, the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • an isolated antibody comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ ID NO:26, SEQ ID NO:38, SEQ ID NO:50, SEQ ID NO:62, SEQ ID NO:74, SEQ ID NO:86 or a CDR having an amino acid sequence at least 75%, more preferably at least 90% identical to any of said CDRs.
  • the one or more CDRs are at least 95% identical to said amino acid sequences.
  • said antibody comprises 2 or more CDRs. Even more preferably, said antibody comprises 3 or more CDRs. Still even more preferably, said antibody comprises 4 or more CDRs. Yet even more preferably said antibody comprises 5 or more CDRs.
  • said antibody comprises 6 CDR sequences.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer. Even more preferably, the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • an isolated antibody comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ ID NO:27, SEQ ID NO:39, SEQ ID NO:51 , SEQ ID NO:63, SEQ ID NO:75, SEQ ID NO:87 or a CDR having an amino acid sequence at least 75%, more preferably at least 90% identical to any of said CDRs.
  • the one or more CDRs are at least 95% identical to said amino acid sequences.
  • said antibody comprises 2 or more CDRs. Even more preferably, said antibody comprises 3 or more CDRs. Still even more preferably, said antibody comprises 4 or more CDRs. Yet even more preferably said antibody comprises 5 or more CDRs.
  • said antibody comprises 6 CDR sequences.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer. Even more preferably, the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • an isolated antibody comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ ID NO:28, SEQ ID NO:40, SEQ ID NO:52, SEQ ID NO:64, SEQ ID NO:76, SEQ ID NO:88 or a CDR having an amino acid sequence at least 75%, more preferably at least 90% identical to any of said CDRs.
  • the one or more CDRs are at least 95% identical to said amino acid sequences.
  • said antibody comprises 2 or more CDRs. Even more preferably, said antibody comprises 3 or more CDRs. Stil! even more preferably, said antibody comprises 4 or more CDRs. Yet even more preferably said antibody comprises 5 or more CDRs.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceuticaify acceptable carrier.
  • the disease or disorder is cancer. Even more preferably, the disease or disorder is melanoma, co!on and/or colorectal cancer or prostate cancer.
  • the invention provides antibodies designated AB3, AB10, AB2, AB1 and AB8, and preferably antibodies designated AB3, AB10 and AB2, as well as antibodies having CDR sequences having 75% or more (e.g. 80%, 85% , 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97% , 98%, 99% or more) amino acid identity to the CDRs in said preferred antibodies.
  • variable region of the light chain of the antibody comprises a VL_CDR1 region having an amino acid sequence as depicted in SEQ I D NO: 19, a VL_CDR2 region having an amino acid sequence as depicted in SEQ I D NO: 31 , and a VL_CDR3 region having an amino acid sequence as depicted in SEQ I D NO. : 43, or a CDR sequence having 75% or more (e.g .
  • variable region of the heavy chain of the antibody comprises a VH_CDR1 region having an amino acid sequence as depicted in SEQ I D NO: 55, a VH_CDR2 region having an amino acid sequence as depicted in SEQ ID NO: 67, and a VH_CDR3 region having an amino acid sequence as depicted in SEQ I D NO.: 79, or a CDR sequence having 75% or more (e.g .
  • variable region of the light chain of the antibody comprises a VL_CDR1 region having an amino acid sequence as depicted in SEQ ID NO: 19, a VL_CDR2 region having an amino acid sequence as depicted in SEQ !D NO: 31 , and a VL_CDR3 region having an amino acid sequence as depicted in SEQ ID NO.
  • variable region of the heavy chain of the antibody comprises a VH_CDR1 region having an amino acid sequence as depicted in SEQ ID NO: 55, a VH_CDR2 region having an amino acid sequence as depicted in SEQ ID NO: 67, and a VH_CDR3 region having an amino acid sequence as depicted in SEQ I D NO.: 79.
  • variable region of the light chain of the antibody comprises a VL_CDR1 region having an amino acid sequence as depicted in SEQ I D NO: 26, a VL_CDR2 region having an amino acid sequence as depicted in SEQ ID NO: 38, and a VL_CDR3 region having an amino acid sequence as depicted in SEQ I D NO. : 50, or a CDR sequence having 75% or more (e.g.
  • variable region of the heavy chain of the antibody comprises a VH_CDR1 region having an amino acid sequence as depicted in SEQ ID NO: 62, a VH_CDR2 region having an amino acid sequence as depicted in SEQ ID NO: 74, and a VH_CDR3 region having an amino acid sequence as depicted in SEQ I D NO . : 86, or a CDR sequence having 75% or more (e.g.
  • variable region of the light chain of the antibody comprises a VL_CDR1 region having an amino acid sequence as depicted in SEQ ID NO: 26, a VL_CDR2 region having an amino acid sequence as depicted in SEQ ID NO: 38, and a VL_CDR3 region having an amino acid sequence as depicted in SEQ I D NO.
  • variable region of the heavy chain of the antibody comprises a VH_CDR1 region having an amino acid sequence as depicted in SEQ I D NO: 62, a VH_CDR2 region having an amino acid sequence as depicted in SEQ I D NO: 74, and a VH_CDR3 region having an amino acid sequence as depicted in SEQ I D NO. : 86.
  • variable region of the light chain of the antibody comprises a VL_CDR1 region having an amino acid sequence as depicted in SEQ I D NO: 18, a VL_CDR2 region having an amino acid sequence as depicted in SEQ ID NO: 30, and a VL__CDR3 region having an amino acid sequence as depicted in SEQ I D NO. : 42, or a CDR sequence having 75% or more (e.g.
  • variable region of the heavy chain of the antibody comprises a VH_CDR1 region having an amino acid sequence as depicted in SEQ ID NO : 54, a VH_CDR2 region having an amino acid sequence as depicted in SEQ ID NO: 66, and a VH_CDR3 region having an amino acid sequence as depicted in S EQ I D NO. : 78, or a CDR sequence having 75% or more (e.g.
  • variable region of the light chain of the antibody comprises a VL_CDR1 region having an amino acid sequence as depicted in SEQ ID NO: 1 8, a VL_CDR2 region having an amino acid sequence as depicted in SEQ I D NO: 30, and a VL_CDR3 region having an amino acid sequence as depicted in SEQ ID NO.: 42; and the variable region of the heavy chain of the antibody comprises a VH_CDR1 region having an amino acid sequence as depicted in SEQ I D NO: 54, a VH_CDR2 region having an amino acid sequence as depicted in SEQ ID NO: 66, and a VH_CDR3 region having an amino acid sequence as depicted in SEQ ID NO. : 78.
  • variable region of the light chain of the antibody comprises a VL_CDR1 region having an amino acid sequence as depicted in SEQ I D NO: 17, a VL_CDR2 region having an amino acid sequence as depicted in SEQ I D NO: 29, and a VL_CDR3 region having an amino acid sequence as depicted in SEQ !D NO.: 41 , or a CDR sequence having 75% or more (e.g.
  • variable region of the heavy chain of the antibody comprises a VH_CDR1 region having an amino acid sequence as depicted in SEQ I D NO: 53, a VH_CDR2 region having an amino acid sequence as depicted in SEQ I D NO: 65, and a VH_CDR3 region having an amino acid sequence as depicted in SEQ ID NO. : 77, or a CDR sequence having 75% or more (e.g.
  • variable region of the light chain of the antibody comprises a VL_CDR1 region having an amino acid sequence as depicted in SEQ ID NO: 17, a VL_CDR2 region having an amino acid sequence as depicted in SEQ I D NO: 29, and a VL_CDR3 region having an amino acid sequence as depicted in SEQ ID NO.: 41 ; and the variable region of the heavy chain of the antibody comprises a VH_CDR1 region having an amino acid sequence as depicted in SEQ I D NO: 53, a VH_CDR2 region having an amino acid sequence as depicted in SEQ ! D NO: 65, and a VH_CDR3 region having an amino acid sequence as depicted in SEQ ID NO. : 77.
  • variable region of the light chain of the antibody comprises a VL_CDR1 region having an amino acid sequence as depicted in SEQ ID NO: 24, a VL_CDR2 region having an amino acid sequence as depicted in SEQ ID NO: 36, and a VL_CDR3 region having an amino acid sequence as depicted in SEQ ID NO.: 48, or a CDR sequence having 75% or more (e.g.
  • variable region of the heavy chain of the antibody comprises a VH_CDR1 region having an amino acid sequence as depicted in SEQ ID NO: 60, a VH_CDR2 region having an amino acid sequence as depicted in SEQ ID NO: 72, and a VH_CDR3 region having an amino acid sequence as depicted in SEQ ID NO. : 84, or a CDR sequence having 75% or more (e.g .
  • variable region of the light chain of the antibody comprises a VL_CDR1 region having an amino acid sequence as depicted in SEQ ID NO: 24, a VL_CDR2 region having an amino acid sequence as depicted in SEQ I D NO: 36, and a VL_CDR3 region having an amino acid sequence as depicted in SEQ ID NO.: 48; and the variable region of the heavy chain of the antibody comprises a VH_CDR1 region having an amino acid sequence as depicted in SEQ I D NO: 60 , a VH_CDR2 region having an amino acid sequence as depicted in SEQ ID NO: 72, and a VH_CDR3 region having an amino acid sequence as depicted in SEQ I D NO.: 84.
  • VL refers to variable lights chain
  • VH refers to variable heavy chain
  • therapeutic antibodies can comprise one or more of the heavy or light chain variable sequences above or a sequence at least 75%, preferably at least 80% identical thereto. More preferably, the therapeutic antibodies can comprise one or more of the heavy or light chain variable sequences above or a sequence at least 90% identical thereto.
  • the invention thus provides an isolated antibody that specifically binds CADM1 wherein said antibody has one or more light chain variable domain corresponding to Antibody-1 , Antibody-2, Antibody-3, Antibody-4, Antibody-5, Antibody-6, Antibody-7, Antibody-8, Antibody-9, Antibody-10, Antibody-1 1 , or Antibody-12 as defined herein, or a sequence having 75% or more (e.g. 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95% , 96% , 97%, 98%, 99% or more) amino acid identity to said light chain variable domain.
  • 75% or more e.g. 80%, 85%, 90%, 91 %, 92%, 93%, 94%, 95% , 96% , 97%, 98%, 99% or more
  • the invention provides an isolated antibody that specifically binds CADM1 wherein said antibody has one or more heavy chain variable domain corresponding to Antibody-1 , Antibody-2, Antibody-3, Antibody-4, Antibody-5, Antibody-6, Antibody-7, Antibody-8, Antibody-9, Antibody-10, Antibody-1 1 , or Antibody-12 as defined herein, or a sequence having 75% or more (e.g. 80% , 85%, 90%, 91 %, 92%, 93%, 94%, 95%,96%,97%,98%,99% or more) amino acid identity to said heavy chain variable domain.
  • the invention provides an isolated antibody that specifically binds CAD 1 wherein said antibody has:
  • one or more heavy chain variable domain corresponding to Antibody-1 , Antibody- 2, Antibody-3, Antibody-4, Antibody-5, Antibody-6, Antibody-7, Antibody-8, Antibody-9, Antibody-10, Antibody-11 , or Antibody-12 as defined herein, or a sequence having 75% or more (e.g . 80%, 85%, 90%, 91 %, 92% , 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) amino acid identity to said heavy chain variable domain.
  • the invention also involves nucleic acids encoding one or more of the above listed heavy or light chain variable sequences or a heavy or light chain variable sequences sequence at least 75%, preferably at least 80%, more preferably at least 90% identical thereto.
  • nucleic acid sequences for variable domains and CDRs are given for Antibody-1 (AB1 ), Antibody-2 (AB2), Antibody-3 (AB3), Antibody-8 (AB8) and Antibody-10 (AB10).
  • the invention relates to a composition
  • a composition comprising a nucleic acid as in SEQ ID NO:92, SEQ ID NO:94, SEQ ID NO:1 10, SEQ ID NO:1 12, SEQ ID 1 17, SEQ ID 1 18; SEQ ID 1 19, SEQ ID 120, SEQ ID 121 , SEQ ID 122 or a sequence 75%, preferably 80%, more preferably 90 % or more identical thereto, or the complement thereof.
  • the invention also relates to a composition comprising a nucleic acid as in SEQ ID NO:92, SEQ ID NO:94, SEQ ID NO: 10, SEQ ID NO:1 12, SEQ ID NO:119 or SEQ ID NO: 120, or a sequence 90 percent or more identical thereto, or the complement thereof.
  • the invention also involves one or more of the heavy or light chain variable sequences sequences above or a heavy or Sight chain variable sequences sequence at least 75%, preferably at least 80%, more preferably at least 90% identical thereto wherein said heavy or light chain variable sequences are in the context of an antibody framework.
  • the antibody framework is a human antibody framework.
  • Preferred antibody CDR (and/or heavy and light chain variable domains) combinations of the invention correspond to those having the same unique CDR identifier e.g., AB1 , AB2, AB3, etc. That is to say the 3 light chain CDRs and 3 heavy chain CDRs corresponding to AB1 or 3 light chain CDRs and 3 heavy chain CDRs corresponding to AB2, etc. See Tab!e 7 or Table 8.
  • the antibody of the invention is as follows:
  • an isolated antibody comprising an amino acid sequence chosen from SEQ ID NO:89, SEQ ID NO:90, or an amino acid sequence at least 75%, preferably at least 90% identical to any of said sequences.
  • the one or more said sequence is at least 95% identical to said amino acid sequence.
  • said antibody comprises (1 ) an isolated amino acid sequence as in SEQ ID NO:89 or an amino acid sequence at least 90% identical and (2) an amino acid sequence as in SEQ ID NO:90 or an amino acid sequence at least 90% identical.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer.
  • the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • an isolated antibody comprising an amino acid sequence chosen from SEQ ID NO:91 , SEQ ID NO:93, or an amino acid sequence at least 75%, preferably at least 90% identical to any of said sequences.
  • the one or more said sequence is at least 95% identical to said amino acid sequence.
  • said antibody comprises (1 ) an amino acid sequence as in SEQ ID NO:91 or an amino acid sequence at least 90% identical and (2) an amino acid sequence as in SEQ ID NO:93 or an amino acid sequence at least 90% identical.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer.
  • the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • an isolated antibody comprising an amino acid sequence chosen from SEQ ID NO:95, SEQ ID NO:96, or an amino acid sequence at least 75%, preferably at least 90% identical to any of said sequences.
  • the one or more said sequence is at least 95% identical to said amino acid sequence.
  • said antibody comprises (1 ) an amino acid sequence as in SEQ ID NO:95 or an amino acid sequence at least 90% identical and (2) an amino acid sequence as in SEQ ID NO:96 or an amino acid sequence at least 90% identical, in a related aspect, the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer.
  • the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • an isolated antibody comprising an amino acid sequence chosen from SEQ ID NO:97, SEQ ID NO:98, or an amino acid sequence at least 75%, preferably at least 90% identical to any of said sequences.
  • the one or more said sequence is at least 95% identical to said amino acid sequence.
  • said antibody comprises (1 ) an amino acid sequence as in SEQ ID NO:97 or an amino acid sequence at least 90% identical and (2) an amino acid sequence as in SEQ ID NO:98 or an amino acid sequence at least 90% identical.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer.
  • the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • an isolated antibody comprising an amino acid sequence chosen from SEQ ID NO:99, SEQ ID NO: 1 00, or an amino acid sequence at least 75%, preferably at least 90% identical to any of said sequences.
  • the one or more said sequence is at least 95% identical to said amino acid sequence.
  • said antibody comprises (1 ) an amino acid sequence as in SEQ I D NO:99 or an amino acid sequence at least 90% identical and (2) an amino acid sequence as in SEQ I D NO: 100 or an amino acid sequence at least 90% identical.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer.
  • the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • an isolated antibody comprising an amino acid sequence chosen from SEQ ID N 0:101 , SEQ I D NO: 102, or an amino acid sequence at least 75%, preferably at least 90% identical to any of said sequences.
  • the one or more said sequence is at least 95% identical to said amino acid sequence.
  • said antibody comprises (1 ) an amino acid sequence as in SEQ I D NO: 101 or an amino acid sequence at least 90% identical and (2) an amino acid sequence as in SEQ I D NO: 102 or an amino acid sequence at least 90% identical.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer.
  • the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • an isolated antibody comprising an amino acid sequence chosen from SEQ ID NO: 103, SEQ ID NO: 104, or an amino acid sequence at least 75%, preferably at least 90% identical to any of said sequences.
  • the one or more said sequence is at least 95% identical to said amino acid sequence.
  • said antibody comprises (1 ) an amino acid sequence as in SEQ ID NO: 103 or an amino acid sequence at least 90% identical and (2) an amino acid sequence as in SEQ ID NO: 104 or an amino acid sequence at least 90% identical.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer.
  • the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • an isolated antibody comprising an amino acid sequence chosen from SEQ ID NO: 105, SEQ I D NO: 106, or an amino acid sequence at least 75%, preferably at least 90% identical to any of said sequences.
  • the one or more said sequence is at least 95% identical to said amino acid sequence.
  • said antibody comprises (1 ) an amino acid sequence as in SEQ ID NO: 105 or an amino acid sequence at least 90% identical and (2) an amino acid sequence as in SEQ ID NO: 1 06 or an amino acid sequence at least 90% identical.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer.
  • the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • an isolated antibody comprising an amino acid sequence chosen from SEQ I D NO: 107, SEQ I D NO: 1 08, or an amino acid sequence at least 75%, preferably at least 90% identical to any of said sequences.
  • the one or more said sequence is at least 95% identical to said amino acid sequence.
  • said antibody comprises (1 ) an amino acid sequence as in SEQ ID NO: 107 or an amino acid sequence at least 90% identical and (2) an amino acid sequence as in SEQ ID NO: 108 or an amino acid sequence at least 90% identical.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer.
  • the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • an isolated antibody comprising an amino acid sequence chosen from SEQ I D NO: 1 09, SEQ ID NO: 1 1 1 , or an amino acid sequence at least 75%, preferably at least 90% identical to any of said sequences.
  • the one or more said sequence is at least 95% identical to said amino acid sequence.
  • said antibody comprises (1 ) an amino acid sequence as in SEQ I D NO: 1 09 or an amino acid sequence at least 90% identical and (2) an amino acid sequence as in SEQ ID NO: 1 1 1 or an amino acid sequence at least 90% identical.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer.
  • the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • (w)An isolated antibody comprising an amino acid sequence chosen from SEQ ID NO: 1 1 3, SEQ ID NO: 1 14, or an amino acid sequence at least 75%, preferably at least 90% identical to any of said sequences.
  • the one or more said sequence is at least 95% identical to said amino acid sequence.
  • said antibody comprises (1 ) an amino acid sequence as in SEQ ID NO: 1 13 or an amino acid sequence at least 90% identical and (2) an amino acid sequence as in SEQ ID NO: 1 14 or an amino acid sequence at least 90% identical.
  • the invention is one or more nucleic acids encoding said antibody.
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer.
  • the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • an isolated antibody comprising an amino acid sequence chosen from SEQ ID NO: 1 1 5, SEQ ID NO: 1 16, or an amino acid sequence at least 75%, preferably at least 90% identical to any of said sequences.
  • the one or more said sequence is at least 95% identical to said amino acid sequence.
  • said antibody comprises (1 ) an amino acid sequence as in SEQ ID NO: 1 1 5 or an amino acid sequence at least 90% identical and (2) an amino acid sequence as in SEQ I D NO: 1 1 6 or an amino acid sequence at least 90% identical.
  • the invention is one or more nucleic acids encoding said antibody
  • the invention is the use of said antibody for the treatment or prevention of a disease or disorder in a subject or is a pharmaceutical composition wherein said composition comprises said antibody and a pharmaceutically acceptable carrier.
  • the disease or disorder is cancer. Even more preferably, the disease or disorder is melanoma, colon and/or colorectal cancer or prostate cancer.
  • the antibody of the invention comprises a variable VH-region as encoded by a nucleic acid molecule as shown in SEQ ID NO: 120, SEQ ID NO:1 12, SEQ I D NO: 94, SEQ ID NO: 1 18 or SEQ I D NO: 122, or a variable VH-region as encoded by a nucleic acid molecule having 75% or more identity to one of said variable VH-regions; or it comprises a variable VH-region having an amino acid sequence as shown in SEQ ID NO:96, SEQ I D NO: 1 1 1 , SEQ ID NO: 93, SEQ ID NO: 90 or SEQ I D NO:106 , or a variable VH-region having an amino acid sequence which has 75% or more identity to one of said variable VH-regions.
  • the antibody comprises a variable VL-region as encoded by a nucleic acid molecule as shown in SEQ I D NO: 1 19, SEQ I D NO:110, SEQ ID NO: 92, SEQ ID NO: 1 17 or SEQ ID NO: 121 , or a variable VL-region as encoded by a nucleic acid molecule having 75% or more identity to one of said variable VL-regions; or a variable VL-region having an amino acid sequence as shown in SEQ ID NO:95, SEQ ID NO: 109, SEQ ID NO: 91 , SEQ I D NO: 89 or SEQ ID NO: 105 , or a variable VL-region having an amino acid sequence which has 75% or more identity to one of said variable VL-regions.
  • the antibody comprises a variable VH-region and a variable VL-region selected from the group consisting of:
  • variable VH-region as encoded by a nucleic acid molecule as shown in SEQ I D NO: 120 or a variable VH-region as encoded by a nucleic acid molecule having 75% or more identity to said variable VH-region , or a variable VH-region having an amino acid sequence as shown in SEQ ID NO:96 or a variable VH-region having an amino acid sequence which has 75% or more identity to said variable VH-region;
  • variable VL-region as encoded by a nucleic acid molecule as shown in SEQ !D NO: 1 19 or a variable VL-region as encoded by a nucleic acid molecule having 75% or more identity to said variable VL-region , or a variable VL-region having an amino acid sequence as shown in SEQ I D NO:95 or a variable VL-region having an amino acid sequence which has 75% or more identity to said variable VL-region ;
  • variable VH-region as encoded by a nucleic acid molecule as shown in S EQ I D NO: 1 12 or a variable VH-region as encoded by a nucleic acid molecule having 75% or more identity to said variable VH-region, or a variable VH-region having an amino acid sequence as shown in SEQ I D NO:111 or a variable VH-regton having an amino acid sequence which has 75% or more identity to said variable VH-region ;
  • variable VL-region as encoded by a nucleic acid molecule as shown in SEQ ID NO: 1 1 0 or a variable VL-region as encoded by a nucleic acid molecule having 75% or more identity to said variable VL-region , or a variable VL-region having an amino acid sequence as shown in SEQ ID NO: 1 09 or a variable VL-region having an amino acid sequence which has 75% or more identity to said variable VL-region;
  • variable VH-region as encoded by a nucleic acid molecule as shown in SEQ ID NO:94 or a variable VH-region as encoded by a nucieic acid molecule having 75% or more identity to said variable VH-region, or a variable VH-region having an amino acid sequence as shown in SEQ I D NO:93 or a variable VH-region having an amino acid sequence which has 75%) or more identity to said variable VH-region;
  • variable VL-region as encoded by a nucieic acid molecule as shown in SEQ I D NO:92 or a variable VL-region as encoded by a nucleic acid molecule having 75% or more identity to said variable VL-region r or a variable VL-region having an amino acid sequence as shown in S EQ I D NO:91 or a variable VL-region having an amino acid sequence which has 75% or more identity to said variable VL-region ;
  • variable VH-region as encoded by a nucleic acid molecule as shown in SEQ ID NO: 1 18 or a variable VH-region as encoded by a nucleic acid molecule having 75% or more identity to said variable VH-region, or a variable VH-region having an amino acid sequence as shown in SEQ I D NO:90 or a variable VH-region having an amino acid sequence which has 75% or more identity to said variable VH-region;
  • variable VL-region as encoded by a nucleic acid molecule as shown in SEQ ID NO: 1 17 or a variable VL-region as encoded by a nucleic acid molecule having 75% or more identity to said variable VL-region, or a variable VL-region having an amino acid sequence as shown in SEQ I D NO:89 or a variable VL-region having an amino acid sequence which has 75% or more identity to said variable VL-region;
  • variable VH-region as encoded by a nucleic acid molecule as shown in SEQ ID NO: 1 22 or a variable VH-region as encoded by a nucleic acid molecule having 75% or more identity to said variable VH-region , or a variable VH-region having an amino acid sequence as shown in SEQ I D NO: 106 or a variable VH-region having an amino acid sequence which has 75% or more identity to said variable VH-region;
  • variable VL-region as encoded by a nucleic acid molecule as shown in SEQ ID NO: 121 or a variable VL-region as encoded by a nucleic acid molecule having 75% or more identity to said variable VL-region, or a variable VL-region having an amino acid sequence as shown in SEQ I D NO:105 or a variable VL-region having an amino acid sequence which has 75% or more identity to said variable VL-region.
  • the antibody comprises a variable VH-region and a variable VL-region selected from the group consisting of:
  • variable VH-region as encoded by a nucleic acid molecule as shown in SEQ I D NO: 1 20 or a variable VH-region as encoded by a nucleic acid molecule having 75% or more identity to said variable VH-region, or a variable VH-region having an amino acid sequence as shown in SEQ I D NO:96 or a variable VH-region having an amino acid sequence which has 75% or more identity to said variable VH-region;
  • variable VL-region as encoded by a nucieic acid molecule as shown in SEQ I D NO:1 19 or a variable VL-region as encoded by a nucleic acid molecule having 75% or more identity to said variable VL-region, or a variable VL-region having an amino acid sequence as shown in SEQ I D NO:95 or a variable VL-region having an amino acid sequence which has 75% or more identity to said variable VL-region;
  • variable VH-region as encoded by a nucleic acid molecule as shown in SEQ I D NO: 1 12 or a variable VH-region as encoded by a nucleic acid molecule having 75% or more identity to said variable VH-region , or a variable VH-region having an amino acid sequence as shown in SEQ ID NO: 1 11 or a variable VH-region having an amino acid sequence which has 75% or more identity to said variable VH-region;
  • variable VL-region as encoded by a nucleic acid molecule as shown in SEQ I D NO: 1 1 0 or a variable VL-region as encoded by a nucleic acid molecule having 75% or more identity to said variable VL-region , or a variable VL-region having an amino acid sequence as shown in SEQ ID NO:1 09 or a variable VL-region having an amino acid sequence which has 75% or more identity to said variable VL-region; (iii) a variable VH-region as encoded by a nucleic acid molecule as shown in SEQ ID NO:94 or a variable VH-region as encoded by a nucleic acid molecule having 75% or more identity to said variable VH-region, or a variable VH-region having an amino acid sequence as shown in SEQ ID NO:93 or a variable VH-region having an amino acid sequence which has 75% or more identity to said variable VH-region; and
  • variable VL-region as encoded by a nucleic acid molecule as shown in SEQ I D NO:92 or a variable VL-region as encoded by a nucleic acid molecule having 75% or more identity to said variable VL-region, or a variable VL-region having an amino acid sequence as shown in SEQ ID NO:91 or a variable VL-region having an amino acid sequence which has 75% or more identity to said variable VL-region.
  • the antibody comprises a variable VH-region as encoded by a nucleic acid molecule as shown in SEQ ID NO: 120, or a variable VH-region having an amino acid sequence as shown in SEQ ID NO:96; and
  • variable VL-region as encoded by a nucleic acid molecule as shown in SEQ ID NO: 1 19, or a variable VL-region having an amino acid sequence as shown in SEQ ID NO:95.
  • the antibody comprises a variable VH-region as encoded by a nucleic acid molecule as shown in SEQ I D NO: 1 12 ; or a variable VH-region having an amino acid sequence as shown in SEQ I D NO:1 11 ; and
  • variable VL-region as encoded by a nucleic acid molecule as shown in SEQ ID NO: 1 10, or a variable VL-region having an amino acid sequence as shown in SEQ I D NO: 109.
  • the antibody comprises a variable VH-region as encoded by a nucleic acid molecule as shown in SEQ ID NO:94, or a variable VH-region having an amino acid sequence as shown in SEQ ID NO:93; and a variable VL-region as encoded by a nucleic acid molecule as shown in SEQ I D NO:92, or a variable VL-region having an amino acid sequence as shown in SEQ ID NO:91 .
  • the antibody comprises a variable VH-region as encoded by a nucleic acid molecule as shown in SEQ I D NO: 1 1 8, or a variable VH-region having an amino acid sequence as shown in SEQ I D NO:90; and
  • variable VL-region as encoded by a nucleic acid molecule as shown in SEQ ID NO.H 7, or a variable VL-region having an amino acid sequence as shown in SEQ I D NO:89.
  • the antibody comprises a variable VH-region as encoded by a nucleic acid molecule as shown in SEQ ID NO: 122, or a variable VH-region having an amino acid sequence as shown in SEQ !D NO:106; and
  • variable VL-region as encoded by a nucleic acid molecule as shown in SEQ ID NO: 1 21 , or a variable VL-region having an amino acid sequence as shown in SEQ I D NO:105.
  • the herein provided antibodies can comprise one or more of the heavy or light chain variable sequences above or a sequence at least 75%, 80%, 85 %, 90 %, 91 % ,92%, 93%, 94%, 95 %, 96 %, 97 %, 98 % » or 99 % identical thereto.
  • the invention further relates to an antibody that specifically binds to CADM1 , wherein said antibody binds to an epitope on CADM1 recognized by the antibodies as disclosed above.
  • the antibody/binding molecule of the present invention may be a full antibody (immunoglobulin), an antibody fragment such as a F(ab)-fragment, a F(ab)2-fragment or an epitope-binding fragment, as well as a single-chain antibody.
  • the antibodies/binding molecules of the invention may be a monoclonal antibody, a recombinantly produced antibody, a chimeric antibody, a humanized antibody, a human antibody, a fully human antibody, a CDR-grafted antibody, a bivalent antibody-construct, a synthetic antibody or a cross-cloned antibody, a diabody, a triabody, a tetrabody, a single chain antibody, a bispecific single chain antibody, etc.
  • the antibody may also be a multispecific antibody, including a bi-specific antibody.
  • the antibodies of the invention may be multifunctional, i.e.
  • the antibodies of the invention include, but are not limited to, synthetic antibodies, monoclonal antibodies, recombinantly produced antibodies, multispecific antibodies (including bi-specific antibodies), human antibodies, humanized antibodies, chimeric antibodies, single-chain Fvs (scFv) (including bi-specific scFvs), single chain antibodies, Fab fragments, F(ab') fragments, disulf tde-linked Fvs (sdFv), and anti-idiotypic (anti-Id) antibodies, and epitope-binding fragments of any of the above.
  • synthetic antibodies monoclonal antibodies, recombinantly produced antibodies, multispecific antibodies (including bi-specific antibodies), human antibodies, humanized antibodies, chimeric antibodies, single-chain Fvs (scFv) (including bi-specific scFvs), single chain antibodies, Fab fragments, F(ab') fragments, disulf tde-linked Fvs (sdFv), and anti-idiotypic (anti-Id) antibodies
  • antibodies of the present invention include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds to a CADM1 antigen (e.g., one or more complementarity determining regions (CDRs) of an anti-CADM 1 antibody).
  • the antibodies are humanized or human and/or deimmunized. More preferably, the antibodies are humanized and most preferably the antibodies are fully humanized/human .
  • Said "fully humanized antibody” are also characterized and described as "completely human” antibodies. All these antibodies can be generated by methods known in the art. For example, by phage display technology, recombinant antibody molecules may be generated due to the use of in vitro maturation which is the usage of a complete human immunoglobulin ⁇ , subclass-1 framework (IgG ) as described by Knappik (2000) J Mo! Biol. 296(1 ), 57-86, Rauchenberger (2003) J Biol Chem. 278(40), 38194-205, or Hoet el al (2005) Nature Biotechno!, 23(3), 344-48.
  • IgG immunoglobulin ⁇ , subclass-1 framework
  • CDR-grafted As used herein , the term "CDR-grafted”, “humanized” or “humanization” are used interchangeably to refer to a human antibody as defined herein (preferably a igG1 antibody) comprising in its binding domains at least one complementarity determining region (“CDR") from a non-human antibody or fragment thereof.
  • CDR complementarity determining region
  • the term encompasses the case in which a variable region of the binding domain comprises a single CDR region , for example the third CDR region (CDR-H3) of the VH , from another non-human animal, for example a rodent, as well as the case in which a or both variable region/s comprise at each of their respective first, second and third CDRs the CDRs from said non-human animal.
  • CDR-H3 third CDR region
  • a or both variable region/s comprise at each of their respective first, second and third CDRs the CDRs from said non-human animal.
  • humanized also encompasses cases in which, in addition to replacement of one or more CDR regions within a VH and/or VL of the binding domain further mutation/s (e.g . substitutions) of at least one single amino acid residue/s within the framework ⁇ "FR") regions between the CDRs has/have been effected such that the amino acids at that/those positions correspond/s to the amino acid/s at that/those position/s in the animal from which the CDR regions used for replacement is/are derived.
  • individual mutations are often made in the framework regions following CDR-grafting in order to restore the original binding affinity of the non-human antibody used as a CDR-donor for its target molecule.
  • humanized may further encompass (an) amino acid substitution(s) in the CDR regions from a non-human animal to the amino acid(s) of a corresponding CDR region from a human antibody, in addition to the amino acid substitutions in the framework regions as described above.
  • humanized antibodies or related terms encompass antibodies having the amino acid sequence of a human immunoglobulin with a variable region comprising non-human CDR- and/or framework region- sequences. I n contemplating an antibody intended for therapeutic administration to humans, it is highly advantageous that the major part of this antibody is of human origin. Following administration to a human patient, a humanized antibody or a human antibody (or fragment thereof) will most probably not elicit a strong immunogenic response by the patient's immune system, i.e. will not be recognized as being a "foreign", that is non-human protein. This means that no host, i.e.
  • an antibody as defined herein may also be regarded as humanized if it consists of (a) sequence(s) that deviate(s) from its (their) closest human germline sequence(s) by no more than would be expected due to the imprint of somatic hypermutation .
  • the humanized antibodies as defined herein have a human constant region and one or more of the CDR sequences which may be of, but are not limited to, CDRs of non-human, preferably rodent, origin .
  • CDRs of non-human preferably rodent, origin
  • the present invention also provides for "fully-human" antibodies.
  • chimeric antibody encompasses antibodies having human constant regions on the light and heavy chains and non-human variable regions on the light and heavy chains.
  • the non-human regions are from a rodent sequence.
  • the variable regions of the heavy and light chain could be amplified by RT-PCR using RNA extracted from a mouse hybridoma cell which produces the antibody of interest.
  • the amplified sequence could be cloned in frame with the constant heavy-chain or the constant light chain respectively of a human IgG also included in a mammalian expression vector.
  • An expression vector encoding a chimeric IgG could be transfected into the right cell Sine, like for example CHO or HEK293, for chimeric antibody production .
  • the term “deimmunized” or “deimmunization” denotes modification of the binding domain vis-a-vis an original wild type construct by rendering said wild type construct non-immunogenic or less immunogenic in humans. Deimmunization approaches are shown e.g. in WO 00/34317, WO 98/52976, WO 02/079415 or WO 92/1 0755.
  • the term “deimmunized” also relates to constructs, which show reduced propensity to generate T cell epitopes.
  • the term “reduced propensity to generate T cell epitopes” relates to the removal of T-cell epitopes leading to specific T-cel! activation.
  • T cell epitopes means substitution of amino acids contributing to the formation of T cell epitopes, i.e. substitution of amino acids, which are essential for formation of a T ceil epitope.
  • reduced propensity to generate T cell epitopes relates to reduced immunogenicity or reduced capacity to induce antigen independent T cell proliferation .
  • T ceil epitope relates to short peptide sequences which can be released during the degradation of peptides, polypeptides or proteins within cells and subsequently be presented by molecules of the major histocompatibility complex (MHC) in order to trigger the activation of T cells; see inter alia WO 02/066514.
  • MHC major histocompatibility complex
  • T cells presented by MHC class I I such activation of T cells can then give rise to an antibody response by direct stimulation of T ceils to produce said antibodies.
  • "Reduced propensity to generate T-ce!l epitopes” and/or “deimmunization” may be measured by techniques known in the art.
  • de-immunization of proteins may be tested in vitro by T cell proliferation assay, in this assay PB MCs from donors representing > 80 % of HLA-DR a!leles in the world are screened for proliferation in response to either wild type or de-immunized peptides, ideally ceil proliferation is only detected upon loading of the antigen-presenting cells with wild type peptides.
  • HLA-DR tetramers representing all haplotypes. These tetramers may be tested for peptide binding or loaded with peptides substitute for antigen-presenting cells in proliferation assays. I n order to test whether deimmunized peptides are presented on HLA-DR haplotypes, binding of e.g. fluorescence-labeled peptides on PBMCs can be measured . Furthermore, deimmunization can be proven by determining whether antibodies against the deimmunized molecules have been formed after administration in patients.
  • antibody derived molecules are deimmunized in the framework regions and most of the CDR regions are not modified in order to generate reduced propensity to induce T cell epitope so that the binding affinity of the CDR regions is not affected . Even elimination of one T cell epitope results in reduced immunogenicity.
  • the above approaches help to reduce the immunogenicity of the antibodies provided herein when being administered to patients.
  • the invention also involves one or more of the disclosed CDR sequences above or a CDR sequence at least 75 % (at least 80%, at least 90%, at least 95%, at least 96 %, at least 97 %, at least 98 % or at least 99 %) identical in their amino acid sequence hereto wherein said CDR sequences is in the context of an antibody framework/framework region .
  • the antibody framework is a human antibody framework.
  • frameworks include an IgG framework, such as fgG 1 , lgG4, lgG2a and lgG2b, preferably a human IgG framework such as lgG 1 , lgG2, lgG3 and lgG4.
  • the antibodies of the invention may also comprise cross-cloned antibodies, i .e. antibodies comprising different antibody regions (e.g. CDR-regions) from one or more parental or affinity-optimized antibody(ies) as described herein .
  • These cross-cloned antibodies may be antibodies in several, different frameworks, e.g. an IgG-framework, e.g. a IgG 1 lgG4, lgG2a or an IgG2b- framework.
  • said antibody framework is a mammalian, e .g . a human framework such as IgG 1 , lgG2, lgG3 or lgG4.
  • frameworks include IgG frameworks such as lgG1 , lgG4, SgG2a and lgG2b. Most preferred are human frameworks, and particularly human SgG1 or lgG4 frameworks.
  • a "human antibody framework” relates to an antibody framework that is substantially identical ⁇ about 85% or more, usually 90 %, more preferably 95%, 96 %, 97 %, 98 %, 99 % or more) to the antibody framework of a naturally occurring human immunoglobulin.
  • a "human framework region” relates to a framework region that is substantially identical (about 85% or more, usually 90 %, more preferably 95%, 96 %, 97 %, 98 %, 99 % or more) to the framework region of a naturally occurring human immunoglobulin.
  • a framework region relates, accordingly, to a region in the V domain (VH or VL domain) of immunoglobulins and T-cell receptors that provides a protein scaffold for the hypervariabie complementarity determining regions (CDRs) that make contact with the antigen.
  • VH or VL domain a region in the V domain of immunoglobulins and T-cell receptors that provides a protein scaffold for the hypervariabie complementarity determining regions (CDRs) that make contact with the antigen.
  • CDRs hypervariabie complementarity determining regions
  • Framework 1 encompasses the region from the N-terminus of the V domain until the beginning of CDR1
  • framework 2 relates to the region between CDR1 and CDR2
  • framework 3 encompasses the region between CDR2 and CDR3
  • framework 4 means the region from the end of CDR3 until the C-terminus of the V domain; see, inter alia, Janeway, Immunobiology, Garland Publishing, 2001 , 5th ed.
  • the framework regions encompass ail the regions outside the CDR regions in VH or VL domains.
  • transition sequence between a framework and a CDR region relates to a direct junction between the framework and CDR region
  • transition sequence between a framework and a CDR region means the sequence directly located N- and C-terminaily of the CDR regions or amino acids surrounding CDR regions.
  • frameworks may also comprise sequences between different CDR regions.
  • the person skilled in the art is readily in a position to deduce from a given sequence the framework regions, the CDRs as well as the corresponding transition sequences; see Kabat (1991 ) Sequences of Proteins of Immunological Interest, 5th edit., NIH Publication no. 91 -3242 U.S. Department of Health and Human Services, Chothia (1987). J. Mo!.
  • the antibody is an immunoglobulin selected from the group consisting of IgA, IgD, IgE, IgG or SgM antibody, preferably IgG.
  • an "antibody” may denote immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds to CADM1 . Such antibodies are constructed in the same way. They form paired heavy and light polypeptide chains, and the generic term immunoglobulin is used for all such proteins.
  • IgG antibodies are large molecules, having a molecular weight of approximately 150 kDa, composed of two different kinds of polypeptide chain. One, of approximately 50 kDa, is termed the heavy or H chain, and the other, of 25 kDa, is termed the light or L chain.
  • Each IgG molecule consists of two heavy chains and two light chains. The two heavy chains are linked to each other by disulfide bonds and each heavy chain is linked to a light chain by a disulfide bond.
  • the two heavy chains and the two light chains are identical, giving an antibody molecule two identical antigen-binding sites, and thus the ability to bind simultaneously to two identical structures.
  • Two types of light chain termed lambda and kappa, are found in antibodies.
  • a given immunoglobulin either has lambda chains or kappa chains, never one of each. No functional difference has been found between antibodies having lambda or kappa light chains, and either type of light chain may be found in antibodies of any of the five major classes.
  • the ratio of the two types of light chain varies from species to species. In mice, the average kappa to lambda ratio is 20:1 , whereas in humans it is 2:1 and in cattle it is 1 :20.
  • immunoglobulin M immunoglobulin M
  • IgD immunoglobulin D
  • IgG immunoglobulin G
  • IgA immunoglobulin A
  • IgE immunoglobulin E
  • IgG immunoglobulin
  • lgG1 , 2, 3, and 4 in humans lgG1 , lgG2a, lgG2b and lgG3 in mice.
  • Their distinctive functional properties are conferred by the carboxy-terminal part of the heavy chain, where it is not associated with the light chain. The general structural features of all the isotypes are similar.
  • the IgG antibody is the most abundant isotype in plasma. in one embodiment, the antibodies as defined herein are IgG antibodies.
  • an IgG comprises not only the variable antibody regions responsible for the highly discriminative antigen recognition and binding, but also the constant regions of the heavy and light antibody polypeptide chains normally present in endogenously produced antibodies and, in some cases, even decoration at one or more sites with carbohydrates.
  • Such glycosylation is generally a hallmark of the IgG format, and portions of these constant regions make up the so called Fc region of a full antibody which is known to elicit various effector functions in vivo, such as e.g. antibody-dependent celiuiar cytotoxicity (ADCC).
  • ADCC antibody-dependent celiuiar cytotoxicity
  • the Fc region mediates binding of the IgG to an Fc receptor, hence prolonging half life in vivo as wei! as facilitating homing of the IgG to locations with increased Fc receptor presence.
  • the igG antibody is an lgG1 or lgG4 antibody specifically binding to CADM1 .
  • the invention provides antibodies having a human framework and comprising the amino acid sequence for VL_CDR1 ; VL_CDR2; VL_CDR3; VH_CDR1 ; VH_CDR2; and VH_CDR3 as indicated below :
  • the invention provides antibodies having a human framework and comprising the amino acid sequence for VL and VH as indicated beiow .
  • SEQ ID NOs. that correspond to the amino acid sequence of the variable domain of the light chain and the variable domain of the heavy chain for each indicated antibody
  • the antibodies of the invention and particularly antibodies AB3, AB10 and AB2 as disclosed above bind with high affinity and specificity to CADM1 , particularly human CADM1 .
  • Affinity and specificity can be determined experimentally by methods known in the art, Such methods comprise, but are not limited to Flow Cytometry (FC), Western blots, ELISA-, RIA-, ECL-, I R A-tests and peptide scans.
  • Other methods include the use of siRNA agents against CAD 1 .
  • the invention relates to any of the above referenced antibodies that is capable of internalizing.
  • cancer cells or host cells expressing a CAD 1 epitope or protein can be contacted with an antibody of the invention and it is expected that the antibody can internalize.
  • Standard assays to evaluate if an antibody internalizes are well known in the art; for example, a humZAP internalization assay such as the one disclosed in the appended Examples can be used.
  • the therapeutic antibodies of the invention e.g., as disclosed in the preferred embodiments above, and particularly antibodies designated AB3, AB10 and AB2 (as well as antibodies/binding molecules derived therefrom), can be used in methods of treatment to treat cancer, e.g., melanoma, colorectal, prostate, kidney, lung, ovarian, breast, blood (e.g., leukemia), or pancreatic cancer. Accordingly, the antibodies of the invention, including the antibodies AB3, AB10 and AB2 (and antibodies derived therefrom), are particularly useful in the treatment of melanoma, colon and/or colorectal cancer or prostate cancer..
  • the utility of the antibodies/binding molecules of the invention in the treatment of cancer can be tested using standard in vitro and in vivo assays well known in the art. In vitro assays that can be used are disclosed for example in the appended Examples. In vivo, the antibodies/binding molecules of the invention can be tested for example in xenograft models, such as melanoma, colon and/or colorectal cancer or prostate cancer xenografts, for example in mice. Briefly, a human cancer cell line, such as a melanoma, colon and/or colorectal cancer or prostate cancer cell line, is s.c.
  • mice are treated with the antibodies/binding molecules to be tested.
  • Routes of antibody administration into mice include intravenous or intraperitoneal administration.
  • Various dosages of potentially therapeutic antibodies or fragments thereof according to the invention can be tested in the in-vivo model.
  • the treated animals and control animals are then followed over time and scored for reduction in proliferation; reduction in tumor growth; appearance of cytotoxicity; reduction in cell-adhesion; reduction in metastasis, reduction in cell invasion, or reduction in cell migration.
  • A375 human malignant melanoma ceil line (obtained from ATCC) is grown in DMEM supplemented with 10% fetal bovine serum at 37°C in an atmosphere of 5% C02 in air.
  • the tumor cells are routinely subcuitured twice weekly. Ceils are harvested during the exponential growth period and resuspended in physical PBS with proper cell concentration and kept on ice for tumor inoculation.
  • Balb/c nude mice, female, 6-8 weeks, weighing approximately 18-22g are used. Each mouse is inoculated subcutaneously at the right flank with A375 tumor cells (5X10 6 ) in 0.1 ml of PBS/Matrigel (1 : 1 ) for tumor development. The treatments are started when the mean tumor size reaches approximately 150-200 mm3.
  • mice are weighed and the tumor volumes are measured. Mice are assigned into groups using randomized block design based upon their tumor volumes. This ensures that ail the groups are comparable at the baseline. Treatments to be tested are administered iv to the tumor-bearing mice according to predetermined regimens. At least one week of observation is followed after the final dose
  • the tumor sizes are then used for the calculations of T-C and T/C values.
  • T-C is calculated with T as the time (in days) required for the mean tumor size of the treatment group to reach a predetermined size (e.g., 2000 mm3), and C is the time (in days) for the mean tumor size of the control group to reach the same size.
  • the T/C value (in percent) is an indication of antitumor effectiveness, T and C being here the mean volume of the treated and control groups, respectively, on a given day.
  • the invention further relates to compositions and methods for making the antibodies of the invention.
  • the present invention relates to a nucleic acid molecule having a sequence encoding the antibody as defined and provided herein .
  • the present invention relates to an isolated nucleic acid molecule having a sequence encoding the antibody as defined and provided herein.
  • the nucleic acid mo!ecuies of the invention for example, those encoding anti-CADM1 antibodies, and its subsequences/alternative transcripts, can be inserted into a vector, which will facilitate expression of the insert.
  • the nucleic acid molecules and the antibodies they encode can be used directly or indirectly as therapeutic (or diagnostic) agents (directly in the case of the antibody or indirectly in the case of a nucleic acid molecule).
  • the present invention relates also to a vector comprising the nucleic acid molecule.
  • the vector may further comprise a nucleic acid molecule having a regulatory sequence which is operably linked to the nucleic acid molecule.
  • the vector may be an expression vector.
  • the present invention relates to a host, host cell or host cell line transformed or transfected with the vector as defined above.
  • the host, host cell or host cell line expresses the antibody as provided herein.
  • Said host, host cell or host cell line can be prokaryotic or eukaryotic.
  • the host is preferably a eukaryottc host ceil like COS, CHO, HEK293 or a multiple myeloma host cell.
  • the therapeutic antibody of the invention can be made by any number of methods.
  • an antibody of the invention as described in the embodiments above, including AB3, AB10 and AB2 can be synthesized in a cell line harboring a nucleic acid encoding said antibody as described above, such as AB3, AB10 and AB2, and culturing said cell line under conditions sufficient to allow expression of said antibody.
  • the present invention relates in one embodiment to a process for the production of the antibody as defined herein, said process comprising culturing a host as defined herein under conditions allowing the expression of the antibody and recovering the produced antibody from the culture.
  • the antibody thus obtained can then be conjugated to a therapeutic agent or to a detectable label for diagnostic purposes, as described above.
  • a protein for example a marker or label protein or a therapeutic or a toxic protein
  • a vector encoding the sequence for the fusion protein would be incorporated into the host cell line, which would then be cultured as described above.
  • Techniques for producing and purifying antibodies are well known (see e.g. Liu et al . (2010) MAbs. 2(5):480-99; Shukla et a!. (2010) Trends Biotechnoi. 28(5):253-61 ; and Backliwai et al . (2008) Nucleic Acids Res. 36(1 5):e96).
  • the invention also is:
  • Said ceil or cell line can be a prokaryotic or eukaryotic.
  • said cell or cell line is chosen from COS, CHO, HEK293 or a Multiple Myeloma cell or cell line.
  • Said cell or ceil line can be a prokaryotic or eukaryotic.
  • said ceil or cell line is chosen from COS, CHO, HEK293 or a Multiple Myeloma cell or cell line.
  • CADM1 like polyclonal, monoclonal, humanized, human antibodies or antibody fragments
  • Antibodies and fragments thereof to a CADM1 protein or a CADM1 epitope for therapeutic and/or diagnostic uses can be obtained in any number of ways known to those of ordinary skill in the art. These antibodies can be used in the methods of the invention and/or as the basts of engineering new antibodies. Phage display techniques can be used to generate an antibody and/or fragment thereof to a CADM1 protein or a CADM1 epitope. Standard hybridoma technologies can be used to generate antibodies and fragments thereof to a CADM1 protein or a CADM1 epitope. In one aspect, the antibody or fragment thereof to a CADM1 or a CADM1 epitope is a monoclonal antibody or a fragment thereof.
  • the antibody or fragment thereof to a CADM1 or a CADM1 epitope is a polyclonal antibody or a fragment thereof. In one aspect, the antibody or fragment thereof to a CADM1 or a CADM1 epitope is a recombinant antibody or a fragment thereof. In one aspect, the antibody or fragment thereof to a CADM1 or a CADM1 epitope is humanized antibody or a fragment thereof. In one aspect, the antibody or fragment thereof to a CADM1 or a CADM1 epitope is fully human antibody or a fragment thereof. In one aspect, the antibody or fragment thereof to a CADM1 or a CADM1 epitope is a chimeric antibody or fragment thereof. In one aspect, the antibody or fragment thereof (e.g., CDR(s)) to CADM1 is derived from an animal source (e.g., mouse, rat, or rabbit).
  • an animal source e.g., mouse, rat, or rabbit.
  • the target protein antibodies may comprise polyclonal antibodies. Methods of preparing polyclonal antibodies are known to the skilled artisan. Polyclonal antibodies can be raised in a mammal, for example, by one or more injections of an immunizing agent and, if desired, an adjuvant. Typically, the immunizing agent and/or adjuvant will be injected in the mammal by multiple subcutaneous or intraperitoneal injections.
  • the immunizing agent may include the target protein polypeptide CADM1 (or fragment or epitope thereof) or a fusion protein thereof, !t may be useful to conjugate the immunizing agent to a protein known to be immunogenic in the mammal being immunized.
  • immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor.
  • adjuvants which may be employed include Freund's complete adjuvant and MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate).
  • the immunization protocol may be selected by one skilled in the art without undue experimentation.
  • the CADM1 protein antibodies may, alternatively, be monocionaf antibodies and/or fragments thereof.
  • Monoclonal antibodies may be prepared using known hybridoma methods, such as those described by Kohier and Milstein (1975) Nature 256:495.
  • a hybridoma method a mouse, hamster, or other appropriate host animal (e.g., rabbit, goat etc.), is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent.
  • the lymphocytes may be immunized in vitro.
  • the immunizing agent will typically include the target protein polypeptide CADM1 (or fragment thereof) or a fusion protein thereof.
  • PBLs peripheral blood lymphocytes
  • the lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp, 59-103).
  • Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin.
  • rat or mouse myeloma cell lines are employed.
  • the hybridoma cells may be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells.
  • a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells.
  • the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (“HAT medium”), which substances prevent the growth of HGPRT-deficient cells.
  • Preferred immortalized ceil lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. More preferred immortalized ceil lines are murine myeloma lines, which can be obtained, for instance, from the Salk institute Cell Distribution Center, San Diego, Calif, and the American Type Culture Collection, Manassas, Va. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies (Kozbor (1984) Immunol, 1 33:3001 ; Brön et a/., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. 51 -63).
  • the culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against target protein.
  • the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by tmmunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA).
  • RIA radioimmunoassay
  • ELISA enzyme-linked immunoabsorbent assay
  • the binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysts of Munson and Pollard (1980) Anal. Biochem. 107:220.
  • the clones may be subcloned by limiting dilution procedures and grown by standard methods [Goding, supra]. Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively, the hybridoma ceils may be grown in vivo as ascites in a mammal.
  • the monoclonal antibodies secreted by the subclones may be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.
  • the monoclonal antibodies may also be made by recombinant DNA methods, such as those described in U.S. Pat. No. 4,816,567.
  • DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies).
  • the hybridoma cells of the invention serve as a preferred source of such DNA.
  • the DNA may be placed into expression vectors, which are then transfected into host ceils such as simian COS cells, Chinese hamster ovary (CHO) cells, HEK293 cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host ce!ls.
  • host ceils such as simian COS cells, Chinese hamster ovary (CHO) cells, HEK293 cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host ce!ls.
  • the DNA also may be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences (e.g., U.S. Pat. No.
  • non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.
  • the antibodies and fragments thereof may be monovalent antibodies.
  • Methods for preparing monovalent antibodies are well known in the art. For example, one method involves recombinant expression of immunoglobulin light chain and modified heavy chain. The heavy chain is truncated generally at any point in the Fc region so as to prevent heavy chain crosslinking. Alternatively, the relevant cysteine residues are substituted with another amino acid residue or are deleted so as to prevent crosslinking. in vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce fragments thereof, particularly, Fab fragments, can be accomplished using routine techniques known in the art.
  • the CADM1 protein antibodies of the invention may further comprise humanized antibodies or human antibodies (and/or fragments thereof).
  • Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab') 2 or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non- human immunoglobulin.
  • Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity.
  • CDR complementary determining region
  • donor antibody non-human species
  • Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • Humanized antibodies (and/or fragments thereof) may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences.
  • the humanized antibody (and/or fragments thereof) will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially ail of the FR regions are those of a human immunoglobulin consensus sequence.
  • the humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (Jones et al. (1986) Nature, 321 :522-525; Riechmann ef a/.(1988) Nature 332:323- 329; and Presta (1992) Curr. Op. Struct. Biol. 2:593-596).
  • Fc immunoglobulin constant region
  • a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as "import" residues, which are typically taken from an "import” variable domain. Humanization can be essentially performed following the method of Winter and co-workers (Jones et al. (1986) Nature, 321 :522- 525; Riechmann et al. (1988) Nature 332:323-327; Verhoeyen et al.
  • humanized antibodies are chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species.
  • humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.
  • Human antibodies can also be produced using various techniques known in the art, including phage display libraries (Hoogenboom and Winter (1991 ) J. Mol. Biol. 227:381 ; Marks et al. (1991 ) J. Mol. Biol. 222:581 , Hoet el al (2005) Nature Biotechnol, 23(3), 344-48).
  • the techniques of Cole et al. and Boerner et al. are also available for the preparation of human monoclonal antibodies (Cole ef al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boerner et al. (1991 ) J. Immunol.
  • human antibodies can be made by introducing of human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in ail respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661 ,016, and in the following scientific publications: Marks et at. (1992) Bio/Technology 10:779-783; Lonberg et al.
  • the antibodies (and/or fragments thereof) may also be affinity matured using known selection and/or mutagenesis methods as described above.
  • Preferred affinity matured antibodies have an affinity which is 5 times, more preferably 10 times, even more preferably 20 or 30 times greater than the starting antibody (generally murine, humanized or human) from which the matured antibody is prepared.
  • Antibody fragments can also be produced directly by recombinant host ce!is and the antibody phage libraries discussed above.
  • Fab'-SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab')2 fragments (Carter et af (1992) Bio/Technology 10: 163-167).
  • F(ab')2 fragments can be isolated directly from recombinant host cell culture.
  • the antibody of choice is a single chain Fv fragment (scFv). See WO 93/16185; U.S. Pat. No. 5,571 ,894; and U.S. Pat. No. 5,587,458.
  • the antibody fragment may also be a "linear antibody", e.g., as described in U.S. Pat. No. 5,641 ,870, for example. Such linear antibody fragments may be monospecific or bispecific.
  • Bispecific antibodies with binding specificities for at least two different epitopes may bind to two different epitopes of the CADM1 protein.
  • An anti-CADM1 arm may be combined, for example, with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2 or CD3), or Fc receptors for IgG (FcyR), such as FcyRi (CD64), FcyRll (CD32) and FcyRlll (CD16) so as to focus cellular defense mechanisms to the CADM1 -expressing ceil.
  • a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2 or CD3), or Fc receptors for IgG (FcyR), such as FcyRi (CD64), FcyRll (CD32) and FcyRlll (CD16) so as to focus cellular defense mechanisms to the CADM1 -expressing ceil
  • Bispecific antibodies may also be used to localize cytotoxic agents to cells which express CADM1 (WO 96/16673; U.S. Pat. No. 5,837,234; WO98/02463; U.S. Pat. No. 5,821 ,337). Purification methods for bispecific antibodies have been disclosed (WO 93/08829; Traunecker et ai (1991 ) EMBO J. 10:3655-3659; WO 94/04690; Suresh et al (1986) Methods in Enzymology 121.210; U.S. Pat. No. 5,731 , 168). Bispecific antibodies can be produced using leucine zippers ⁇ Kostelny et al (1992) J. Immunol. 148(5):1547- 553), and single- chain Fv (sFv) dimers (Gruber et al (1994) J. Immunol. 152:5368).
  • bispecific antibodies from antibody fragments
  • Techniques for generating bispecific antibodies from antibody fragments have also been described, such as using chemical linkage wherein intact antibodies are proteoiyticaSly cleaved to generate F(ab')2 fragments (Brennan et al (1985) Science 229:81 ).
  • Fab'-SH fragments can be recovered from E. coii and chemically coupled to form bispecific antibodies (Shalaby et al (1992) J. Exp. Med. 175:217-225.
  • the "diabody” technology provides an alternative method for making bispecific antibody fragments (Hollinger et al (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448).
  • Multivalent, Octopus" antibodies with three or more antigen binding sites and two or more variable domains can be readily produced by recombinant expression of nucleic acid encoding the polypeptide chains of the antibody (US 2002/0004586; WO 01/77342).
  • trispecific antibodies can be prepared (Tutt et al (1991 ) J. Immunol. 147:60.
  • the antibodies (and fragments thereof) of the invention can be conjugated to molecules for therapeutic purposes.
  • an antibody and/or fragments thereof to CADM1 can be conjugated to a molecule (e.g., a toxin, cytotoxic or therapeutic agent) for therapeutic purposes, for example for treating cancer (e.g., melanoma, colon and/or colorectal cancer or prostate cancer).
  • a molecule e.g., a toxin, cytotoxic or therapeutic agent
  • Antibody conjugates with antibodies to CADM1 can prepared for various types of antibodies (and/or fragments thereof) including chimeric antibodies, humanized antibodies, and fully human antibodies.
  • conjugated means that the antibody/binding molecule is bound to a molecule such as a toxin or therapeutic agent via any type of bonding, and thus it also includes bonding via fusion proteins (in case the molecule to which the antibody is to be conjugated is of peptidic nature) or any other type of coupling or linkage between the toxin/therapeutic agent and the antibody/binding molecule.
  • Conjugated to is thus to be understood as including fused to, linked to or coupled to.
  • a molecule of antibody may conjugate with more than one molecule of the other therapeutic agent or toxin (as used herein, "conjugation agent"), depending on the number of sites in the antibody available for conjugation and the experimental conditions employed for performing the conjugation.
  • conjugation agent used herein, "conjugation agent”
  • a preparation of the antibody conjugate may analyze for a non-integer ratio of conjugation agent molecules per molecule of antibody, reflecting a statistical average.
  • Therapeutic agent refers to any molecule (including small molecules, macromolecuies, peptides, polypeptides, proteins (including other therapeutic antibodies), radioactive isotopes, etc) exerting a beneficial effect in the treatment of diseases in humans or other mammals.
  • therapeutic agents are suitable for the therapy of cancer.
  • therapeutic agents also comprises toxins, in particular toxins used in cancer therapy.
  • Examples of molecules that can be conjugated to the antibodies of the invention targeting CADM1 include, but are not limited to, anticancer agents such as antimetabolites (e.g., methotrexate, azathioprine, 6-mercaptopurine, 6-thioguanine, cytarabsne, 5-fluorouracif decarbazine), alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, meiphalan, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, ifosfamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dich!orodiamine platinum (II) (DDP) cisplatin, carboplatin, oxaliplatin, nedap!atin, satraplatin, tripiatin tetranitrate, procarbazine, altretamine and
  • cytotoxic and/or therapeutic agents that can be conjugated to the antibodies of the invention to CADM1 include, but are not limited to taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, glucocorticoids, , monomethyl auristatin E (M AE), DM1 , DM4, and puromycin and analogs or homologs thereof.
  • taxol cytochalasin B
  • gramicidin D ethidium bromide
  • emetine mitomycin
  • etoposide tenoposide
  • vincristine vinblastine
  • colchicin colchicin
  • doxorubicin daunorubi
  • inhibitory peptide means any peptide that inhibits cell proliferation or affects cell viability via any mechanism of action.
  • the therapeutic agent for conjugation is a toxin.
  • toxins that can be conjugated to the antibodies/binding molecules of the invention to CADM1 include, but are not limited to plant toxins such as saporin, Ricin or Geionin, and bacterial toxins such as Pseudomona exotoxin or diphteria toxin.
  • ribonucieases can be considered as toxins due to their ability to degrade RNA and cause cell death.
  • Rnases which are considered to have cytotoxic effects and can be used also as toxins are Binase (from Bacillus intermedius), a- sarcin (from Aspergillus giganteus), Ranpimase (from amphinian) and Onconase (from Rana pipiens).
  • the antibodies (and fragments thereof) of the invention can be conjugated to or have a detectable label to molecules for diagnostic purposes.
  • an antibody to CADM1 can be conjugated to a detectable label (e.g. , for imaging purposes) for diagnosing or detecting cancer such as prostate cancer, melanoma or colon and/or colorectal cancer.
  • Suitable detectable markers include, but are not limited to, a radioisotope, a nanoparticle, a fluorescent compound , a bioluminescent compound, chemiluminescent compound, a metal chelator or an enzyme.
  • Techniques for conjugating diagnostic agents to antibodies are well known (Holmes et al. (2001 ) Curr Protoc Cytom.
  • kits for conjugating agents (such as detectable labels) to diagnostic antibodies are commercially available.
  • Such antibody conjugates with antibodies/binding molecules to CADM1 can readily be prepared for various types of antibodies (and/or fragments thereof) as described above, including chimeric antibodies, deimmunized antibodies, humanized antibodies, fuily humanized/human antibodies, single chain antibodies, diabodies and the like.
  • Conjugates can be prepared using a variety of cleavable linkers such as for example disulfide-based linkers, hydrazone linkers or peptide linkers (Alley et al. (2010) Curr Opin Chem Biol 14(4):529-37; Webb (201 1 ) Nat.Biotech, 29(4):297-8) or the TAP Sinker technology from ImmunoGen.
  • cleavable linkers such as for example disulfide-based linkers, hydrazone linkers or peptide linkers (Alley et al. (2010) Curr Opin Chem Biol 14(4):529-37; Webb (201 1 ) Nat.Biotech, 29(4):297-8) or the TAP Sinker technology from ImmunoGen.
  • the antibodies of the invention may also be conjugated to nanoparticies comprising human serum albumin (HSA) to optimize preparation and uptake of antibodies in cancer cells, as described, for example, by Sieinhauser et ai., Blomaterials 2006 Oct;27 ⁇ 28):4975-83.
  • HSA human serum albumin
  • the antibodies of the invention may also be a fusion wherein the antibody portion (comprising one or more CDRs) is fused to another protein or polypeptide.
  • an antibody according to the invention can be fused to another protein or polypeptide wherein said protein or polypeptide is an agent which improve the properties of said antibody e.g. , enhances therapeutic effect.
  • proteins or polypeptides which e.g. , can enhance therapeutic effect through a number of mechanisms like attracting or enhancing an immune response or delivering a therapeutic agent such a cytotoxic peptide or inhibitory peptide as defined above.
  • proteins or polypeptides are cytokines like I L2 or a I L2 homolog or GM-CSF.
  • inhibitory peptides include but are not limited to the following peptide sequences: • YARAAARGARAGRGYVSTT (wherein Y represents a phosphotyrosine), which is a peptide inhibitor of the transcription factor STAT6 which binds only to the phosphory!ated form of STAT6 to prevent its d/merization and activity
  • PYLKTK (wherein Y represents a phosphotyrosine), which is a phosphopeptide which inhibits the activity of the transcription factor STAT3 in vitro and in vivo
  • a nucleic acid encoding the antibody of the invention operably linked to the desired protein or polypeptide can be prepared and introduced into an expression vector, which is then inserted into a host cell for production of the fusion protein.
  • the invention relates to a CAD 1 antibody that induces, enhances, or mediates antibody-dependent cellular cytotoxicity (ADCC).
  • ADCC is a type of immune reaction in which a target cell is coated with antibodies and killed by certain types of white blood cells. The white biood cells bind to the antibodies and release substances that kill the target ceils or microbes. Not all antibodies produce ADCC.
  • the invention relates to an antibody to CADM1 that can induce, enhance or mediate ADCC.
  • antibodies of the invention to CADM1 can be engineered to have improved, increased or enhanced ADCC.
  • an antibody of the invention that does not induce, enhance, or mediate ADCC can be engineered, e.g., by making certain amino acid modifications to the antibody or by producing the antibody in certain strains of cells, to induce, enhance or mediate ADCC or have improved/enhanced ADCC properties.
  • an antibody to CADM1 has antibody-dependent cellular cytotoxicity when used in a human subject.
  • One example of an antibody with increased or improved ADCC activity is a antibody to CADM1 that is defucosy!ated.
  • an antibody to CADM1 having ADCC or increased ADCC is generated by producing the antibody in a cell-line that lacks or has decreased alpha-1 ,6-fucosyitransferase activity.
  • an antibody to CADM1 having ADCC or increased ADCC is generated by producing the antibody in a cell-line that has reduced or lacks GDP- fucose transporter activity
  • an antibody to CADM1 having ADCC or increased ADCC is generated by producing the antibody in a cell-line that has reduced or lacks GDP-mannose 4,6-dehydratase activity
  • an antibody to CAD 1 having ADCC or increased ADCC is generated by producing the antibody in a cell-line that has reduced or lacks both alpha-1 ,6-fucosyltransferase activity and GDP-mannose 4,6- dehydratase activity. See e.g., Yamane-Ohnuki et al. (2004) Biotechnol Bioeng, 87(5):614-22; imai-Nishiya et al. (2007) BMC Biotechnology 7:84.
  • ADCC can be enhanced or improved by increasing the levels of interieukin-21 (!L-21 ) in a patient or by treating the patient with IL-21 in combination with the antibody of the invention. See e.g., Watanabe et al. Br J Cancer. 2009 Dec 22. [Epub ahead of print].
  • the invention relates to a CADM1 antibody that enhances, induces or mediates complement dependent cytotoxicty (CDC).
  • CDC is a cytolytic cascade mediated by complement proteins in the serum. CDC is initiated by the binding of C1 q to the constant region of celi bound antibody molecule.
  • the invention relates to an antibody to CADM1 that induces, enhances or mediates CDC.
  • antibodies of the invention to CADMI can be engineered to have improved, increased or enhanced ADCC.
  • an antibody of the invention that does not induce or mediate ADCC can be engineered, e.g., by making certain modifications to the antibody like amino acid rnuations in Fc or the hinge region thereby improving or enhancing CDC.
  • Another method of producing CDC or enhancing antibodies an antibody's CDC is by shuffling lgG1 and lgG3 sequences within the heavy chain constant region. See e.g., Natsume ef al. (2008) Cancer Res. 68:3863-3872.
  • CADM1 is a therapeutic target.
  • CADM1 is a cancer therapeutic target.
  • the invention therefore provides a method for treating cancer comprising administering to an individual in need of treatment a therapeutic agent that modulates CADM1 .
  • said cancer is selected from melanoma, colon and/or colorectal cancer and prostate cancer, in a more specific aspect, the invention provides a method for treating prostate cancer comprising administering to an individual in need of treatment a therapeutic agent that modulates CAD 1 .
  • the invention provides a method for treating melanoma comprising administering to an individual in need of treatment a therapeutic agent that modulates CADM1 .
  • the invention provides a method for treating colon and/or colorectal cancer comprising administering to an individual in need of treatment a therapeutic agent that modulates CADM1.
  • the therapeutic agent that modulates CADM1 is chosen from an antisense molecule, an interfering RNA molecule, a small organic molecule, or a therapeutic antibody or fragment thereof, in a more specific aspect, the therapeutic agent is a therapeutic antibody or fragment thereof that binds CADM1 protein. In a more specific aspect, the therapeutic agent is an antibody, antibody fragment or binding molecule specifically binding to CADM1 as provided herein.
  • the therapeutic agent has one or more of the follow effects on cancer, cancer cells expressing CAD 1 , melanoma, melanoma cells, colon and/or colorectal cancer, colon and/or colorectal cancer cells, prostate cancer, or prostate cancer cells: reduces or inhibits proliferation; reduces or inhibits cellular growth; causes cytotoxicity; reduces or inhibits metastasis; modulates, reduces or inhibits cel!-adhesion; modulates, reduces or inhibits cell migration; or modulates, reduces or inhibits cell invasion.
  • the therapeutic antibody is chosen from the antibodies defined in the embodiments described herein above, including the antibodies defined in (a)-(x) above and antibodies designated AB3, AB10, AB2, AB1 and AB8.
  • a group of particularly preferred antibodies for use in therapy are the antibodies designated AB3, AB10 and AB8, as well as antibodies/binding molecules derived therefrom.
  • the invention provides a method of treating an individual having cancer comprising administering to said individual a therapeutically effective amount of a therapeutic antibody or fragment thereof to CADM1 .
  • the invention provides a method of treating an individual having melanoma, colon and/or colorectal cancer or prostate cancer comprising administering to said individua! a therapeutically effective amount of a therapeutic antibody or fragment thereof to CADM1 .
  • the therapeutic antibody reduces levels of activity of CADM1.
  • the therapeutic antibody or fragment thereof to CADM1 inhibits or reduces proliferation; causes cytotoxicity; inhibits or reduces metastasis; modulates, inhibits or reduces eel!
  • adhesion modulates, inhibits or reduces migration; or modulates, inhibits or reduces invasion of cancer cells, cancer, meianoma, colon and/or colorectal cancer or prostate cancer, or melanoma, colon and/or colorectal or prostate cancer cells expressing CADM1 .
  • the therapeutic antibody or fragment thereof to CADM1 inhibits or reduces proliferation of melanoma, co!on and/or colorectal cancer or prostate cancer, melanoma cancer cells, colon and/or colorectal cancer cells, prostate cancer cells, cancer, or cancer cells expressing CAD 1 .
  • the therapeutic antibody or fragment thereof to CADM1 causes cytotoxicity to melanoma, colon and/or colorectal cancer or prostate cancer, melanoma cancer cells, colon and/or colorectal cancer cells or prostate cancer cells, cancer, or cancer cells expressing CADM1 .
  • the therapeutic antibody or fragment thereof to CADM1 reduces or inhibits metastasis of melanoma, colon and/or colorectal cancer or prostate cancer, melanoma cancer cells, colon and/or colorectal cancer cells or prostate cancer cells, cancer, or cancer cells expressing CAD 1 .
  • the therapeutic antibody or fragment thereof to CADM1 reduces or inhibits cell adhesion of melanoma, colon and/or colorectal cancer or prostate cancer, melanoma cancer cells, colon and/or colorectal cancer cells or prostate cancer cells, cancer or cancer cells expressing CADM1 .
  • the therapeutic antibody or fragment thereof to CAD 1 reduces or inhibits invasion of melanoma, colon and/or colorectal cancer or prostate cancer, melanoma cancer cells, colon and/or colorectal cancer cells or prostate cancer cells, cancer or cancer cells expressing CADM1.
  • the therapeutic antibody or fragment thereof to CADM1 reduces or inhibits migration of melanoma, colon and/or colorectal cancer or prostate cancer, melanoma cancer cells, colon and/or colorectal cancer cells or prostate cancer cells, cancer or cancer cells expressing CADM1 .
  • the therapeutic antibody to CADM1 induces, enhances, or mediates ADCC (antibody dependent cellular cytotoxicity) against cells to which it binds.
  • the therapeutic antibody to CADM1 induces, enhances, or mediates CDC (complement dependent cytotoxicity) against cells to which it binds.
  • the therapeutic antibody to CADM1 is conjugated to another molecule.
  • the therapeutic antibody is conjugated to a cytotoxin, a radioactive agent, enzyme, toxin, an anti-tumor drug or a therapeutic agent.
  • the therapeutic antibody (or fragment thereof) of this embodiment can be provided as a pharmaceutical composition comprising the antibody (or fragment thereof) and a pharmaceutically acceptable carrier.
  • the invention provides a method for treating or preventing prostate cancer.
  • the method comprises identifying a patient having a risk factor for prostate cancer, obtaining a sample from said patient having a risk factor for prostate cancer, and determining the level of CAD 1 biomarker in said sample wherein a patient having an increased level of CAD 1 biomarker is treated with a therapeutic antibody that binds to or modulates CADM1 ,
  • the risk factor for prostate cancer is chosen from age, ethnicity, fami!y history of prostate cancer, or genetic predisposing gene or variant thereof, in a preferred aspect of this embodiment, the therapeutic agent is a therapeutic antibody or fragment thereof.
  • the risk factor for prostate cancer is one or more SNPs that indicated a higher risk of having prostate cancer see e.g., Gudmundsson J, et al. Nat Genet. 2009 Oct;41 (10):1122-6. Epub 2009 Sep 20.
  • the invention provides a method for treating prostate cancer in a patient wherein said patient has androgen dependent prostate cancer.
  • the method comprises identifying a patient having androgen dependent prostate cancer and administering to said patient a CADM1 therapeutic antibody.
  • the method comprises administering to said patient having androgen dependent prostate cancer a CADM1 therapeutic antibody and another therapeutic agent which is hormone therapy.
  • Hormone therapy for prostate cancer are as follows: Luteinizing hormone-releasing hormone agonists, antiandrogens, or modulators of adrenal gland hormone synthesis.
  • Luteinizing hormone-re!eastng hormone agonists include, but are not limited to, !euprolide, goserelin, or buserelin.
  • Antiandrogens include, but are not limited to, bicalutamide, flutamide, or niiutamide.
  • Modulators of adrenal gland hormone synthesis include, but are not limited to, ketoconazole or aminoglutethimide.
  • the therapeutic antibody is chosen from the antibodies defined in the embodiments disclosed herein, , including antibodies AB3, AB10 and AB2, or an antibody/binding molecule derived therefrom.
  • the invention provides a method for treating prostate cancer in a patient wherein said patient has hormone-refractory or resistant prostate cancer.
  • the method comprises identifying a patient having hormone-refractory or resistant prostate cancer and administering to said patient a CADM1 therapeutic antibody.
  • the method comprises administering to said patient having hormone-refractory or resistant prostate cancer a CAD 1 therapeutic antibody and another therapeutic agent which is hormone therapy
  • the therapeutic antibody is chosen from the antibodies defined in the embodiments disclosed above, including antibodies AB3, AB10 and AB2, or an antibody/binding molecule derived therefrom.
  • the invention provides a method for treating cancer in a patient wherein said patient was previously treated or is currently being treated with radiation therapy, !n a more specific embodiment, the invention provides a method for treating prostate cancer in a patient wherein said patient was previously treated or is currently being treated with radiation therapy.
  • the method comprises identifying a patient previously treated or is currently being treated with radiation therapy and administering to said patient a CADM1 therapeutic antibody. Radiation therapy for prostate cancer is generally classified as external or internal.
  • External radiation therapy usually involves the focusing of high energy beams of energy (e.g., x-rays) on the affected area
  • internal radiation therapy involves imp!anting a radioactive substance or composition comprising a radioactive substance near or inside the cancer ⁇ also referred to as brachytherapy, internal radiation therapy, and/or radiation brachytherapy).
  • the therapeutic antibody is chosen from the antibodies defined as in the embodiments disclosed herein, including antibodies AB3, AB10 and AB2, or an antibody/binding molecule derived therefrom.
  • the invention provides a method for treating cancer in a patient wherein said patient was previously treated or is currently being treated with chemotherapy.
  • the invention provides a method for treating prostate cancer in a patient wherein said patient was previously treated or is currently being treated with chemotherapy.
  • the method comprises identifying a patient previously treated or is currently being treated with chemotherapy and administering to said patient a CADM1 therapeutic antibody.
  • the therapeutic antibody is chosen from the antibodies defined in the embodiments described above, including antibodies AB3, AB10 and AB2, or an antibody/binding molecule derived therefrom.
  • the invention provides an antibody to CAD 1 as described herein or as produced by the processes disclosed herein , and particularly as described in the embodiments described above, including an antibody selected from AB3,AB 1 0,AB2,AB 1 or AB8, or an antibody selected from AB3.AB 10 or AB2, or an antibody derived therefrom, for use in medicine.
  • the invention provides an antibody to CADM 1 as described herein or as produced by the processes disclosed herein, and particularly as described in the embodiments described above, including an antibody selected from AB3,AB1 0,AB2,AB1 or AB8, or an antibody selected from AB3.AB 1 0 or AB2 , or an antibody derived therefrom, for use in the treatment of diseases or disorders wherein CADM1 is expressed or involved.
  • the invention further provides an antibody to CADM1 as described herein or as produced by the processes disclosed herein, and particularly as described in the embodiments described above, including an antibody selected from AB3,AB10,AB2,AB1 or AB8, or an antibody selected from AB3,AB 1 0 or AB2, or an antibody derived therefrom, for use in the treatment of cancer.
  • the invention further provides the use of an antibody to CADM1 as described herein or as produced by the processes disclosed herein , and particularly as described in the embodiments described above, including an antibody selected from AB3,AB 10,AB2,AB 1 or AB8, or an antibody selected from AB3,AB 1 0 or AB2, or an antibody derived therefrom, for the preparation of a pharmaceutical composition for the treatment of cancer.
  • the invention further provides a method of treating cancer in an individual in need thereof comprising administering to said individual an antibody to CADM 1 as described herein or as produced by the processes disclosed herein, and particularly as described in the embodiments described above, including an antibody selected from AB3.AB 1 0,AB2,AB 1 or AB8, or an antibody selected from AB3,AB10 or AB2, or an antibody derived therefrom , .
  • the individual is a human .
  • the antibody of the invention for use in the above embodiments can be a full antibody (immunoglobulin), an antibody fragment such as a F(ab)-fragment or a F(ab)2-fragment, a single-chain antibody, a chimeric antibody, a humanized antibody, a human antibody, a fully human antibody, a CDR-grafted antibody, a bivalent antibody-construct, a bispecific single-chain antibody, a synthetic antibody and a cross-cloned antibody.
  • the antibody is a fully human antibody, or a fragment thereof.
  • the antibodies of the invention have shown high affinity for CADM1 in CADM1 - expressing melanoma, colon cancer and prostate cancer cell lines, as shown in the appended Examples.
  • antibodies of the invention have shown very efficient capacity to target CAD 1 -expressing cancer cell lines and deliver a therapeutic agent like a toxin to said CADM1 -expressing cancer cell lines. Remarkable results have been obtained with antibodies designated AB3, AB10 and AB2 in melanoma, colon cancer and prostate cancer cell lines, as shown in Examples 23 and 24.
  • said cancer is melanoma, colon and/or colorectal cancer or prostate cancer.
  • said cancer is melanoma.
  • said cancer is colon and/or colorectal cancer.
  • said cancer is prostate cancer.
  • the antibody of the invention is conjugated to a therapeutic agent or toxin, as disclosed in more detail in the section Conjugated antibodies, above.
  • the antibody of the invention (which can be optionally conjugated) is administered in combination with one or more therapeutic agent(s).
  • Administration of the antibody against CADM1 and the therapeutic agent(s) can be in a successive, sequential or simultaneous treatment regimen, and they can be administered via the same or different routes of administration.
  • the antibody of the invention and the one or more other therapeutic agents may also be combined into a single dosage unit.
  • the therapeutic agent is an anticancer agent. Examples of anticancer agents that can be administered in combination with the antibodies of the invention include the drugs fisted below in the section Combination therapy.
  • the inventors While conducting research with the antibodies of the invention in skin cancers, the inventors have come to the surprising finding that the antibodies of the invention are particularly effective in melanoma cancers containing a BRAF mutation, as shown in the table below. See data obtained for melanoma cell Sines A375 or SKMEL28, both reported to have the BRAF mutation V600E, or melanoma cell line MDA-MB-435S, reported to have the BRAF mutation G463V, where a very potent effect on cell viability is observed, as compared to melanoma Hs895T, for which no BRAF mutation has been reported, or the skin cancer A431 cell line, which corresponds to wild-type BRAF. This finding is highly relevant since BRAF gene mutations are highly prevalent in melanomas.
  • the invention provides an antibody to CADM1 as described herein or as produced by the processes disclosed herein, and particularly as described in the embodiments described above, including an antibody selected from AB3,AB10,AB2,AB1 or AB8, or an antibody selected from AB3.AB10 or AB2, or an antibody derived therefrom , for use in the treatment of melanoma, wherein said melanoma contains a BRAF mutation .
  • said BRAF mutation is V600E.
  • said BRAF mutation is G463V.
  • the invention further provides the use of an antibody to CADM1 as described herein or as produced by the processes disclosed herein, and particularly as described in the embodiments described above, including an antibody selected from AB3.AB1 0,AB2,AB 1 or AB8, or an antibody selected from AB3,AB1 0 or AB2, or an antibody derived therefrom, for the preparation of a pharmaceutical composition for the treatment of melanoma, wherein said melanoma contains a BRAF mutation.
  • said BRAF mutation is V600E.
  • said BRAF mutation is G463V.
  • the invention further provides a method of treating melanoma , wherein said melanoma contains a BRAF mutation, in an individual in need thereof comprising administering to said individual an antibody to CADM 1 as described herein or as produced by the processes disclosed herein , and particularly as described in the embodiments described above, including an antibody selected from AB3,AB 10,AB2,AB1 or AB8, or an antibody selected from AB3,AB10 or AB2, or an antibody derived therefrom.
  • the individual is a human .
  • said BRAF mutation is V600E. in another embodiment, said B RAF mutation is G463V.
  • the antibodies of the invention may be administered in combination with one or more therapeutic agents for the treatment of melanoma, particularly melanoma containing a BRAF mutation.
  • therapeutic agents for the treatment of melanoma, particularly melanoma containing a BRAF mutation.
  • One such class of therapeutic agents are B-raf enzyme inhibitors such as vemurafenib (also known as PLX4032); vemurafenib has been recently approved by the FDA for the treatment of late-stage melanoma.
  • Treatment with the antibodies of the invention may be particularly useful to treat melanoma in vemurafenib-resistant patients.
  • bi- or muitispecific antibodies targeting CADM1 in therapy, in particular in the treatment of cancer, including melanoma, colon and/or colorectal cancer or prostate cancer.
  • bi- or muitispecific antibodies having at least one specificity for/to CADM1 (including full immunoglobulins and/or fragments thereof, including single chain (bispecific or muitispecific) antibodies) based on the CDR sequences and/or VH or VL sequences described herein, including the sequences for AB3, AB10 and AB2 (or sequences derived therefrom), can be prepared exhibiting binding specificities for at least one further target in addition to CADM1.
  • Such an anti- CADM1 arm may be combined, for example, with an arm which binds to/interacts with a triggering molecule and/or surface marker on a leukocyte such as a T-ceN receptor molecule (e.g. CD2 or CD3), or Fc receptors for IgG (FcyR), such as FcyR! (CD64), FcyRII (CD32) and FcyRI II (CD16) so as to focus and/or targets cellular defense mechanisms to the CADM1 -expressing cell.
  • a triggering molecule and/or surface marker on a leukocyte such as a T-ceN receptor molecule (e.g. CD2 or CD3), or Fc receptors for IgG (FcyR), such as FcyR! (CD64), FcyRII (CD32) and FcyRI II (CD16) so as to focus and/or targets cellular defense mechanisms to the CADM1 -expressing cell.
  • CADM1 for the therapy of cancer, including melanoma, colon and/or colorectal cancer or prostate cancer
  • PSMA prostate-specific membrane antigen
  • EpCAM Epithelial cell surface antigen
  • MUC1 cell adhesion molecules like mucin 1
  • CEA1 carcinoembryonic antigen
  • CEA1 Tyrosine kinase-type cell surface receptor HER2
  • ERBB3 Tyrosine kinase-type cell surface receptor HER3
  • CTL4 cytotoxic T-lymphocyte activator-4
  • VEGFR vascular endothelial growth factor receptor
  • EGFR epidermal growth factor receptor
  • integrin alpha L
  • the antibodies of the invention can be co-administered (i.e. administered in combination) with one or more other therapeutic agents.
  • the antibody of the invention may be, as described above, a full antibody (immunoglobulin), an antibody fragment such as a F(ab)-fragment, a F(ab)2-fragment or an epitope-binding fragment, as well as a single-chain antibody and may be a monoclonal antibody, a recombinantly produced antibody, a chimeric antibody, a humanized antibody, a human antibody, a fully human antibody, a CDR- grafted antibody, a bivalent antibody-construct, a synthetic antibody or a cross- cloned antibody, a diabody, a triabody, a tetrabody, a single chain antibody, a bispecific single chain antibody, etc.
  • the antibody of the invention may itself be linked to another agent, i.e. be a conjugated antibody as described above.
  • the administration of the antibody of the invention and the one or more other therapeutic agent(s) can be in a successive, sequentia! or simultaneous treatment regimen, and they can be administered via the same or different routes of administration.
  • the antibody of the invention and the one or more other therapeutic agents may also be combined into a single dosage unit.
  • Such therapeutic agents include, among others, anticancer agents such as antimetabolites (e.g., methotrexate, azathioprine, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracii, dacarbazine, capecitabine), alkylating agents (e.g., mechiorethamine, thioepa chlorambucil, mefphalan, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, ifosfamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichiorodiamine platinum (II) (DDP) cisplatin, carboplatin, oxaliplatin, nedapiatin, satraplatin, triplattn tetranitrate, procarbazine, altretamine and tetrazines), anthracyclines (
  • irinotecan topotecan and camptothecin
  • anti-mitotic agents e.g., vinca alkaloids such as vincristine and vinblastine, taxanes such as paclitaxel (also known as taxol), cabazitaxel and docetaxel, and other tubulin polimeryzation inhibitors such as monomethyl auristatin E (MMAE) and maytansine derivatives like mertansine (also known as DM1 ) and DM4).
  • MMAE monomethyl auristatin E
  • DM1 mertansine
  • protein kinase inhibitors such as imatinib (gieevec), nilotinib and dasatinib, and B-raf inhibitors such as vemurafenib.
  • Preferred therapeutic agents for combination therapy with the antibodies of the invention in the treatment of melanoma include, among others, dacarbazine, aldesleukin , ipiiimumab, and vemurafenib, or combinations thereof.
  • Preferred therapeutic agents for combination therapy with the antibodies of the invention in the treatment of colorectal cancer include, among others, fluorouracii, bevacizumab, irinotecan. capecitabine, cetuximab, oxaliplatin, leucovorin, and panitumumab, or combinations thereof.
  • Preferred therapeutic agents for combination therapy with the antibodies of the invention in the treatment of prostate cancer include, among others, abiraterone, cabazitaxel, docetaxel, degarelix, leuprolide acetate, and prednisone, or combinations thereof.
  • Preferred antibodies of the invention for use in combination therapy include antibodies AB3 , AB 10 and AB2, as well as antibodies/binding molecules derived therefrom .
  • the invention provides therapeutic reagents targeting the CADM1 biomarker of the invention.
  • the invention provides a therapeutic reagent for treating cancer expressing and/or overexpressing the CADM1 biomarker of the invention.
  • the invention provides a therapeutic reagent for treating prostate cancer.
  • the therapeutic agent of the invention for treating prostate cancer is chosen from a an antisense molecule to a CAD 1 nucleic acid, an interfering RNA molecule to a CAD 1 nucleic acid, a small organic molecule that binds covendedly or non- covalently to CADM1 protein, or a therapeutic antibody or fragment thereof that binds to a CADM1 protein or epitope.
  • the invention includes a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a therapeutic agent ⁇ e.g., therapeutic antibody or fragment thereof to CAD 1 ).
  • the invention relates to molecules that modulate the expression of CADM1 protein, CADM1 gene, or CADM1 .
  • an antisense compound specific to a nucleic acid encoding a CAD 1 protein invention is administered an individual in need of such treatment.
  • the antisense compound for use in the invention specifically inhibits the expression of CADM1 protein.
  • antisense drugs generally act by hybridizing to a particular target nucleic acid thus blocking gene expression.
  • Methods for designing antisense compounds and using such compounds in treating diseases are well known and well developed in the art.
  • the antisense drug, fomivirsen, a 21 -base long oligonucleotide has been successfully developed and marketed by Isis Pharmaceuticals, I c, for treating cytomegalovirus (CMV)- induced retinitis.
  • CMV cytomegalovirus
  • Antisense compounds are oligonucleotides designed based on the nucleotide sequence of the mRNA or gene of the CADM1 protein.
  • the antisense compound can be designed to specifically hybridize to a particular region of the gene sequence or mRNA of CADM1 to modulate (increase or decrease) replication, transcription, or translation.
  • “specifically hybridize” means a sufficient degree of complementarity or pairing between an antisense compound and a target DNA or mRNA such that stable and specific binding occurs therebetween.
  • Specific hybridization takes place when sufficient hybridization occurs between the antisense compound and its intended target nucleic acids in the substantial absence of non-specific binding of the antisense compound to non-target sequences under predetermined conditions, e.g., for purposes of in vivo treatment, preferably under physiological conditions.
  • specific hybridization results in the interference with normal expression of the target DNA or mRNA.
  • antisense oligonucleotides can be designed to specifically hybridize to target genes, in regions critical for regulation of transcription; to pre-mRNAs, in regions critical for correct splicing of nascent transcripts; and to mature mRNAs, in regions critical for translation initiation or mRNA stability and localization.
  • oligonucleotides are oligomers or polymers of ribonucleotides or deoxyribonucleotides, thai are composed of a naturally-occurring nitrogenous base, a sugar (ribose or deoxyribose) and a phosphate group. In nature, the nucleotides are linked together by phosphodiester bonds between the 3' and 5' positions of neighboring sugar moieties.
  • oligonucleotides also encompasses various non-naturally occurring mimetics and derivatives, i.e., modified forms, of naturally occurring oligonucleotides as described below.
  • an antisense compound of the present invention is an oligonucleotide having from about 6 to about 200, and preferably from about 8 to about 30 nucleoside bases.
  • the antisense compounds preferably contain modified backbones or non-natural internucieoside linkages, including but not limited to, modified phosphorous- containing backbones and non-phosphorous backbones such as morpholino backbones; siloxane, sulfide, sulfoxide, sulfone, sulfonate, sulfonamide, and sulfamate backbones; formacetyl and thioformacetyl backbones; aikene-containing backbones; methyleneimino and methylenehydrazino backbones; amide backbones, and the like.
  • modified backbones or non-natural internucieoside linkages including but not limited to, modified phosphorous- containing backbones and non-phosphorous backbones such as morpholino backbones; siloxane, sulfide, sulfoxide, sulfone, sulfonate, sulfonamide, and sul
  • CADM1 is a diagnostic cancer biomarker.
  • CADM1 is a diagnostic marker for melanoma, colon and/or colorectal cancer or prostate cancer.
  • the invention provides a method for diagnosis of cancer by determining the level or activity of a CADM1 biomarker in a biological sample from an individual wherein an altered level of CADM1 biomarker in the biological sample as compared to a control or normal value is diagnostic of cancer or an increased likelihood of cancer.
  • the invention provides a method for diagnosis of melanoma, colon and/or colorectal cancer or prostate cancer by determining the level of a CAD 1 biomarker in a biological sample from an individual wherein an altered level of CADM1 biomarker in the biological sampie as compared to a control or normal value is diagnostic of melanoma, colon and/or colorectal cancer or prostate cancer, respectively, or an increased likelihood of melanoma, colon and/or colorectal cancer or prostate cancer.
  • the CADM1 biomarker can be CADM1 nucleic acid biomarker or a CADM1 protein biomarker.
  • the agent capable of detecting CADM1 is a diagnostic antibody or fragment thereof to a CADM1 protein or CADM1 epitope, particularly the antibodies against CADM1 having the CDRs and/or variable domains as described herein, including antibodies AB3, AB10 or AB2, or antibodies/binding molecules derived therefrom.
  • the invention therefore relates to a method for the diagnosis of prostate cancer by contacting an agent capable of detecting a CADM1 biomarker with a biological sampie from an individua! and determining the level of the CADM1 biomarker wherein an altered level of CADM1 biomarker in the biological sample as compared to a control or normal value is diagnostic of cancer or an increased likelihood of cancer.
  • the invention provides a method for the diagnosis of prostate cancer by contacting an agent capable of detecting a CADM1 biomarker with a tissue, tumor, blood, serum, plasma or urine sampie from an individual and determining the level of the CADM1 biomarker wherein an altered Ievei of CADM1 biomarker in the biological sample as compared to a control or normal value is diagnostic of cancer or an increased likelihood of cancer.
  • the biological sample is a blood, serum, plasma or urine.
  • the biological sample is a blood, serum, or plasma sample.
  • the biological sample is a plasma sample.
  • an increased or elevated level of CADM1 biomarker as compared to a control or normal value is indicative of prostate cancer or an increased likelihood of prostate cancer.
  • the agent capable of detecting CADM1 is a diagnostic antibody or fragment thereof to a CADM1 protein or CADM1 epitope
  • the agent capable of detecting CADM1 is a diagnostic antibody or fragment thereof to a CADM1 protein as in SEQ ID NOs:1 -3, a CADM1 epitope which is chosen from one or more of the peptide sequences of SEQ ID NOs: 4-16 as described above which are extracellular domain epitopes of CADM1 or a transmembrane and/or intracellular domain epitopes.
  • the agent capable of detecting CADM1 is a diagnostic antibody or fragment thereof having the CDRs and/or variable domain sequences as described herein.
  • the agent capable of detecting CAD 1 is a monoclonal antibody or fragment thereof that binds to CADML
  • the agent capable of detecting CADM1 is a recombinant antibody that binds to CADM1 protein or epitope.
  • the agent capable of detecting CADM1 is a polyclonal antibody that binds to CADM1 or epitope.
  • the diagnostic antibody or fragment thereof binds selectively to CADM1 or epitope, in one aspect, the diagnostic antibody or fragment thereof binds specifically to CADM1 or epitope. In one aspect, the diagnostic antibody or fragment thereof is conjugated to a detectable label.
  • the agent capable of detecting CADM1 is a nucleic probe capable of hybridizing to a CADM1 nucleic acid. In one aspect, the agent capable of detecting CADM1 is a set of primers capable of hybridizing to a CADM1 nucleic acid and are useful for amplifying said CADM1 nucleic acid.
  • CADM1 activity may be measured so as to determine relati Is of CADM1 when compared to a control level of activity. CADM1 activity may be measured using any method available to one of ordinary skill in the art including, but not limited to, measurement of product levels.
  • the invention includes a method of diagnosing prostate cancer comprising:
  • the sample is a serum , blood, plasma, or urine sample.
  • the sample is a serum, blood, plasma or sample.
  • the sample is a plasma sample.
  • the CADM 1 biomarker is a nucleic acid biomarker.
  • the CADM1 biomarker is a protein biomarker.
  • said CADM 1 biomarker is detected with an antibody that binds to CADML
  • said antibody to CADM1 is an antibody having the CDRs and/or variable domain sequences as described herein.
  • said antibody to CADM 1 is an antibody as described in (a)-(x).
  • said antibody to CADM1 is AB3, AB10 or AB2, or antibodies/binding molecules derived therefrom.
  • the invention provides a method for diagnosing prostate cancer comprising obtaining a biological sample from an individual and determining the expression level or activity level of CADM 1 in the biological sample wherein if CADM 1 levels are altered compared to a control value, then the individual is diagnosed with prostate cancer or an increased likelihood of prostate cancer.
  • the sample is a serum , blood , plasma, or urine sample.
  • the samp!e is a plasma sample.
  • increased levels or increasing levels of CADM1 over time indicates prostate cancer or an increased likelihood of prostate.
  • said CADM1 biomarker is detected with an antibody that binds to CADM 1 .
  • said antibody to CADM1 is an antibody having the CDRs and/or variable domain sequences as described herein.
  • said antibody to CAD 1 is an antibody as described in (a)-(x).
  • said antibody to CADM1 is AB3, AB10 or AB2, or antibodies/binding molecules derived therefrom.
  • the present invention provides a method for characterizing a sample obtained from a patient for prognostic, diagnostic and/or pharmacogenomic uses. Characterization of a sample obtained from a patient by determining the level of a CADM1 biomarker can be used to provide information regarding diagnosis of prostate cancer, prognosis of prostate, disease progression of prostate, diagnosis of prostate cancer type (and/or subtype), and selection of an appropriate therapeutic treatment for prostate.
  • a biological sample is obtained from an individual.
  • the individual can be a healthy person, an individual diagnosed with cancer, an individual suspected of having cancer, an individual displaying one or more symptoms of cancer and/or an individual desiring screening for cancer.
  • the method comprises the step of determining the level of a CADM 1 biomarker in a sample obtained for a patient wherein the CADM1 biomarker is a protein or nucleic acid biomarker.
  • the CADM 1 biomarker is a CADM1 protein biomarker.
  • characterization of a sample obtained from a patient by determining the protein or activity level of CAD 1 can be used to provide information regarding prognosis of prostate.
  • characterization of a sample obtained from a patient by determining the protein or activity level of CADM1 can be used to provide information regarding disease progression of prostate.
  • characterization of a sample obtained from a patient by determining the protein or activity level of CADM 1 can be used to provide information diagnosis of prostate cancer cell type (and/or subtype). In one specific aspect, characterization of a sample obtained from a patient by determining the protein or activity levei of CADM1 can be used to provide information regarding selection of an appropriate therapeutic treatment for prostate.
  • one or more additional auxiliary prostate biomarkers are detected .
  • the one or more auxiliary prostate cancer diagnostic biomarkers are chosen from differential diagnosis biomarkers, prognostic biomarkers, biomarkers useful for detecting prostate cancer, biomarkers for classifying prostate cancer and additional biomarkers for detecting prostate cancer.
  • Auxiliary biomarkers for differential diagnosis biomarkers, prognostic biomarkers, biomarkers useful for detecting prostate cancer, biomarkers for classifying prostate cancer and additional biomarkers for detecting prostate cancer are know in the art including patients with LNM PCa who had sign ificantly higher levels of serum e-FABP5 (Pang et al (2010) J Proteome Res. Jan;9(1 ):216-26); BSP, DSPP, and OPN were elevated in serum from prostate cancer subjects, with serum DSPP exhibiting the greatest difference, yielding an area under the receiver operator characteristic curve value of 0.98. Clin Cancer Res. 2009 Aug 1 5; 1 5(1 6):5199-207.
  • MIC-1 is a serum PCa prognostic marker.
  • Epub 2009 Aug 21 showed that elevated fasting levels of serum insulin within the normal range appear to be associated with a higher risk of prostate cancer.
  • Epub 2009 Aug 1 8. showed that decreased SEPP concentration in serum might represent an additional valuable marker for prostate cancer diagnostics.
  • the diagnostic methods of the invention may be used in combination with other well-known markers used in the clinical for characterizing prostate cancer, prostate cancer risk, prostate cancer prognosis, prostate cancer diagnosis, and prostate cancer therapy selection .
  • markers used in the clinical for characterizing prostate cancer For example, standard staging procedures, PSA levels, PSA velocity, PCA-3 levels.
  • Other new markers for characterizing prostate cancer inc!ude TMPRSS2 fusions as detected in primary tumor and/or blood See e.g., Barwick et al. Br. J, Cancer. 2010 Jan 12. [Epub ahead of print] and Rostad et al . APMI S. 2009 Aug; 1 17(8):575-82.
  • the diagnostic antibodies of the present invention can be generated against a CAD 1 protein or an epitope of a CADM1 protein.
  • the diagnostic antibodies of the present invention bind to a CADM1 protein or an epitope of a CADM1 protein.
  • the diagnostic antibody binds to or can be generated against a polypeptide having the full length sequence of a CADM1 protein as in SEQ !D NO:1 - 3 as described herein.
  • the binding site or epitope for the diagnostic antibody is located on an extracellular domain of the protein as defined by the amino acid sequence as in SEQ ID NO:4.
  • the diagnostic antibody binds or can be generated against a epitope having the amino acid sequence of one or more of SEQ ID NOs: 5-16.
  • epitope is chosen from the amino acid sequences as in SEQ ID NOs:1-3.
  • the epitope as in SEQ ID NO:4 is epitope as in SEQ ID NO:4
  • said diagnostic antibody to CADM1 is an antibody having the CDRs and/or variable domain sequences as described above.
  • the invention provides a nucleic acid chosen from CADM1 mRNA, cDNA, or complement thereof; for use for diagnosing prostate cancer or an increased likelihood of having prostate cancer.
  • the invention provides a primers for a CADM1 nucleic acid for use for diagnosing prostate cancer and/or an increased likelihood of having prostate cancer.
  • the invention provides a probe for CADM1 for diagnosing prostate cancer and/or an increased likelihood of having prostate cancer.
  • the invention provides primers that can hybridize to a nucleic acid corresponding to a biomarker described herein and be used to amplify a nucleic acid or fragment thereof corresponding to said biomarker for diagnosing prostate cancer according to the methods of the invention.
  • the primers are designed to amplify one or more exons of the biomarker.
  • the primers are designed to amplify a fragment of one or more exons of the biomarker.
  • the primers are suitable for RT-PCR analysis.
  • the method of the invention involves the use of primers to amplify a nucleic acid corresponding to a CADM1 , and detecting the amplification product with a probe to the amplification product. In another aspect, the method of the invention involves the use of primers to amplify a nucleic acid corresponding to CADM1 , and detecting the amplification product with a dye that allows for quantification of the amplification product.
  • the invention provides probes to the CAD 1 biomarker for detecting a nucleic acid or fragment thereof corresponding to the biomarker.
  • the probes can be used in the methods of the invention e.g., for diagnosing prostate cancer.
  • the probe is for the biomarker mRNA or a nucleic acid, is obtained from the mRNA corresponding to the biomarker.
  • the probe corresponds to two contiguous exons of the biomarker, (or fragments of two or more contiguous exons).
  • the probe corresponds to an exon of the biomarker or a fragment thereof.
  • the probe corresponds to at least a portion of the promoter region of the biomarker and at least a portion of exon 1 of the biomarker.
  • the invention relies on quantitative PCR to determine the level of one or more biomarkers corresponding to CADM1 .
  • the quantitative PCR method is quantitative RT-PCR.
  • the methods can be semiquantitative or fully quantitative.
  • the methods of the invention for detecting the biomarkers of the invention can comprise competitive quantitative PCR or reai-time quantitative PCR which both estimate target gene concentration in a sample by comparison with standard curves constructed from amplifications of serial dilutions of standard DNA. Quantitative PCR or real-time quantitative PCR differ substantially in how the standard curves are generated.
  • competitive QPCR an internal competitor DNA is added at a known concentration to both serially diluted standard samples and unknown (e.g., obtained from a patient) samples.
  • ratios of the internal competitor and target PCR products are calculated for both standard dilutions and unknown samples, and a standard curve is constructed that plots competitor-target PCR product ratios against the initial target DNA concentration of the standard dilutions. Given equal amplification efficiency of competitor and target DNA, the concentration of the latter in patient samples can be extrapolated from this standard curve.
  • real-time QPCR the accumulation of amplification product is measured continuously in both standard dilutions of target DNA and samples containing unknown amounts of target DNA.
  • a standard curve is constructed by correlating initial template concentration in the standard samples with the number of PCR cycles (Ct) necessary to produce a specific threshold concentration of product.
  • target PCR product accumulation is measured after the same Ct, which allows interpolation of target DNA concentration from the standard curve.
  • RT-PCR is applied quantitatively PCR. Often termed “relative quantitative PCR,” this method determines the relative concentrations of specific nucleic acids.
  • RT-PCR is performed on mRNA species isolated from patients. By determining that the concentration of a specific mRNA species, it can be determined if the gene encoding the specific mRNA species is differentially expressed.
  • the invention relates to the use of the identification of CADM1 being overexpressed in prostate cancer for screening for small molecule therapeutics.
  • the invention therefore provides therapeutic methods for diseases which overexpress CADM1 , and in particular prostate cancer using small molecule therapeutics.
  • CADM1 can be used as a target for screening assays. For example, cells overexpressing CADM1 can be treated with a test compound to see the effect of the test compound on biomarker expression. Compounds that effect expression of the biomarker are candidates for modulating expression and therefore modulating the disease (e.g., treating and/or preventing). Any number of typical screening formats can be used to identify compounds that effect biomarkers levels. In some formats, the screen for modulators of CAD 1 expression is performed in a medium to high throughput format.
  • the modulators contemplated by the present invention can be small organic compounds. Such modulators can be identified by assays (e.g., in microtiter formats on microtiter plates in robotic assays) used to screen iarge numbers of compounds. There are many suppliers of chemical compounds, including Sigma ⁇ St. Louis, Mo.), Aldrich (St. Louis, Mo.), Sigma-Aldrich (St. Louis, Mo.), Fluka Chemika-Biochemica Analytika (Buchs, Switzerland) and the like. in particular, modulators displaying a desired activity can be identified from combinatorial libraries (/.e. t collections of diverse chemical compounds generated by either chemical synthesis or biological synthesis by combining a number of "building, blocks").
  • combinatorial libraries include, but are not limited to, peptide libraries (see e.g., U.S. Pat. 5,010,175, Furka, Int. J. Pept. Prot. Res. 37:487-493 (1991 ) and Houghton ei al., Nature 354:84-88 (1991 )).
  • chemistries for generating chemical diversity libraries also can be used. Such chemistries include, but are not limited to, peptoids (see, for example, PCT Publication No.
  • nucleic acid libraries see e.g., Ausube!; Berger and Sambrook, all supra
  • peptide nucleic acid libraries see e.g., U.S. Pat. No. 5,539,083
  • antibody libraries see e.g., Vaughn et al. (1996) Nature Biotechnology 14(3):309 ⁇ 314 (1996) and PCT/US96/10287)
  • carbohydrate libraries see e.g., Liang et al. Science, 274:1520-1522 and U.S. Pat. No. 5,593,853
  • small organic molecule libraries see, for example, benzodiazepines, Baum C&EN, Jan 18, page 33 (1993); isoprenoids, U.S. Pat.
  • High-throughput assays also can be used to identify the modulators. Using the high-throughput assays, it is possible to screen thousands of potential modulators in a single day. For example, each well of a microtiter plate can be used to run a separate assay against a selected potential modulator, or, if concentration or incubation time effects are to be observed, every 5-10 wells can test a single modulator. Thus, a single standard microtiter plate can assay about 100 (for example, 96) modulators. If 1536 well plates are used, then a single plate easily can assay from about 100 to about 1500 different compounds.
  • Additionaify when the biomarker has a known assayable activity, this activity can be the target of the screen.
  • the present invention provides methods for treating or controlling a cancer or tumor and the symptoms associated therewith. Any compounds, for example, those identified in the aforementioned assay systems, can be tested for the ability to prevent and/or ameliorate symptoms of tumors and cancers. As used herein, inhibit, control, ameliorate, prevent, treat, and suppress collectively and interchangeably mean stopping or slowing cancer formation, development, or growth and/or eliminating or reducing cancer symptoms.
  • Cell- based and anirnai model-based trial systems for evaluating the ability of the tested compounds to prevent and/of ameliorate tumors and cancer symptoms are used according to the present invention, in a specific aspect, the modulator of CAD 1 is useful for treating prostate cancer. In another specific aspect, the modulator of CADM1 is an antibody to CAD 1 ,
  • cell based systems can be exposed to a compound suspected of ameliorating cancer symptoms, at a sufficient concentration and for a time sufficient to elicit such an amelioration in the exposed population of cells.
  • the populations of cells are examined to determine whether one or more tumor/cancer phenotypes represented in the population has been altered to resemble a more normal or more wild-type, non-cancerous phenotype.
  • the levels of target gene mRNA expression and DNA amplification within these cells may be determined, according to the methods provided herein. A decrease in the observed level of expression and amplification would indicate the successful intervention of tumors and cancers (e.g. , prostate cancer).
  • animal models can be used to identify compounds for use as drugs and pharmaceuticals (including the antibodies of the inventions) that are capable of treating or suppressing symptoms of tumors and cancers.
  • animal models can be exposed to a test compound at a sufficient concentration and for a time sufficient to elicit such amelioration in the exposed animals.
  • the response of the animals to the exposure can be monitored by assessing the reversal of symptoms associated with the tumor or cancer, or by evaluating the changes in DNA copy number in cell populations and levels of mRNA expression of the target gene. Any treatments which reverse any symptom of tumors and cancers, and/or which reduce overexpression and amplification of the target gene may be considered as candidates for therapy in humans.
  • Dosages of test agents can be determined-by deriving dose-response curves.
  • the present invention also provides assays for compounds that interfere with gene and cellular protein interactions involving CADM1 .
  • the target gene product protein may interact in vivo with one or more cellular or extracellular macromolecules, for example, proteins and nucleic acid molecules. Such cellular and extracellular macromolecules are referred to as "binding partners.”
  • Bining partners Such cellular and extracellular macromolecules are referred to as "binding partners.”
  • Compounds that disrupt such interactions can be used to regulate the activity of the target gene product protein, especially mutant target gene product.
  • Such compounds can include, but are not limited to, molecules, for example, antibodies, peptides and other chemical compounds.
  • compositions e.g., a pharmaceutical composition, containing an antibody of the invention to CADIvll , formulated together with a pharmaceutically acceptable carrier.
  • compositions may include one or a combination of (e.g., two or more different) antibodies, or immunoconjugates or bispecific molecules of this disclosure.
  • a pharmaceutical composition of this disclosure can comprise a combination of antibodies (or immunoconjugates or bispecifics) that bind to different epitopes on the target antigen or that have complementary activities.
  • compositions of this disclosure also can be administered in combination therapy, i.e., combined with other agents.
  • the combination therapy can include an anti-CADMI antibody of the present disclosure combined with at least one other anti-cancer agent.
  • therapeutic agents that can be used in combination therapy are described in greater detail above in the section Combination therapy.
  • pharmaceutically acceptable carrier relates to any component of a pharmaceutical composition other than the active ingredient and includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion).
  • the active compound i.e., antibody, immunoconjugate, or bispecific molecule
  • the pharmaceutical compounds of this disclosure may include one or more pharmaceutically acceptable salts.
  • a “pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicologicai effects (see e.g., Berge, S. M., et ai. (1977) J. Pharm. Sci. 66: 1-19). Examples of such salts include acid addition salts and base addition salts.
  • Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxyiic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
  • nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like
  • nontoxic organic acids such as aliphatic mono- and dicarboxyiic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
  • Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N.N'-dibenzylethylenediamine, N- methy!glucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.
  • a pharmaceutical composition of this disclosure also may include a pharmaceutically acceptable anti-oxidant.
  • pharmaceutically acceptable antioxidants include: (1 ) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyi palmitate, butylated hydroxyanisole (BHA) 5 butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyi palmitate, buty
  • aqueous and nonaqueous carriers examples include water, ethanol, polyois (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyois such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms may be ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanoi, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of this disclosure is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants, in many cases, it will be preferable to include isotonic agents, for example, sugars, pofyalcohois such as mannitol, sorbitol, or sodium chloride in the composition.
  • isotonic agents for example, sugars, pofyalcohois such as mannitol, sorbitol, or sodium chloride
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated, and the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition which produces a therapeutic effect. Generally, this amount will range from about 0.01 per cent to about ninety-nine percent of active ingredient, preferably from about 0.1 per cent to about 70 per cent, most preferably from about 1 per cent to about 30 per cent of active ingredient in combination with a pharmaceutically acceptable carrier. Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response).
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of this disclosure are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
  • the dosage ranges from about 0.0001 to 100 mg/kg, and more usually 0.01 to 5 mg/kg, of the host body weight.
  • dosages can be 0.3 mg/kg body weight, 1 mg/kg body weight, 3 mg/kg body weight, 5 mg/kg body weight or 10 mg/kg body weight or within the range of 1 -10 mg/kg.
  • An exemplary treatment regime entails administration once per week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months or once every three to 6 months.
  • Exemplary dosage regimens for an anti-CADM1 antibody of this disclosure include 1 mg/kg body weight or 3 mg/kg body weight via intravenous administration, with the antibody being given using one of the following dosing schedules: (i) every four weeks for six dosages, then every three months; (ii) every three weeks; (iii) 3 mg/kg body weight once followed by 1 mg/kg body weight every three weeks.
  • two or more therapeutic antibodies with different binding specificities are administered simultaneously, in which case the dosage of each antibody administered falls within the ranges indicated.
  • Antibody is usually administered on multiple occasions. Intervals between single dosages can be, for example, weekly, monthly, every three months or yearly. Intervals can also be irregular as indicated by measuring blood levels of antibody to the target antigen in the patient, in some methods, dosage is adjusted to achieve a plasma antibody concentration of about 1 - 000 pg/ml and in some methods about 25-300 pg/m!.
  • antibody can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the half-life of the antibody in the patient. In general, human antibodies show the longest haif life, followed by humanized antibodies, chimeric antibodies, and nonhuman antibodies. The dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, a relatively low dosage is administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the rest of their lives. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, and preferably until the patient shows partial or complete amelioration of symptoms of disease. Thereafter, the patient can be administered a prophylactic regime. For use in the prophylaxis and/or treatment of diseases related to abnormal cellular proliferation, a circulating concentration of administered compound of about 0.001 ⁇ to 20 ⁇ is preferred, with about 0.01 ⁇ to 5 ⁇ being preferred.
  • Patient doses for oral administration of the compounds described herein typically range from about 1 mg/day to about 10,000 mg/day, more typically from about 10 mg/day to about 1 ,000 mg/day, and most typically from about 50 mg/day to about 500 mg/day. Stated in terms of patient body weight, typical dosages range from about 0.01 to about 150 mg/kg/day, more typically from about 0.1 to about 15 mg/kg/day, and most typically from about 1 to about 10 mg/kg/day, for example 5 mg/kg/day or 3 mg/kg/day. In at least some embodiments, patient doses that retard or inhibit tumor growth can be 1 pmol/kg/day or less.
  • the patient doses can be 0.9, 0.8, 0.7, 0.6, 0.5, 0.45, 0.3, 0.2, 0.15, 0.1 , 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01 , or 0.005 pmol/kg or less ⁇ referring to moles of the drug).
  • the antibody-drug conjugate retards growth of the tumor when administered in the daily dosage amount over a period of at least five days.
  • the tumor is a human-type tumor in a SCID mouse.
  • the SCID mouse can be a CB 17. SCID mouse (available from Taconic, Germantown, NY).
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present disclosure employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a “therapeutically effective dosage” of an anti-CADM1 antibody of this disclosure preferably results in a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • a "therapeutically effective dosage” preferably inhibits cell growth or tumor growth by at least about 5%, more preferably by at least about 10%, even more preferably by at least about 20%, and stil! more preferably by at least about 60% relative to untreated subjects (or cells in cell based studies).
  • the ability of a compound to inhibit tumor growth can be evaluated in an animal model system predictive of efficacy in human tumors.
  • this property of a composition can be evaluated by examining the ability of the compound to inhibit ceil growth. Such inhibition can be measured in vitro by assays known to the skilled practitioner (cell proliferation, metastasis, cytotoxicty, invasion, migration, ,etc).
  • a therapeutically effective amount of a therapeutic compound can decrease tumor size, or otherwise ameliorate symptoms in a subject.
  • One of ordinary skill in the art would be able to determine such amounts based on such factors as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected.
  • a composition of the present disclosure can be administered via one or more routes of administration using one or more of a variety of methods known in the art.
  • routes and/or mode of administration will vary depending upon the desired results.
  • Preferred routes of administration for antibodies of this disclosure include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion.
  • parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection arid infusion.
  • an antibody of this disclosure can be administered via a non- parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasal!y, orally, vaginally, rectally, sublingually or topically.
  • the active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • a controlled release formulation including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, poiyanhydrides, polyglyco!ic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, eds, Marcel Dekker, Inc., New York, 1978.
  • Therapeutic compositions can be administered with medical devices known in the art.
  • a therapeutic composition of this disclosure can be administered with a needleless hypodermic injection device, such as the devices disclosed in U .S. Patent Nos. 5,399, 163; 5,383,851 ; 5,312,335; 5,064,413; 4,941 ,880; 4,790,824; or 4,596,556.
  • a needleless hypodermic injection device such as the devices disclosed in U .S. Patent Nos. 5,399, 163; 5,383,851 ; 5,312,335; 5,064,413; 4,941 ,880; 4,790,824; or 4,596,556.
  • Examples of well-known implants and modules useful in the present disclosure include: U.S. Patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Patent No. 4,486, 194, which discloses a therapeutic device for administering medicants through the skin; U.S. Patent No.
  • the therapeutic compounds of this disclosure cross the BBB (if desired), they can be formulated, for example, in liposomes.
  • liposomes For methods of manufacturing liposomes, see, e.g., U.S. Patents 4,522,81 1 ; 5,374,548; and 5,399,331 .
  • the liposomes may comprise one or more moieties which are selectively transported into specific cells or organs, thus enhance targeted drug delivery (see, e.g., V. V. Ranade (1989) J. Clin. Pharmacol. 29:685).
  • targeting moieties include folate or biotin (see, e.g., U .S.
  • the present invention relates to methods for comparing and compiling data wherein the data is stored in electronic or paper format.
  • Electronic format can be selected from the group consisting of electronic mail, disk, compact disk (CD), digital versatile disk (DVD), memory card, memory chip, ROM or RAM, magnetic optical disk, tape, video, video clip, microfilm, internet, shared network, shared server and the like; wherein data is displayed, transmitted or analyzed via electronic transmission, video display, telecommunication, or by using any of the above stored formats; wherein data is compared and compiled at the site of sampling specimens or at a location where the data is transported following a process as described above.
  • the data of this embodiment is information regarding the results of the analysis of CADM1.
  • the compounds, targets, assays, tests, inquiries and methodologies described herein can be employed in a variety of contexts, including diagnostic and therapeutic discovery, diagnostic and therapeutic development, safety and efficacy monitoring, compound and treatment regimen potency determination and validation, treatment assessment, comparative studies, marketing and the like.
  • the information provided by the invention can be communicated to regulators, physicians and other healthcare providers, manufacturers, owners, investors, patients, and/or the genera! public. This information and the like can be used in exploratory research, pre-clinical and clinical settings, labeling, production, advertising, and sales, for example.
  • a "CADM1 biomarker” refers to a "CADM1 nucleic acid” or a "CADM1 protein” that can be specifically detected for diagnostic purposes or targeted for therapeutic purposes.
  • a CADM1 nucleic acid can be a RNA molecule, DNA molecule, or other nucleic acid that corresponds to the CADM1 gene or a fragment thereof.
  • a CADM1 gene may correspond to a human CADM1 gene.
  • a CADM1 nucleic acid can be a cDNA, or fragment thereof, corresponding to a CADM1 mRNA molecule.
  • a CADM1 protein refers to a protein (or fragment thereof) encoded or expressed by the CADM1 gene. Examples of CADM1 biomarkers are given in the examples as we!l as some reagents useful for detecting CADM1 biomarkers, nucleic acids, and proteins.
  • antibodies or fragments bind immunospecifically to a CAD 1 polypeptide or fragment thereof do not non-specificaliy cross-react with other antigens (e.g.
  • binding cannot be competed away with a non-CADM1 protein, e.g., BSA in an appropriate immunoassay).
  • a non-CADM1 protein e.g., BSA
  • Antibodies or fragments that immunospecifically bind to a CADM1 polypeptide can be identified, for example, by immunoassays or other techniques known to those of skill in the art.
  • Antibodies of the invention include, but are not limited to, synthetic antibodies, monoclonal antibodies, recombinantly produced antibodies, intrabodies, mu!tispecific antibodies (including bi-specific antibodies), human antibodies, humanized antibodies, chimeric antibodies, synthetic antibodies, single-chain Fvs (scFv) (including bi-specific scFvs), single chain antibodies Fab fragments, F(ab') fragments, disu!fide-linked Fvs (sdFv), and anti-idiotypic (anti-Id) antibodies, and epitope-binding fragments of any of the above.
  • synthetic antibodies single-chain Fvs (scFv) (including bi-specific scFvs), single chain antibodies Fab fragments, F(ab') fragments, disu!fide-linked Fvs (sdFv), and anti-idiotypic (anti-Id) antibodies, and epitope-binding fragments of any of the above.
  • antibodies of the present invention include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that immunospecifically binds to a CADM1 antigen (e.g., one or more complementarity determining regions (CDRs) of an anti-CAD 1 antibody).
  • a CADM1 antigen e.g., one or more complementarity determining regions (CDRs) of an anti-CAD 1 antibody.
  • CADM1 protein refers to a protein (or fragment or epitope thereof) encoded or expressed by the CADM1 gene.
  • a “cancer” in an animal refers to the presence of cells possessing one or more characteristics typical of cancer-causing cells, for example, uncontrolled proliferation, loss of specialized functions, immortality, significant metastatic potential, significant increase in anti-apoptotic activity, rapid growth and proliferation rate, and certain characteristic morphology and cellular markers.
  • the cancer is melanoma, colon and/or colorectal cancer or prostate cancer.
  • Colorectal cancer as used herein, comprises colon cancer.
  • the phrase "detecting a cancer” or “diagnosing a cancer” refers to determining the presence or absence of cancer or a precancerous condition in an animai.
  • Detecting a cancer also can refer to obtaining indirect evidence regarding the likelihood of the presence of precancerous or cancerous ceils in the animal or assessing the predisposition of a patient to the development of a cancer. Detecting a cancer can be accomplished using the methods of this invention alone, in combination with other methods, or in light of other information regarding the state of health of the animal.
  • a "tumor,” as used herein, refers to ail neoplastic cell growth and proliferation, whether malignant or benign, and ail precancerous and cancerous ceils and tissues.
  • precancerous refers to cells or tissues having characteristics relating to changes that may lead to malignancy or cancer.
  • Treating does not require a complete cure. It means that the symptoms of the underlying disease are at least reduced, and/or that one or more of the underlying cellular, physiological, or biochemical causes or mechanisms causing the symptoms are reduced and/or eliminated . It is understood that reduced , as used in this context, means relative to the state of the disease, including the molecular state of the disease, not just the physiological state of the disease.
  • a “target gene,” as used herein, refers to a differentialiy expressed gene in which modulation of the level of gene expression or of gene product activity prevents and/or ameliorates tumor and cancer symptoms.
  • compounds that modulate the expression of a target gene, the target gene, or the activity of a target gene product can be used in the diagnosis, treatment or prevention of tumors and cancers.
  • a "CADM1 gene” is a region on the genome that is capable of being transcribed to an RNA that encodes a CADM1 protein as well as the regulatory sequences associated with or operably linked to the coding region.
  • the skilled artisan will appreciate that the present invention encompasses all encoding transcripts that may be found, including splice variants, allelic variants and transcripts that occur because of alternative promoter sites or alternative poiyadenylation sites of CAD1V11 .
  • a "full-length" gene or RNA therefore encompasses any naturally occurring splice variants, allelic variants, other alternative transcripts, splice variants generated by recombinant technologies which bear the same function as the naturally occurring variants, and the resulting RNA molecules.
  • a "fragment" of a gene can be any portion from the gene, which may or may not represent a functional domain, for example, a catalytic domain, a DNA binding domain, etc.
  • a fragment may preferably include nucleotide sequences that encode for at least 25 contiguous amino acids, and preferably at least about 30, 40, 50, 60, 65, 70, 75 or more contiguous amino acids or any integer thereabout or therebetween.
  • transformed cell means a cell into which ⁇ or into predecessor or an ancestor of which) a nucleic acid molecule encoding a polypeptide of the invention has been introduced, by means of, for example, recombinant DNA techniques or viruses.
  • nucleic acid molecules of the invention for example, those corresponding to CAD 1 , and its subsequences/alternative transcripts, can be inserted into a vector, as described below, which will facilitate expression of the insert.
  • the nucleic acid moiecules and the polypeptides they encode can be used directly as therapeutic agents, or can be used (directly in the case of the polypeptide or indirectly in the case of a nucleic acid molecule) to generate antibodies that, in turn, are clinically useful as a therapeutic agent.
  • vectors containing the nucleic acids of the invention, cells transfected with these vectors, the polypeptides expressed, and antibodies generated against either the entire polypeptide or an antigenic fragment or epitope thereof, are among the aspects of the invention.
  • isolated DNA molecule is a fragment of DNA that has been separated from the chromosomal or genomic DNA of an organism. Isolation also is defined to connote a degree of separation from original source or surroundings.
  • cDNA complementary DNA
  • copy DNA is a single- stranded DNA molecule that is formed from an mRNA template by the enzyme reverse transcriptase.
  • cDNA complementary DNA
  • Those skilled in the art also use the term “cDNA” to refer to a double-stranded DNA molecule that comprises such a single-stranded DNA molecule and its complement DNA strand.
  • expression refers to the biosynthesis of a gene product, such as a protein or an mRNA molecule.
  • An "expression vector” is a nucleic acid construct, generated recombinantiy or synthetically, bearing a series of specified nucleic acid elements that enable transcription of a particular gene in a host ceil. Typically, gene expression is placed under the control of certain regulatory elements, including constitutive or inducible promoters, tissue-preferred regulatory elements, and enhancers.
  • a “recombinant host” may be any prokaryotic or eukaryotic cell that contains a cloning vector, expression vector, or other heterologous nuclide acid seqeunces. This term also includes those prokaryotic or eukaryotic celis that have been genetically engineered to contain the cloned gene(s) in the chromosome or genome of the host cell.
  • operbiy linked is used to describe the connection between regulatory elements and a gene or its coding region. That is, gene expression is typically placed under the control of certain regulatory elements, including constitutive or inducible promoters, tissue-specific regulatory elements, and enhancers. Such a gene or coding region is said to be “operabiy linked to” or “operatively linked to” or “operabiy associated with” the regulatory elements, meaning that the gene or coding region is controlled or influenced by the regulatory element.
  • sequence identity is used to describe the sequence relationships between two or more nucleic acids, polynucleotides, proteins, or polypeptides, and is understood in the context of and in conjunction with the terms including: (a) reference sequence, (b) comparison window, (c) sequence identity, (d) percentage of sequence identity, and (e) substantial identity or “homologous.”
  • a "reference sequence” is a defined sequence used as a basis for sequence comparison.
  • a reference sequence may be a subset of or the entirety of a specified sequence, for example, a segment of a full-length cDNA or gene sequence, or the complete cDNA or gene sequence.
  • the length of the reference polypeptide sequence can be chosen from at least about 16 amino acids, at least about 20 amino acids, at least about 25 amino acids, about 35 amino acids, about 50 amino acids, or about 100 amino acids.
  • the length of the reference nucleic acid sequence can be chosen from at least about 10 nucleotides, at least about 15 nucleotides, at least about 20 nucleotides, at least about 21 nucleotides, at least about 50 nucleotides, at least about 60 nucleotides, at least about 75 nucleotides, about 100 nucleotides or about 300 nucleotides or any integer thereabout or therebetween.
  • a “comparison window” includes reference to a contiguous and specified segment of a polynucleotide or polypeptide sequence, wherein the polynucleotide or polypeptide sequence may be compared to a reference sequence and wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions, substitutions, or deletions (i.e., gaps) compared to the reference sequence (which does not comprise additions, substitutions, or deletions) for optimal alignment of the two sequences.
  • the comparison window is at least 20 contiguous nucleotides in length, and optionaify can be 30, 40, 50, 100, or longer.
  • Optimal alignment of sequences for comparison may be conducted by the local homology algorithm of Smith and Waterman, Adv. Appl. Math., 2: 482, 1981 ; by the homology alignment algorithm of Need!eman and Wunsch, J. Mol. Biol., 48: 443, 1970; by the search for similarity method of Pearson and Lipman, Proc. Natl. Acad. Sci.
  • the BLAST family of programs which can be used for database similarity searches includes: BLASTN for nucleotide query sequences against nucleotide database sequences; BLASTX for nucleotide query sequences against protein database sequences; BLASTP for protein query sequences against protein database sequences; TBLASTN for protein query sequences against nucleotide database sequences; and TBLASTX for nucleotide query sequences against nucleotide database sequences.
  • sequence identity/similarity values refer to the value obtained using the BLAST 2.0 suite of programs, or their successors, using default parameters. Altschul ef a/. (1997) Nucleic Acids Res, 2:3389-3402. It is to be understood that default settings of these parameters can be readily changed as needed in the future.
  • BLAST searches assume that proteins or nucleic acids can be modeled as random sequences. However, many real proteins and nucleic acids comprise regions of nonrandom sequences which may be homopolymeric tracts, short-period repeats, or regions enriched in one or more amino acids or nucleic acids. Such low-complexity regions may be aligned between unrelated proteins even though other regions of the protein or nucfeic acid are entirely dissimilar. A number of low-complexity filter programs can be employed to reduce such low-complexity alignments. For example, the SEG (Wooten ef al. (1993) Comput. Chem. 17: 149-163) and XNU (Claverie ef a/. (1993) Comput. Chem. 17:191 -1 ) low-complexity filters can be employed alone or in combination.
  • Sequence identity in the context of two nucleic acid or polypeptide sequences includes reference to the residues in the two sequences which are the same when aligned for maximum correspondence over a specified comparison window, and can take into consideration additions, deletions and substitutions.
  • percentage of sequence identity is used in reference to proteins it is recognized that residue positions which are not identical often differ by conservative amino acid substitutions, where amino acid residues are substituted for other amino acid residues with similar chemical properties (for example, charge or hydrophobicity) and therefore do not deleteriously change the functional properties of the molecule.
  • sequences differ in conservative substitutions the percent sequence identity may be adjusted upwards to correct for the conservative nature of the substitution. Sequences which differ by such conservative substitutions are said to have sequence similarity.
  • Percentage of sequence identity means the value determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or nucleic acid sequence in the comparison window may comprise additions, substitutions, or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions, substitutions, or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity.
  • substantially identical or “homologous” in their various grammatical forms in the context of polynucleotides means that a polynucleotide comprises a sequence that has a desired identity, for example, at least 60% identity, preferably at least 70% sequence identity, more preferably at least 75% sequence identity, more preferably at least 80%, still more preferably at least 90% and even more preferably at least 95%, 96%, 97%, 98% or 99%, compared to a reference sequence using one of the alignment programs described using standard parameters.
  • a desired identity for example, at least 60% identity, preferably at least 70% sequence identity, more preferably at least 75% sequence identity, more preferably at least 80%, still more preferably at least 90% and even more preferably at least 95%, 96%, 97%, 98% or 99%.
  • a desired identity for example, at least 60% identity, preferably at least 70% sequence identity, more preferably at least 75% sequence identity, more preferably at least 80%, still more preferably at least 90% and even more preferably at least
  • nucleotide sequences are substantially identical if two molecules hybridize to each other under stringent conditions.
  • the detection of only specifically hybridizing sequences wilt usually require stringent hybridization and washing conditions such as, for example, the highly stringent hybridization conditions of 0.1 x SSC, 0.1 % SDS at 65°C or 2 x SSC , 60°C, 0.1 % SDS.
  • Low stringent hybridization conditions for the detection of homologous or not exactly complementary sequences may, for example, be set at 6 x SSC, 1 % SDS at 55°C or 60°C.
  • nucleic acids which do not hybridize to each other under stringent conditions are still substantially identical if the polypeptides which they encode are substantially identical.
  • nucleic acid sequences are substantially identical is that the polypeptide which the first nucleic acid encodes is immunologically cross reactive with the polypeptide encoded by the second nucleic acid, although such cross-reactivity is not required for two polypeptides to be deemed substantially identical.
  • substantially identical or “homologous” in their various grammatical forms in the context of peptides indicates that a peptide comprises a sequence that has a desired identity, for example, at least 60% identity, preferably at least 70% sequence identity to a reference sequence, more preferably at least 75%, more preferably 80%, still more preferably 85%, even more preferably at least 90% or 95% or even 96%, 97%, 98% or 99% sequence identity to the reference sequence over a specified comparison window.
  • a desired identity for example, at least 60% identity, preferably at least 70% sequence identity to a reference sequence, more preferably at least 75%, more preferably 80%, still more preferably 85%, even more preferably at least 90% or 95% or even 96%, 97%, 98% or 99% sequence identity to the reference sequence over a specified comparison window.
  • optimal alignment is conducted using the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol., 48:443.
  • peptide sequences are substantially identical.
  • a peptide is substantially identical to a second peptide, for example, where the two peptides differ only by a conservative substitution.
  • Peptides which are "substantially similar" share sequences as noted above except that residue positions which are not identical may differ by conservative amino acid changes.
  • Conservative substitutions are known to those skilled in the art and typically include, but are not limited to, substitutions within the following groups: glycine and alanine; valine, isoleucine, and leucine; aspartic acid and glutamic acid; asparagine and glutamine; serine and threonine; lysine and arginine; and phenylalanine and tyrosine, and others as known to the skilled person. Examples of conservative substitutions include, but are not limited to, substitutions listed in the following table: Exemplary
  • Arginine Arg (R) Polar, hydrophilic, charge Lys, His, Gin, Asn Lys
  • Glycine Gly (G) Aliphatic, neutral Pro, Ala Ala
  • Leucine Leu (L) Aliphatic, hydrophobic, lie, Val, Met, Phe, He neutral Aia
  • Lysine Lys (K) polar, hydrophilic, charge Arg, Gin, Asn, Arg
  • Phenylalanine Phe (F) Aromatic, hydrophobic, Leu, lie, Val, Ala, Leu neutral Tyr
  • Serine Ser (S) Polar, hydrophilic, neutral Thr, Ala, Cys Thr
  • Threonine Thr (T) Polar, hydrophilic, neutral Ser Ser
  • Tyrosine Tyr (Y) Aromatic, polar, Trp, Phe, Thr, Phe hydrophobic Ser
  • Valine Val Aliphatic, hydrophobic, lie, Met, Leu, Leu neutral Phe, Ala,
  • Glutamic Acid Giu (E) Polar, hydrophilic, charge Asp, Gin Asp
  • Aspartic Acid Asp (D) Polar, hydrophilic, charge Glu, Asn Glu
  • Subject refers to a biological subject that contains or is suspected of containing nucleic acids or polypeptides corresponding to CADM1 .
  • the subject may be a mammalian subject such as a human.
  • Biological sample refers to a sample obtained from a subject, including sample of biologica! tissue or fluid origin, obtained, reached, or collected in vivo, ex-vivo, or in situ, that contains or is suspected of containing nucleic acids or polypeptides corresponding to CAD 1 .
  • a biologica! sample also includes samples from a region of a bioiogical subject containing or suspected of containing precancerous or cancer ceils or tissues.
  • Such samples can be, but are not limited to, organs, tissues, fractions and ceils isolated from mammals inc!uding, humans such as a patient.
  • Bioiogical samples also may include sections of the biologica! sample including tissues, for example, frozen sections taken for histologic purposes.
  • a biological sample, as described herein, can be: a "control” or a "control sample” or a "test sample”.
  • a biological sample can be obtained from the prostate using commonly employed clinical practices (e.g., fine needle biopsy, blood from a blood draw, serum or plasma derived from blood, tumor sections, circulating tumor cells, sample obtained from prostate massage techniques).
  • a “control” refers to a representative of healthy, cancer-free biological subject or information obtained from a different individual or a normalized value, which can be based on baseline data obtained from a population or other acceptable sources.
  • a control also can refer to a given level of CADM1 , representative of the cancer-free population, that has been previously established based on measurements from normal, cancer-free animals.
  • a control also can be a reference data point in a database based on data obtained from control samples representative of a cancer- free population. Further, a control can be established by a specific age, sex, ethnicity or other demographic parameters, in some situations, the control is implicit in the particular measurement.
  • control sample refers to a sample of biological material representative of healthy, cancer-free animals or a normal biological subject obtained from a cancer- free population.
  • the level of CADIV11 , in a control sample is desirably typical of the general population of normal, cancer-free animals of the same species.
  • This sample either can be collected from an animal for the purpose of being used in the methods described in the present invention or it can be any biological material representative of normal, cancer-free animals suitable for use in the methods of this invention.
  • a control sample also can be obtained from normal tissue from the animal that has cancer or is suspected of having cancer.
  • test samp!e refers to a biological sample, including sample of biological tissue or fluid origin, obtained, reached, or collected in vivo, ex-vivo, or in situ, that contains or is suspected of containing nucleic acids or polypeptides corresponding to CADM1 ,
  • a test sample also includes biological samples containing or suspected of containing precancerous or cancer cells or tissues.
  • a test sample also may include sections of the biological sample including tissues, for example, frozen sections taken for histologic purposes.
  • Providing a sample, a biological sample, or a test sample means to obtain from a subject a sample, in vivo, ex-vivo, or in situ, including tissue or cell sample for use in the methods described in the present invention. Most often, this will be done by removing a sample of cells from an animal, but also can be accomplished in vivo, ex-vivo, or in situ, or by using previously isolated cells (for example, isolated from another subject, at another time, and/or for another purpose).
  • Data includes, but is not limited to, information obtained that relates to "biological sample,” “test sample.” “control sample,” and/or “control,” as described above, wherein the information is applied in generating a test level for diagnostics, prevention, monitoring or therapeutic use.
  • the present invention relates to methods for comparing and compiling data wherein the data is stored in electronic or paper formats.
  • Electronic format can be selected from the group consisting of electronic mail, disk, compact disk (CD), digital versatile disk (DVD), memory card, memory chip, ROM or RAM, magnetic optical disk; tape, video, video clip, microfilm, internet, shared network, shared server and the like; wherein data is displayed, transmitted or analyzed via electronic transmission, video display, telecommunication, or by using any of the above stored formats; wherein data is compared and compiled at the site of sampling specimens or at a location where the data is transported following a process as described above.
  • “Overexpression” of a gene or an "increased,” or “elevated,” level of a ribonucleotide or protein refers to a level of the gene, ribonucleotide or polypeptide that, in comparison with a control level of gene, ribonucleotides or polypeptide, is detectably higher. Comparison may be carried out by statistical analyses on numeric measurements of the expression; or, it may be done through visual examination of experimental results by qualified researchers.
  • a level of ribonucleotide or polypeptide, that is "expected" in a control sample refers to a level that represents a typical, cancer-free sample, and from which an elevated, or diagnostic, presence of the polypeptide or polynucleotide, can be distinguished.
  • an "expected” level will be controlled for such factors as the age, sex, medical history, etc., of the mammal, as well as for the particular biological subject being tested.
  • phrases "functional effects" in the context of an assay or assays for testing compounds that modulate a particular gene's activity includes the determination of any parameter that is indirectly or directly under the influence of the gene, for example, a functional, physical, or chemical effect, for example, of the genes activity, activity of a polypeptide encoded by the gene, the ability to induce gene amplification or overexpression in cancer cells, and to aggravate cancer cell proliferation.
  • “Functional effects” include in vitro, in vivo, and ex vivo activities.
  • Determining the functional effect refers to assaying for a compound that increases or decreases a parameter that is indirectly or directly under the influence of the gene or the polypeptide encoded by the gene, for example, functional, physical, and chemical effects.
  • Such functional effects can be measured by any means known to those skilled in the art, for example, changes in spectroscopic characteristics (for example, fluorescence, absorbance, refractive index), hydrodynamic ⁇ for example, shape), chromatographic, or solubility properties for the protein, measuring inducible markers or transcriptional activation of the gene, measuring binding activity or binding assays (for example, substrate binding, and measuring cellular proliferation), measuring signal transduction, or measuring cellular transformation.
  • Inhibitors refer to molecules that activate, inhibit, modulate, regulate and/or block an identified function. Any molecule having potential to activate, inhibit, modulate, regulate and/or block an identified function can be a "test molecule,” as described herein. For example, referring to oncogenic function or anti-apoptotic activity of the gene, such molecules may be identified using in vitro and in vivo assays of gene. Inhibitors are compounds that partially or totally block the genes activity, respectively, decrease, prevent, or delay their activation, or desensitize their cellular response. This may be accomplished by binding to protein expressed by the gene directly or via other intermediate molecules.
  • An antagonist or an antibody that blocks the activity of the genes expression product, including inhibition of oncogenic function or anti- apoptotic activity of gene's expression product, respectively, is considered to be such an inhibitor.
  • Activators are compounds that bind to a gene's protein expression product directly or via other intermediate molecules, thereby increasing or enhancing their activity, stimulating or accelerating their activation, or sensitizing their cellular response.
  • An agonist of a genes expression product is considered to be such an activator.
  • a modulator can be an inhibitor or activator, A modulator may or may not bind the gene or its protein expression product directly; it affects or changes the activity or activation of gene's expression product or the cellular sensitivity to the gene or its expression product, respectively.
  • a modulator also may be a compound, for example, a small molecule, that inhibits transcription of the gene's mRNA.
  • a regulator of a gene includes any element, for example, nucleic acid, peptide, polypeptide, protein, peptide nucleic acid or the like, that influences and/or controls the transcription/expression of the gene or its coding region.
  • the group of inhibitors, activators, modulators and regulators of this invention also includes genetically modified versions of CADM , for example, versions with altered activity.
  • the group is inclusive of the naturally occurring protein as well as synthetic ligands, antagonists, agonists, antibodies, small chemical molecules and the like.
  • Assays for inhibitors, activators, modulators, or regulators refer to experimental procedures including, for example, expressing CAD 1 , in vitro, in cells, applying putative inhibitor, activator, modulator, or regulator compounds, and then determining the functional effects on the gene's (or its expressed protein product) activity or transcription, as described above.
  • Samples that contain or are suspected of containing the gene (or its expressed protein product) are treated with a potential activator, inhibitor, or modulator.
  • the extent of activation, inhibition, or change is examined by comparing the activity measurement from the samples of interest to control samples.
  • a threshold level is established to assess activation or inhibition. For example, inhibition of a polypeptide is considered achieved when the activity value relative to the control is 80% or lower. Similarly, activation of a polypeptide is considered achieved when the activity value relative to the control is two or more fold higher.
  • isolated refers to material that is free to varying degrees from components which normally accompany it as found in its native state.
  • Isolate denotes a degree of separation from original source or surroundings.
  • Purify denotes a degree of separation that is higher than isolation.
  • a “purified” or “biologically pure” protein is sufficiently free of other materials such that any impurities do not materially affect the biological properties of the protein or cause other adverse consequences. That is, a nucleic acid or peptide of this invention is purified if it is substantially free of cellular material, viral material, or culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized.
  • Purity and homogeneity are typically determined using analytical chemistry techniques, for example, polyacrylamide gel electrophoresis or high performance liquid chromatography.
  • the term "purified" can denote that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel.
  • modifications for example, phosphorylation or glycosylation
  • different modifications may give rise to different isolated proteins, which can be separately purified.
  • Various levels of purity may be applied as needed according to this invention in the different methodologies set forth herein.
  • the customary purity standards known in the art may be used if no standard is otherwise specified.
  • isolated nucleic acid molecule can refer to a nucleic acid molecule, depending upon the circumstance, that is separated from the 5' and 3' coding sequences of genes or gene fragments contiguous in the naturally occurring genome of an organism.
  • isolated nucleic acid molecule also includes nucleic acid molecules which are not naturally occurring, for example, nucleic acid molecules created-by recombinant DNA techniques.
  • Nucleic acid refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double-stranded form.
  • the term encompasses nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral methyl phosphonates, 2-O-methyl ribonucleotides, and peptide-nucleic acids (PNAs).
  • PNAs peptide-nucleic acids
  • nucleic acid can be used interchangeably with gene, cDNA, mRNA, oligonucleotide, and polynucleotide.
  • a "host cell” is a naturally occurring cell or a transformed cell or a transfected cell that contains an expression vector and supports the replication or expression of the expression vector.
  • Host cells may be cultured cells, explants, cells in vivo, and the like.
  • Host cells may be prokaryotic cells, for example, E. coii, or eukaryotic cells, for example, yeast, insect, amphibian, or mammalian cells, for example, Vero, CHO, HeLa, and others.
  • a “label” or a “detectable moiety” is a composition that when linked with the nucleic acid or protein molecule of interest renders the latter detectable, via spectroscopic, photochemical, biochemical, immunochemical, or chemical means.
  • useful labels include radioactive isotopes, magnetic beads, metallic beads, colloidal particles, fluorescent dyes, electron-dense reagents, enzymes ⁇ for example, as commonly used in an ELISA), biotin, digoxigenin, or haptens.
  • a "labeled nucleic acid or oligonucieotide probe” is one that is bound, either covalently, through a linker or a chemical bond, or noncovalently, through ionic bonds, van der Waals forces, electrostatic attractions, hydrophobic interactions, or hydrogen bonds, to a label such that the presence of the nucleic acid or probe may be detected by detecting the presence of the label bound to the nucleic acid or probe.
  • CAD 1 gene or "CADM1 biomarker” or “CADM1 nucleic acid” or ll CAD 1 protein” can refer to a target nucleic acid (DNA and RNA) or protein (or polypeptide), (e.g., corresponding to CADM1 ) and can include their polymorphic variants, alleles, mutants, and interspecies homoiogs that have (i) substantial nucleotide sequence homology (for example, at least 60% identity, preferably at least 70% sequence identity, more preferably at least 80%, still more preferably at least 90% and even more preferably at least 95%) with the nucleotide sequence indicated in EnsembI database for the indicated ID number; or (ii) at least 65% sequence homology with the amino acid sequence as indicated in the EnsembI record; or (iii) substantial nucleotide sequence homology (for example, at least 60% identity, preferably at least 70% sequence identity, more preferably at least 80%, still more preferably at least 90% and even more
  • these terms refer to the entire gene sequence, mRNA sequence, and/or protein sequence as well as fragments of these sequences. In a more specific definition, these terms refer to the minimal amount of nucleic acid or amino acid sequence that can be used to identify biomarker in a specific manner.
  • the target genes/biomarker can have numerous spiice forms and variants. When referring to a specific target gene or iocus by a reference number (e.g., Entrez gene ID or ENSE BL), all splices forms and variant which are included in the various embodiments of the invention.
  • the target gene/biomarker can also comprise a regulatory element. These sequences are representative of one particular individual in the population of humans.
  • allelic variants Humans vary from one to another in their gene sequences. These variations are very minima!, sometimes occurring at a frequency of about 1 to 10 nucleotides per gene. Different forms of any particular gene exist within the human population. These different forms are called allelic variants. Allelic variants often do not change the amino acid sequence of the encoded protein; such variants are termed synonymous. Even if they do change the encoded amino acid (non-synonymous), the function of the protein is not typically affected. Such changes are evolutionary or functionally neutral. When a gene !D (e.g., Genbank or ENSEMBL) is referred to in the present application all allelic variants are intended to be encompassed by the term. The gene ID sequences given for a biomarker are provided merely as representative examples of a wild-type human sequence. The invention is not limited to a single allelic form of the amplified genes or regions (and proteins they encode).
  • binding selectively to or “binds specifically to” means that a compound binds (immunologically in the context) to CADM1 and not to any other materials in the medium containing CADM1 .
  • Selective binding refers to compound (e.g., antibody) binding to CAD 1 preferentially as compared to non-CADM1 molecules.
  • Specific binding refers to compound (e.g., antibody) binding only to CADM1 or a portion of CADM1 and not binding other material in the sample.
  • An isolated antibody that specifically binds CAD 1 wherein said antibody has one or more CDRs each CDR corresponding to a CDR chosen from the CDRs of Antibody-1 , Antibody-2, Antibody-3, Antibody-4 s Antibody-5, Antibody-6, Antibody-7, Antibody-8, Antibody-9, Antibody-10, Antibody-1 1 , or Antibody-12 or a CDR sequence having 75% or more amino acid identity to said CDR.
  • the isolated antibody of embodiment 1 having 2 or more CDRs each CDR corresponding to a CDR chosen from the CDRs of Antibody-1 , Antibody-2, Antibody-3, Antibody-4, Antibody-5, Antibody-6, Antibody-7, Antibody-8, Antibody-9, Antibody-10, Antibody-1 1 , or Antibody- 2 or a CDR sequence having 75% or more amino acid identity to said CDR.
  • the isolated antibody of embodiment 1 having 3 or more CDRs each CDR corresponding to a CDR chosen from the CDRs of Antibody-1 , Antibody-2, Antibody-3, Antibody-4, Antibody-5, Antibody-6, Antibody-7, Antibody-8, Antibody-9, Antibody-10, Antibody-1 1 , or antibody-12 or a CDR sequence having 75% or more amino acid identity to said CDR,
  • the isolated antibody of embodiment 1 having 6 CDRs each CDR corresponding to a CDR chosen from the CDRs of Antibody-1 , Antibody-2, Antibody-3, Antibody-4, Antibody-5, Antibody-6, Antibody-7, Antibody-8, Antibody-9, Antibody-10, Antibody-1 1 , or Antibody-12 or a CDR sequence having 75% or more amino acid identity to said CDR.
  • An isolated antibody having (a) one or more light chain variable domains corresponding to Antibody-1 , Antibody-2, Antibody-3, Antibody-4, Antibody-5, Antibody-6, Antibody-7, Antibody-8, Antibody-9, Antibody-10, Antibody-1 1 , or Antibody-12 or a sequence having 90% or more identity thereto and (b) one or more heavy chain variable domains corresponding to Antibody-1 , Antibody-2, Antibody-3, Antibody-4, Antibody-5, Antibody-6, Antibody-7, Antibody-8, Antibody-9, Antibody-10, Antibody-11 , or Antibody-12 or a sequence having 90% or more amino acid identity thereto.
  • the isolated antibody of embodiment 1 comprising one or more consensus light chain CDR amino acid sequences derived from the alignment of 2 or more light chain CDRs of Antibody-1 , Antibody-2, Antibody-3, Antibody-4, Antibody-5, Antibody-6, Antibody-7, Antibody-8, Antibody-9, Antibody-10, Antibody-1 1 , or Antibody-12 wherein said consensus sequence has 75% or more identical amino acid residues.
  • the isolated antibody of embodiment 1 comprising one or more consensus heavy chain CDR sequences derived from the alignment of 2 or more heavy chain sequence CDRs of Antibody-1 , Antibody-2, Antibody-3, Antibody-4, Antibody-5, Antibody-6, Antibody-7, Antibody-8, Antibody-9, Antibody-10, Antibody-1 1 , or Antibody-12 wherein said consensus sequence has 75% or more identical amino acid residues.
  • the isolated antibody of embodiment 1 comprising a consensus variable heavy chain sequence derived from the alignment of 2 or more variable heavy chain sequences of Antibody-1 , Antibody-2, Antibody-3, Antibody-4, Antibody-5, Antibody-6, Antibody-7, Antibody-8, Antibody-9, Antibody- 0, Antibody-1 , or Antibody-12 wherein said consensus sequence has 75% or more identical amino acid residues.
  • the isolated antibody of embodiment 1 comprising a consensus variable light chain sequence derived from the alignment of 2 or more variable light chain sequences of Antibody-1 , Antibody-2, Antibody-3, Antibody-4, Antibody-5, Antibody-6, Antibody-7, Antibody-8, Antibody-9, Antibody-10, Antibody-1 1 , or Antibody-12 wherein said consensus sequence has 75% or more identical amino acid residues.
  • the isolated antibody of embodiment 8 comprising 3 or more consensus light chain CDR sequences.
  • the isolated antibody of embodiment 8 comprising 6 consensus light chain CDR sequences.
  • the isolated antibody of embodiment 9 comprising 3 or more consensus heavy chain CDR sequences.
  • the isolated antibody of embodiment 9 comprising 6 consensus heavy chain CDR sequences.
  • the isolated antibody of embodiment 10 comprising 2 consensus variable heavy chain sequences.
  • the isolated antibody of embodiment 11 comprising 2 consensus variable light chain sequences.
  • the isolated antibody of embodiment 1 comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ ID NO: 1 7, SEQ I D NO:29, SEQ I D NO:41 , S EQ ID NO:53, SEQ ID NO;65 , SEQ I D NO: 77 or a CDR having an amino acid sequence at least 90% identical to any of said CDRs.
  • the isolated antibody of embodiment 1 comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ I D 1x10: 18, SEQ ID NO:30, SEQ I D NO:42, SEQ I D NO:54, SEQ I D NO:66, SEQ I D NO:78 or a CDR having an amino acid sequence at least 90% identical to any of said CDRs,
  • the isolated antibody of embodiment 1 comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ ID NO: 19, SEQ I D NO:31 , SEQ I D NO:43, SEQ I D NO:55, SEQ ID NO:67, SEQ I D NO: 79 or a CDR having an amino acid sequence at least 90% identical to any of said CDRs.
  • the isolated antibody of embodiment 1 comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ ID NO:20, SEQ I D NO:32, SEQ I D NO:44, SEQ I D NO:56, SEQ ID NO:68, SEQ ID NO:80 or a CDR having an amino acid sequence at least 90% identical to any of said CDRs.
  • the isolated antibody of embodiment 1 comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ I D NO:21 , SEQ ID NO: 33, SEQ I D NO:45, SEQ I D NO:57, SEQ I D NO:69, SEQ ID NO:81 or a CDR having an amino acid sequence at least 90% identical to any of said CDRs.
  • the isolated antibody of embodiment 1 comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ ID NO:22, SEQ ID NO:34, SEQ I D NO:46, SEQ I D NO:58, SEQ ID NO:70, SEQ ID NO :82 or a CDR having an amino acid sequence at least 90% identical to any of said CDRs.
  • the isolated antibody of embodiment 1 comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ ID NO:23, SEQ ID NO:35, SEQ I D NO:47, SEQ I D NO:59, SEQ ID NO:71 , SEQ ID NO:83 or a CDR having an amino acid sequence at least 90% identical to any of said CDRs.
  • the isolated antibody of embodiment 1 comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ I D NO:24, SEQ ID NO:36, SEQ I D NO:48, SEQ I D NO:60, SEQ ID NO:72, SEQ I D NO:84 or a CDR having an amino acid sequence at least 90% identical to any of said CDRs.
  • the isolated antibody of embodiment 1 comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ ID NO:25, SEQ I D NO:37, SEQ I D NO:49, SEQ ID NO:61 , SEQ ID NO:73, SEQ ID NO:85 or a CDR having an amino acid sequence at least 90% identical to any of said CDRs.
  • the isolated antibody of embodiment 1 comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ I D NO:26, SEQ I D NO:38, SEQ I D NO:50, SEQ I D NO:62, SEQ I D NO:74, SEQ I D NO: 86 or a CDR having an amino acid sequence at least 90% identical to any of said CDRs.
  • the isolated antibody of embodiment 1 comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ I D NO:27, SEQ I D NO:39, SEQ I D NO:51 , SEQ I D NO:63 , SEQ ID NO:75, SEQ I D NO:87 or a CDR having an amino acid sequence at least 90% identical to any of said CDRs.
  • the isolated antibody of embodiment 1 comprising one or more CDRs each CDR having an independent amino acid sequence chosen from SEQ I D NO :28, SEQ I D NO;40, SEQ I D NO:52, SEQ I D NO:64, SEQ I D NO:76, SEQ I D NO:88 or a CDR having an amino acid sequence at least 90% identical to any of said CDRs.
  • the isolated antibody of embodiment 5 comprising an amino acid sequence chosen from SEQ ID NO:89, SEQ I D NO:90, or an amino acid sequence at least 90% identical to any of said sequences.
  • the isolated antibody of embodiment 30 which comprises (1 ) an amino acid sequence as in SEQ I D NO:89 or an amino acid sequence at least 90% and (2) an amino acid sequence as in SEQ I D NO:90 or an amino acid sequence at least 90%.
  • the isolated antibody of embodiment 5 comprising an amino acid sequence chosen from SEQ ID NO:91 , SEQ ID NO:93, or an amino acid sequence at least 90% identical to any of said sequences.
  • the isolated antibody of embodiment 32 which antibody comprises (1 ) an amino acid sequence as in SEQ ID NO:91 or an amino acid sequence at least 90% and (2) an amino acid sequence as in SEQ ID NO:93 or an amino acid sequence at least 90%.
  • the isolated antibody of embodiment 5 comprising an amino acid sequence chosen from SEQ ID NO:95, SEQ ID NO:96, or an amino acid sequence at least 90% identical to any of said sequences.
  • the isolated antibody of embodiment 34 which comprises (1 ) an amino acid sequence as in SEQ ID NO: 95 or an amino acid sequence at least 90% and (2) an amino acid sequence as in SEQ ID NO:96 or an amino acid sequence at least 90%
  • the isolated antibody of embodiment 5 comprising an amino acid sequence chosen from SEQ ID NO:97, SEQ ID NO:98, or an amino acid sequence at least 90% identical to any of said sequences.
  • the isolated antibody of embodiment 36 which comprises (1 ) an amino acid sequence as in SEQ ID NO:97 or an amino acid sequence at least 90% and (2) an amino acid sequence as in SEQ ID NO:98 or an amino acid sequence at least 90%.
  • the isolated antibody of embodiment 5 comprising an amino acid sequence chosen from SEQ I D NO:99, SEQ I D NO: 100, or an amino acid sequence at least 90% identical to any of said sequences.
  • the isolated antibody of embodiment 38 which comprises (1 ) an amino acid sequence as in SEQ I D NO:99 or an amino acid sequence at least 90% and (2) an amino acid sequence as in SEQ ID NO: 100 or an amino acid sequence at least 90%.
  • the isolated antibody of embodiment 5 comprising an amino acid sequence chosen from SEQ I D NO: 101 , SEQ I D NO: 102, or an amino acid sequence at least 90% identical to any of said sequences.
  • the isolated antibody of embodiment 40 which comprises (1 ) an amino acid sequence as in SEQ ID NO: 101 or an amino acid sequence at least 90% and (2) an amino acid sequence as in SEQ ID NO: 102 or an amino acid sequence at least 90%.
  • the isolated antibody of embodiment 5 comprising an amino acid sequence chosen from SEQ ID NO: 103, SEQ ID NO: 104, or an amino acid sequence at least 90% identical to any of said sequences.
  • the isolated antibody of embodiment 42 which comprises (1 ) an amino acid sequence as in SEQ ID NO: 103 or an amino acid sequence at least 90% and (2) an amino acid sequence as in SEQ ID NO: 104 or an amino acid sequence at least 90%.
  • the isolated antibody of embodiment 5 comprising an amino acid sequence chosen from SEQ ID NO: 1 05, SEQ ID NO: 106, or an amino acid sequence at least 90% identical to any of said sequences.
  • the isolated antibody of embodiment 44 which comprises (1 ) an amino acid sequence as in SEQ I D NO: 105 or an amino acid sequence at least 90% and (2) an amino acid sequence as in SEQ I D NO: 106 or an amino acid sequence at least 90.
  • the isolated antibody of embodiment 5 comprising an amino acid sequence chosen from SEQ I D NO: 1 07, SEQ ID NO: 1 08, or an amino acid sequence at least 90% identical to any of said sequences.
  • the isolated antibody of embodiment 46 which comprises (1 ) an amino acid sequence as in SEQ ! D NO: 107 or an amino acid sequence at !east 90% and (2) an amino acid sequence as in SEQ I D NO: 1 08 or an amino acid sequence at least 90%.
  • the isolated antibody of embodiment 5 comprising an amino acid sequence chosen from SEQ ID NO: 1 09, SEQ ID NO: 1 1 1 , or an amino acid sequence at least 90% identical to any of said sequences.
  • the isolated antibody of embodiment 48 which comprises (1 ) an amino acid sequence as in SEQ I D NO: 1 09 or an amino acid sequence at least 90% and (2) an amino acid sequence as in SEQ ID NO: 1 1 1 or an amino acid sequence at least 90%.
  • the isolated antibody of embodiment 5 comprising an amino acid sequence chosen from SEQ ID NO: 1 1 3, SEQ ID NO: 1 4, or an amino acid sequence at least 90% identical to any of said sequences.
  • the antibody of embodiment 50 which comprises (1 ) an amino acid sequence as in SEQ ID NO.1 1 3 or an amino acid sequence at least 90% and (2) an amino acid sequence as in SEQ I D NO: 1 14 or an amino acid sequence at least 90%.
  • the isolated antibody of embodiment 5 comprising an amino acid sequence chosen from SEQ ID NO: 1 15, SEQ ID NO: 1 16, or an amino acid sequence at least 90% identical to any of said sequences.
  • the isolated antibody of embodiment 52 which comprises (1 ) an amino acid sequence as in SEQ I D NO: 1 15 or an amino acid sequence at least 90% and (2) an amino acid sequence as in SEQ ID NO 1 16 or an amino acid sequence at least 90%.
  • the isolated antibody of any one of embodiments 1-53 wherein said antibody is an antibody conjugated to a toxin and/or therapeutic agent.
  • An isolated antibody that blocks or inhibits the binding of an antibody of anyone of embodiments 1-53 to CADM1 or a protein having SEQ ID NO:1 , SEQ ID NO:2, or SEQ ID NO:3.
  • the isolated antibody of embodiments 63 having a detectable label.
  • the isolated nucleic acid of embodiment 68 in a vector is isolated.
  • a host cell comprising an isolated nuc!eic acid of embodiment 68 or the vector of embodiment 69.
  • the host cell of embodiment 72 which is a prokaryotic or eukaryotic host cell.
  • the host cell of embodiment 73 which is a eukaryotic host cell chosen from COS, CHO, HEK293 or a multiple myeloma host cell.
  • a pharmaceutical composition comprising the isolated antibody of any one of embodiments 1-53 and a pharmaceutically acceptable carrier.
  • composition comprising an isolated antibody as in any of embodiments 1 -53 wherein said pharmaceutical acceptable carrier is a carrier suitable for IV infusion.
  • a method for identifying an antibody that binds to CADM1 comprising providing a CADM1 antigen;contacting said CADM1 antigen with an antibody or fragment thereof; and identifying an antibody or fragment thereof that binds to a CADM1 antigen.
  • a method of treating an individual having cancer comprising administering to said individual a therapeutically effective amount of a therapeutic antibody to CAD 1 wherein said antibody is as in any one of embodiments 1 -53.
  • a method of diagnosing prostate cancer comprising:
  • a method of diagnosing prostate cancer comprising:
  • CADM1 increased levels indicate prostate cancer and/or an increased likelihood of prostate cancer and wherein the protein level of CADM1 is determined using an antibody of any one of embodiments 1 -53.
  • a method of treating an individual having cancer comprising administering to said individual a therapeutically effective amount the isolated antibody of embodiment 85.
  • RNA expression microarray techniques In order to identify biomarkers for predicting and/or diagnosing prostate cancer, gene expression levels from prostate primary tumors in several differentiation stages were compared with normal matched prostate tissues by RNA expression microarray techniques. This technique allowed us to check the expression of the whole genome in a particular type of cell, tissue, organ, or in this case, check the differential gene expression between prostate cancer and healthy prostate tissue.
  • a microarray chip contains small oligonucleotide sequences arranged in a regular pattern with specific addresses for probes for typically thousands of genes.
  • the amount of specific mRNAs in a sample can be estimated by its hybridization signal on the array.
  • Tumor samples were obtained from prostate cancer patients who underwent surgery and had not received any treatment previous to surgery. Normal samples were also obtained from non-affected regions of the prostate of the same patients (paired samples). During preparation of the specimens, care was taken to microdissect the epithelial tissue away from any adjacent stroma. 27 paired tissue samples were included in set 1 (Table 1 ) and 7 in set 2 (Table 2). Both tables summarize some tumor sample characteristics and the stage (Gleason grade) of prostate cancer biopsy assigned by the pathologists. In the first set, three samples of RNA isolated from prostate stroma were co-hybridized with a pool of normal RNA.
  • test samples from prostate stroma were analysed to rule out that stroma contamination could account for the differential expression of candidate genes in normal versus tumoral tissue.
  • the basic characteristics of the test samples for sample set 1 are summarized in the Table 1 below.
  • the basic characteristics of the test samples in sample set 2 are summarized in Table 2.
  • Table 1 Set 1 Sample Used in Microarray Study
  • Microarrays for gene expression were designed by the Tethys algorithm using the ENSEMBL database. For sequences where we did not find high quality probes, we complemented the design with Oryzon optimized Agilent probes. DNA microarray synthesis was outsourced to Agilent.
  • the Whole Genome Gene Expression Array contains:
  • Cy3- and Cy5-iabeied aRNA was produced using the MessageAmplification Kit by Ambion ⁇ Ref: 1819 for 96x kit or Ref: 1751 for 20x kit). These kits are used with some modifications introduced by Oryzon genomics. RNA labeling was performed essentially using the Eberwine protocol (Van Gelder, 1992) commercialized by Ambion with the MessageAmplification Kit (Ambion/Applied Biosystems) with minor modifications. 500 ng of total RNA was reverse transcribed in the presence of oligo ⁇ dT) 2 4 , second-strand synthesis was generated and transcription of this dsDNA was prepared using CTP_Cy3 or CTP_Cy5 (PerkinElmer). Amplified cRNA was quantified by Nanodrop ND-1000 and cRNA quality was controlled with the Agilent RNA Bionaiyzer 2100.
  • Microarray hybridization was performed at 60°C and 17 hours hybridization time according to Agilent indications, using Agilent gaskets (G2534-60002), Agilent hybridization chambers (G2534A) and in an Agilent DNA Hybridization Oven (G2545A). Oryzon hybridization controls were also used in the hybridization process. Controls for the hybridization process corresponding to 3 cDNA clones of maize (Xet, Zrn42,Exp) were included in all analysis. Exp is used as the negative spike control and was not amplified or labeled.
  • PCR fragments were generated by PCR amplification from the vector with universal primers and cRNA was generated using in vitro transcription systems (T7 or T3 Megascript kit; Ambion) with CTP_Cy3 or CTP_Cy5 (PerkinElmer). Both of the positive spike controls Xet and Zm42 were with both the Cy5 and Cy3 fluorophore.
  • the mean fold change or M values can be ranked based on their probability of being different from 0, according to the absolute value of the regularized t-statistic ⁇ Baldi and Long, 2001 ) which uses a Bayesian framework to derive a modified and improved t-student statistics.
  • the mean M distribution was used. This distribution is adjusted to a normal distribution and an iterative process is used to define the mean M numbers that are outside the distribution.

Abstract

La présente invention concerne des anticorps/molécules de liaison qui se lient spécifiquement à CADM 1. La présente invention concerne en outre l'utilisation de ces anticorps en médecine humaine et vétérinaire, par exemple dans le traitement et le diagnostic du cancer.
PCT/EP2012/053759 2011-03-04 2012-03-05 Procédés et anticorps pour le diagnostic et le traitement du cancer WO2012119989A2 (fr)

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US9464111B2 (en) * 2014-06-26 2016-10-11 L'oreal Short peptides and a method of use as an antioxidant
EP3766898A4 (fr) * 2018-03-16 2021-12-29 The University of Tokyo Anticorps reconnaissant cadm1 v9
WO2023075176A1 (fr) * 2021-10-29 2023-05-04 주식회사 이뮤노로지컬디자이닝랩 Protéine recombinante reconnaissant cadm1 et composition pharmaceutique pour le traitement de cancers la comprenant en tant que principe actif

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