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WO 2015/037005 Al 19 March 2015 (19.03.2015) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/037005 Al 19 March 2015 (19.03.2015) P O P C T (51) International Patent Classification: (74) Agents: AVERBUCH, Ariel et al; Dr.D.Graeser Ltd., 10 A61K 39/395 (2006.01) C07K 16/30 (2006.01) Zarhin St., Corex Building, 4366238 Raanana (IL). C07K 16/18 (2006.01) G01N 33/564 (2006.01) (81) Designated States (unless otherwise indicated, for every G01N 33/574 (2006.0 1) G01N 33/569 (2006.0 1) kind of national protection available): AE, AG, AL, AM, (21) International Application Number: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, PCT/IL20 14/0508 14 BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 11 September 2014 ( 11.09.2014) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (25) Filing Language: English MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (30) Priority Data: TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 61/876,324 11 September 2013 ( 11.09.2013) US (84) Designated States (unless otherwise indicated, for every (71) Applicant: COMPUGEN LTD. [IL/IL]; 72 Pinhas Rosen kind of regional protection available): ARIPO (BW, GH, St., 69512 Tel Aviv (IL). GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (72) Inventors: LEVINE, Zurit; 47 Hahistradrut Street, 46420 TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Herzeliya (IL). ROTMAN, Galit; 5 Yair Stern Street, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 46412 Herzlia (IL). DASSA, Liat; 9 Alterman Natan st, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 6941 509 Tel Aviv (IL). LEVY, Ofer; 182 Har Yeela st., SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, 99770 Moshav Mesilat Zion Doar Na Shimson (IL). CO- GW, KM, ML, MR, NE, SN, TD, TG). JOCARU, Gad S.; 41/7 HaSayfan Street, 47248 Ram- Published: at-HaSharon (IL). TOPORIK, Amir; 19B Hadasim 3701 6 Pardes Hanah Carkur (IL). KLIGER, Yossef; 60 — with international search report (Art. 21(3)) Mivtza Horev Street, 75444 Rishon Le Zion (IL). POW, — before the expiration of the time limit for amending the 1045 Mission St., San Francisco, California Andrew; claims and to be republished in the event of receipt of 94103 (US). LIANG, Spencer; 33 15 Countryside Dr., San amendments (Rule 48.2(h)) Mateo, California 94403 (US). — with sequence listing part of description (Rule 5.2(a)) (54) Title: ANTI-VSTM5 ANTIBODIES AND THE USE THEREOF IN THERAPY AND DIAGNOSIS o © FIG. 1 (57) Abstract: The present invention relates to VSTM5 -specific antibodies, antibody fragments, and VSTM5 polypeptides, conjug o ates and compositions comprising same, for modulating (antagonizing or agonizing) one or more of the effects of VSTM5 expres - sion on immunity. More specifically, the present invention relates to VSTM5-specific antibodies, antibody fragments, and VSTM5 polypeptides, conjugates and compositions comprising same for treating and aiding in the diagnosis of cancer, infectious diseases o and immune related diseases, e.g., those associated with aberrant (higher or lower than normal) VSTM5 expression by diseased and/or immune cells and/or aberrant (increased or reduced) VSTM5 -mediated effects on immunity. TITLE OF THE INVENTION ANTI-VSTM5 ANTIBODIES AND THE USE THEREOF IN THERAPY AND DIAGNOSIS FIELD OF THE INVENTION The present invention, in at least some aspects, relates to anti-VSTM5 antibodies, antigen-binding fragments, conjugates thereof, and compositions containing such which modulate (agonize or antagonize) the effects of VSTM5 on immunity, as well as methods of production and therapeutic use thereof. BACKGROUND OF THE INVENTION Naive T cells must receive two independent signals from antigen-presenting cells (APC) in order to become productively activated. The first, Signal 1, is antigen- specific and occurs when T cell antigen receptors encounter the appropriate antigen-MHC complex on the APC. The fate of the immune response is determined by a second, antigen-independent signal (Signal 2) which is delivered through a T cell costimulatory molecule that engages its APC-expressed ligand. This second signal could be either stimulatory (positive costimulation) or inhibitory (negative costimulation or coinhibition). In the absence of a costimulatory signal, or in the presence of a coinhibitory signal, T-cell activation is impaired or aborted, which may lead to a state of antigen-specific unresponsiveness (known as T-cell anergy), or may result in T-cell apoptotic death. Costimulatory molecule pairs usually consist of ligands expressed on APCs and their cognate receptors expressed on T cells. The prototype ligand/receptor pairs of costimulatory molecules are B7/CD28 and CD40/CD40L. The B7 family consists of structurally related, cell-surface protein ligands, which may provide stimulatory or inhibitory input to an immune response. Members of the B7 family are structurally related, with the extracellular domain containing at least one variable or constant immunoglobulin domain. Both positive and negative costimulatory signals play critical roles in the regulation of cell-mediated immune responses, and molecules that mediate these signals have proven to be effective targets for immunomodulation. Based on this knowledge, several therapeutic approaches that involve targeting of costimulatory molecules have been developed, and were shown to be useful for prevention and treatment of cancer by turning on, or preventing the turning off, of immune responses in cancer patients and for prevention and treatment of autoimmune diseases and inflammatory diseases, as well as rejection of allogenic transplantation, each by turning off uncontrolled immune responses, or by induction of "off signal" by negative costimulation (or coinhibition) in subjects with these pathological conditions. Manipulation of the signals delivered by B7 ligands has shown potential in the treatment of autoimmunity, inflammatory diseases, and transplant rejection. Therapeutic strategies include blocking of costimulation using monoclonal antibodies to the ligand or to the receptor of a costimulatory pair, or using soluble fusion proteins composed of the costimulatory receptor that may bind and block its appropriate ligand. Another approach is induction of co-inhibition using soluble fusion protein of an inhibitory ligand. These approaches rely, at least partially, on the eventual deletion of auto- or allo-reactive T cells (which are responsible for the pathogenic processes in autoimmune diseases or transplantation, respectively), presumably because in the absence of costimulation (which induces cell survival genes) T cells become highly susceptible to induction of apoptosis. Thus, novel agents that are capable of modulating costimulatory signals, without compromising the immune system's ability to defend against pathogens, are highly advantageous for treatment and prevention of such pathological conditions. Costimulatory pathways play an important role in tumor development. Interestingly, tumors have been shown to evade immune destruction by impeding T cell activation through inhibition of co-stimulatory factors in the B7-CD28 and TNF families, as well as by attracting regulatory T cells, which inhibit anti-tumor T cell responses (see Wang (2006), "Immune Suppression by Tumor Specific CD4+ Regulatory T cells in Cancer", Semin. Cancer. Biol. 16:73-79; Greenwald, et al. (2005), "The B7 Family Revisited", Ann. Rev. Immunol. 23:515-48; Watts (2005), "TNF/TNFR Family Members in Co-stimulation of T Cell Responses", Ann. Rev. Immunol. 23:23-68; Sadum, et al., (2007) "Immune Signatures of Murine and Human Cancers Reveal Unique Mechanisms of Tumor Escape and New Targets for Cancer Immunotherapy", Clin. Cane. Res. 13(13): 4016-4025). Such tumor expressed co-stimulatory molecules have become attractive cancer biomarkers and may serve as tumor-associated antigens (TAAs). Furthermore, costimulatory pathways have been identified as immunologic checkpoints that attenuate T cell dependent immune responses, both at the level of initiation and effector function within tumor metastases. As engineered cancer vaccines continue to improve, it is becoming clear that such immunologic checkpoints are a major barrier to the vaccines' ability to induce therapeutic anti-tumor responses. In that regard, costimulatory molecules can serve as adjuvants for active (vaccination) and passive (antibody-mediated) cancer immunotherapy, providing strategies to thwart immune tolerance and stimulate the immune system. Over the past decade, agonists and/or antagonists to various costimulatory proteins have been developed for treating autoimmune diseases, graft rejection, allergy and cancer. For example, CTLA4-Ig (Abatacept, Orencia®) is approved for treatment of RA, mutated CTLA4-Ig (Belatacept, Nulojix®) for prevention of acute kidney transplant rejection and by the anti-CTLA4 antibody (Ipilimumab, Yervoy®), recently approved for the treatment of melanoma. Other costimulation regulators are currently in advanced stages of clinical development including anti-PD-1 antibody (BMS-936558) which is in development for treatment of Non-Small Cell Lung cancer and
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