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WO 2016/090347 Al 9 June 2016 (09.06.2016) P O P C T

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WO 2016/090347 Al 9 June 2016 (09.06.2016) 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 2016/090347 Al 9 June 2016 (09.06.2016) P O P C T (51) International Patent Classification: (74) Agents: TESKIN, Robin L. et al; Leclair Ryan, P.C., In A61K 39/395 (2006.01) A61K 38/16 (2006.01) tellectual Property Department, 23 18 Mill Road, Suite C07K 16/46 (2006.01) 1100, Alexandria, Virginia 223 14 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/US20 15/064 146 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (22) International Filing Date: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 5 December 2015 (05.12.2015) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (26) Publication Language: English MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (30) Priority Data: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 62/088,058 5 December 2014 (05. 12.2014) US SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant: IMMUNEXT, INC. [US/US]; 16 Cavendish Court, Lebanon, New Hampshire 03766 (US). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (72) Inventors; and GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicants : MOLLOY, Michael [US/US]; 11 Marsten TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, Lane, Unit 35, Enfield, New Hampshire 03748 (US). TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, GUO, Yalin [US/US]; 4 1 Camp Brook Common, Han DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, over, New Hampshire 03755 (US). ROTHSTEIN, Jay LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, [US/US]; 18 Elm Street, Norwich, Vermont 05055 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventor: ROSENZWEIG, Michael; 20 Fayette Street, Apt. 2, Boston, Massachusetts 021 16 (US). Published: — with international search report (Art. 21(3)) [Continued on next page] (54) Title: IDENTIFICATION OF VSIG8 AS THE PUTATIVE VISTA RECEPTOR AND ITS USE THEREOF TO PRODUCE VISTA/VSIG8 MODULATORS (57) Abstract: The receptor for VISTA is identi fied (VSIG8) as well as the use of this receptor in the identification or synthesis of agonist or antag onist compounds, preferably antibodies, poly peptides and fusion proteins which agonize or ant agonize the effects of VSIG8 and/or VISTA and/or the VSIG8/VISTA binding interaction. These antagonists may be used to suppress VISTA's suppressive effects on T cell immunity, and more particularly used in the treatment of can cer, or infectious disease. These agonist com pounds may be used to potentiate or enhance VISTA's suppressive effects on T cell immunity and thereby suppress T cell immunity, such as in the treatment of autoimmunity, allergy or inflam matory conditions. Screening assays for identify ing these agonists and antagonist compounds are also provided. Fig 1. VISTA Inhibits early TCR-lnduced T cell activation. T cells were isolated and cultured for o 10 minutes with the aCD3 */- control g or VISTA- © Ig. Total ERK and phosphor-Erk was detected. w o 2016/090347 Al III 111 II II 111 I Illlll I ll l l llll II lllll II I II — with sequence listing part of description (Rule 5.2(a)) IDENTIFICATION OF VSIG8 AS THE PUTATIVE VISTA RECEPTOR AND ITS USE THEREOF TO PRODUCE VISTA/VSIG8 MODULATORS RELATED APPLICATIONS [1] This application claims priority to US Provisional Serial No. 62/088,058 filed on December 5, 2014, the contents of which are incorporated by reference in their entirety. FIELD [2] The present application generally relates to the identification of the receptor for VISTA (V-region Immunoglobulin-containing Suppressor of T cell Activation f ), a previously identified immunomodulatory polypeptide in the B7 family that regulates T cell activation and proliferation. The invention also relates to the use of the resultant receptor to produce compounds that agonize or antagonize the effects of VSIG8 which may be used as therapeutics, especially in the treatment of cancer, infectious conditions, autoimmunity, inflammation and allergic disorders. The invention specifically relates to the use of the resultant receptor to produce compounds that agonize or antagonize the VISTA/VISTA-R binding interaction. Also, the invention relates to the use of such agonists or antagonists to enhance or inhibit immune functions affected by VISTA such as CD4+ or CD8+ T cell proliferation, CD4* or CD8+ T cell activation and the production of immune cytokines. BACKGROUND [3] Immune negative checkpoint regulator (NCR) pathways have proven to be extraordinary clinical targets in the treatment of human immune-related diseases. Blockade of two NCRs, CTLA-4 and PD-1 , using monoclonal antibodies (mAbs) to enhance tumor immunity is revolutionizing the treatment of cancer and has established these pathways as clinically validated targets in human disease. More recently, soluble versions of NCR ligands that trigger NCR pathways have entered the clinic as immunosuppressive drugs to treat autoimmunity (i.e., AMP-1 10/B7-H4- Ig for Rheumatoid arthritis), and early clinical results are eagerly awaited. [4] VISTA (V-region Immunoglobulin-containing Suppressor of T cell Activation (1), is a recently-identified, NCR ligand, whose closest phyiogenetic relative is PD-L1 . Like PD-L1 , VISTA is a ligand that profoundly suppresses immunity ( 1), and like PD-L1 , blocking VISTA allows for the development of therapeutic immunity to cancer in pre-clinical oncology models (2). Whereas blocking VISTA enhances immunity, especially CD8* and CD4+ mediated T ceil immunity, treatment with a soluble Ig fusion protein of the extracellular domain of VISTA (VISTA-lg) suppresses immunity and has been shown to arrest the progression of multiple murine models of autoimmune disease. [5] Clear scientific evidence has shown that VISTA is a ligand that induces profound T cell suppression; however, the identity of the receptor that transduces this suppressive effect is currently unknown. Identification of receptors in the field of NCR pathways has been particularly challenging given their extremely low uM affinity and low density. [6] Herein we present experimental methods which have identified that "V-Set and immunoglobulin domain containing 8"as the receptor for VISTA (hereinafter "V- R" or "VSIG8"). We further disclose assays that validate that VSIG8 specifically interacts with VISTA in vitro and in vivo and that the interaction of VISTA with VSIG8 has a suppressive effect on T cell activation, proliferation and/or immune cytokine production. [7] The identification of VSIG8 as the receptor for VISTA has much clinical and scientific promise. It is known that VISTA antagonists, e.g., crVISTA mAbs are useful as therapeutics in the treatment of oncology and infection. Also, fragments of VISTA may be used as VISTA antagonists and are potentially useful as therapeutics in the treatment of oncology and infection. Further, VISTA polypeptides, e.g., VISTA- lg fusion proteins have been demonstrated to be useful in preventing and treating autoimmunity, inflammation and allergic disorders. [8] Therefore, VSIG8 will similarly be useful as it will provide a second, independent target for the development of VISTA-R agonists and antagonists, indeed, with regard to receptors in the B7 family, the most effective therapeutics to emerge thus far are (aCTLA4 {Yervoy} and aPD-1 {Novolumab}) which both are antibodies that block receptor signaling rather than antibodies to the respective ligands. [9] Therefore, antibodies to VSIG8 which block or inhibit the VISTAA/ISTA-R interaction should be effective in treating oncology and infectious disease. Particularly, VISTA-R antagonists will be potentially useful in the treatment of cancer or infectious disease indications such as melanoma and lung cancer or HIV infection. By contrast, VISTA-R agonists which promote or enhance the VISTA/VISTA-R binding interaction will potentially be useful in the treatment of autoimmune, allergic, and inflammatory indications, GVHD, transplant or other indications wherein the suppression of T cell activation, T cell proliferation or cytokine production is desired. [10] Moreover, the identification of the V-R will greatly expedite the clinical development of VISTA-lg as an immunosuppressive drug, and further facilitate the ascertainment of pharmacodynamics, target engagement, and pharmacokinetic studies, which may be used to ascertain the level of receptor occupancy required to produce optimal clinical results. [1 1] The present invention satisfies these objectives by identifying VSIG8 as the receptor for VISTA. [1 2] It is an object of the invention to identify and confirm using binding and functional assays that VSIG8 is the receptor for VISTA. [13] It is also an object of the invention to use the identified receptor to produce compounds, such as agonistic and antagonistic anti-VISTA-R antibodies, and VISTA-R polypeptides, VISTA-R fragments and derivatives and VISTA-R fusion proteins that agonize or antagonize the VISTA/VISTA-R binding interaction. [14] It is also an object of the invention to use VSIG8 agonists or antagonists, e.g., agonistic and antagonistic antl-VSIG8 antibodies, and VSIG8 polypeptides, VSIG8 fragments and derivatives and VISTA-R fusion proteins that agonize or antagonize VISTA-R and/or the VISTA/VISTA-R binding interaction to modulate immunity, especially T cell and dendritic cell immunity.
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