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(51) International Patent Classification: EE, ES, FI, FR, GB, GR, HR, HU, IE

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(51) International Patent Classification: EE, ES, FI, FR, GB, GR, HR, HU, IE ( (51) International Patent Classification: EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Not classified MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, (21) International Application Number: KM, ML, MR, NE, SN, TD, TG). PCT/IB20 19/00 1108 (22) International Filing Date: Declarations under Rule 4.17: 27 September 2019 (27.09.2019) — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.17(iii)) (25) Filing Language: English Published: (26) Publication Language: English — without international search report and to be republished (30) Priority Data: upon receipt of that report (Rule 48. 2(g)) 62/738,895 28 September 2018 (28.09.2018) US 62/847,830 14 May 2019 (14.05.2019) US (71) Applicant: IMMPACT-BIO LTD. [EVIL]; 2 Ilan Ramon St., P.O. Box 4044, 7403635 Ness Ziona (EL). (72) Inventors; and (71) Applicants: SAGI, Yael [IL/IL]; c/o ImmPACT-Bio Ltd., 2 Ilan Ramon St., P.O. Box 4044, 7403635 Ness Ziona (IL). SHARBI-YUNGER, Adi [IL/IL]; c/o ImmPACT-Bio Ltd., 2 Ilan Ramon St., P.O. Box 4044, 7403635 Ness Ziona (IL). (72) Inventors: GROSS, Gideon; III-1-5 Address M.P. Koraz- im, 1292200 Moshav Ahnagor (IL). GIBSON, William, J.; c/o ImmPACT-Bio Ltd., 2 Ilan Ramon St., P.O. Box 4044, 7403635 Ness Ziona (IL). DAHARY, Dvir; c/o Imm¬ PACT-Bio Ltd., 2 Ilan Ramon St, P.O. Box 4044, 7403635 Ness Ziona (IL). BEIMAN, Merav; c/o ImmPACT-Bio Ltd., 2 Ilan Ramon St., P.O. Box 4044, 7403635 Ness Ziona (IL). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 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, 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. (84) Designated States (unless otherwise indicated, for every kind of regional protection available) : ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (54) Title: METHOD SFOR IDENTIFYING ACTIVATING ANTIGEN RECEPTOR (ACAR)/INHIBITORY CHIMERIC ANTIGEN RECEPTOR (ICAR) PAIRS FOR USE IN CANCER THERAPIES (57) Abstract: The present invention provides a method for identifying a target pair comprising i) an inhibitory chimeric antigen receptor (iCAR) or a protective chimeric antigen receptor (pCAR) capable of preventing or attenuating undesired activation of an effector immune cell, wherein the iCAR or pCAR target is directed to a target extracellular polymorphic epitope, and it) an activating chimeric antigen receptor (aCAR), wherein the aCAR is directed to a target non-polymorphic cell surface epitope of a protein, as well as methods of making and use of such pairs in the treatment of cancer. METHODS FOR IDENTIFYING ACTIVATING ANTIGEN RECEPTOR (aCAR)/INHIBITORY CHIMERIC ANTIGEN RECEPTOR (iCAR) PAIRS FOR USE IN CANCER THERAPIES CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No. 62/738,895, filed September 28, 20 8, and U.S. Provisional Application No. 62/847,830, filed May 14, 2019, each of which is herein incorporated by reference. ASCII TABLE [0002] This patent application contains a lengthy table section. Copies of the tables were submitted concurrently with the corresponding U.S. Patent Application No. 16/586,730 filed on September 27, 2019, as well as with the provisional applications to which the current case claims priority. Said ASCII tables, created September 28, 2018 is as follows: (1) 120575-5004-PR aCAR_iCARjpairs_6_27_l 8 Part l.txt, 66,627,779 bytes, (2) 120575- 5004-PR aCAR_iCAR_pairs_6_27_l 8 Part 2.txt, 99,298,408 bytes, (3) 120575-5004-PR candGenes598_AFlO_LOH20.txt, 9,3 0 bytes, (4) 120575-5004-PR extCellAFnLOH1306.txt, 94,814 bytes, (5) 120575-5004-PR onlyExtCellll67genes no filter.txt, 18,122 bytes, (6) 120575-5004-PR onlyExtCell3288_ no filter.txt, 388,102 bytes. FIELD OF THE INVENTION [0003] The invention relates to the field of cancer immunotherapy by adoptive cell transfer, employing activating chimeric antigen receptors (aCARs) recognizing antigens expressed on the surface of tumor cells, inhibitory CARs (iCARs) and protective CARs (pCARs) directed at allelic variants of the same or other cell surface antigens expressed by normal cells but not by the tumor due to loss of heterozygosity . l ) . BACKGROUND OF THE INVENTION [0004] e identification of targetable antigens that are exclusively expressed by tumor ceils but not by healthy tissue is undoubtedly the major challenge in cancer immunotherapy today. Clinical evidence that T cells are capable of eradicating tumor cells comes from numerous studies evaluating highly diverse approaches for harnessing T cells to treat cancer (Rosenberg and Restifo, 2015). These approaches employ bone marrow transplantation with donor lymphocyte infusion, adoptive transfer of tumor-infiltrating lymphocytes (TILs), treatment with T cells genetically redirected at pre-selected antigens via CARs (Gross and Eshliar, 2016a) or T cell receptors (TCRs), the use of immune checkpoint inhibitors or active vaccination. Of these, the use of genetically engineered T cells and different strategies for active immunization entail pre-existing information on candidate antigens wliich are likely to exert a durable clinical response but minimal adverse effects. Yet, as stated in the title of a recent review by S. Rosenberg, “Finding suitable targets is the major obstacle to cancer gene therapy” (Rosenberg, 2014). 005 The concept of using chimeric antigen receptors (or CARs) to genetically redirect T cells (or other killer cells of the immune system such as natural killer (NK) cells and cytokine-induced killer cells) against antigens of choice in an MHC-independent manner was first introduced by Gross and Eshhar in the late 1980s (Gross et a ., 1989). They are produced synthetically from chimeric genes encoding an extracellular single-chain antibody variable fragment (scFv) fused through a flexible hinge and transmembrane canonic motif to signaling components comprising immunoreceptor tyrosine-based activation motifs of CDS-ζ or FcRy chains capable of T cell activation. At present, CARs are being examined dozens of clinical trials and have so far shown exceptionally high efficacy in B ceil malignancies (Doth et a , 2014; Gill and June, 2015; Gross and Eshhar, 2016a). The safety of CAR-T cell therapy is determined, in large, by its ability to discriminate between the tumor and healthy tissue. A major risk and the direct cause for adverse autoimmune effects that have been reported in clinical and preclinical studies is off-tumor, on-target toxicity resulting from extra-tumor expression of the target antigen (dealt with detail in our recent review (Gross and Eshhar, 2016b) and (Klebanoff et al., 2016)). Concerning this risk, shared, non-mutated cell surface antigens which are currently tested clinically or pre-clinically for CAR therapy can be generally divided into a number of categories according to their tissue distribution and mode of expression: Strictly tumor-specific antigens. Perhaps the only member in this group which is already being examined clinically is variant III of the epidermal growth factor receptor (EGFRvIII) that is frequently overexpressed in glioblastoma and is also found in non-small cell lung carcinoma and prostate, breast, head and neck and ovarian cancers but not on normal tissue. Surface antigens expressed on the tumor and on non-vitai healthy tissue . Potential CAR antigens in this group are differentiation-related molecules that are mainly restricted to the B cell lineage. Prominent among these (and a target antigen in numerous clinical trials) is CD 19, apan-B cell marker acquired very early in B cell differentiation and involved in signal transduction by the B cell receptor (BCR). Membrane prostate antigens constitute another class of antigens in this category. Antigens that are typically expressed by non-malignant tumor-promoting cells. One such antigen is fibroblast activation protein (FAP), a cell surface serine protease which is almost invariably expressed by tumor-associated fibroblasts in diverse primary' and metastatic cancers. Another antigen is vascular endothelial growth factor (VEGF), which is highly expressed during tumor angiogenesis and is normally expressed on vascular and lymphatic endothelial cells in many vita organs. Tumor associated antigens (TAAs) shared with vital healthy tissue. 0 6 Most other TAAs which are presently evaluated in preclinical and clinical studies are overexpressed by tumors but are also present, usually at lower level, on essential normal tissue. [0007] The broad spectrum of strategies devised to tackle autoimmunity in CAR T cell therapy can be divided into those which seek to eliminate, or suppress transferred T cells once damage is already evident (reactive measures) and those that aim at preventing potential damage in the first place (proactive measures) (Gross and Eshhar, 2 16a). Reactive approaches often use suicide genes such as herpes simplex virus thymidine kinase (HSV-tk) and iC9, a fusion polypeptide comprising a truncated human caspase 9 and a mutated FK506- bindtng protein. Other approaches utilize antibodies to selectively remove engineered ceils which go havoc or, as recently demonstrated, a heterodimerizing small-molecule agent which governs the coupling of the CAR recognition moiety to the intracellular signaling domain (Wu et al., 2015).
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