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WO 2016/154621 Al 29 September 2016 (29.09.2016) 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 2016/154621 Al 29 September 2016 (29.09.2016) P O P C T (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 48/00 (2006.01) C12N 15/62 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61 38/17 (2006.0V) C12N 15/63 (2006.01) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, A61K 35/17 (2015.01) CI2N 9/22 (2006.01) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, C07K 14/435 (2006.01) C07K 14/325 (2006.01) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, C07K 14/32 (2006.01) 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, (21) International Application Number: TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. PCT/US20 16/024524 (84) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of regional protection available): ARIPO (BW, GH, 28 March 2016 (28.03.2016) GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (25) Filing Language: English TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (26) Publication Language: English DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (30) Priority Data: LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, 62/138,901 26 March 2015 (26.03.2015) U S SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (71) Applicant: THE CALIFORNIA INSTITUTE FOR BIOMEDICAL RESEARCH [US/US]; 11119 North Declarations under Rule 4.17 : Torrey Pines Road, Suite 100, La Jo11a, California 92037 — as to applicant's entitlement to apply for and be granted a (US). patent (Rule 4.1 7(H)) (72) Inventors: YOUNG, Travis; 8012 Paseo del Ocaso, La — as to the applicant's entitlement to claim the priority of the Jolla, California 92037 (US). KIM, Chanhyuk; 9434 earlier application (Rule 4.1 7(in)) Twin Trails Drive, Apt. 103, San Diego, California 92129 Published: (US). SCHULTZ, Peter G.; 1650 La Jolla Rancho Road, La Jolla, California 92037 (US). — with international search report (Art. 21(3)) (74) Agents: NUDELMAN, Aaron S. et al; Cooley LLP, 1299 — before the expiration of the time limit for amending the Pennsylvania Avenue, NW, Suite 700, Washington, Dis claims and to be republished in the event of receipt of trict of Columbia 20004 (US). amendments (Rule 48.2(h)) (81) Designated States (unless otherwise indicated, for every — with sequence listing part of description (Rule 5.2(a)) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (54) Title: SWITCHABLE NON-scFv CHIMERIC RECEPTORS, SWITCHES, AND USES THEREOF (57) Abstract: Disclosed herein are switchable chimeric receptors, switchable chimeric receptor effector cells and chimeric receptor effector cell switches. The switchable chimeric receptor-ECs are generally T cells. The chimeric receptors have non-antibody extra cellular domains that recognize a chimeric receptor binding partner on the chimeric receptor-EC switch or target cell. The chimeric receptor-ECs and switches may be used for the treatment of a disease or condition in a subject in need thereof. SWITCHABLE NON-scFv CHIMERIC RECEPTORS, SWITCHES, AND USES THEREOF CROSS-REFERENCE [001] This application claims priority to U.S. Provisional Application No. 62/138,901, filed March 26, 2015, which application is incorporated by reference herein in its entirety. STATEMENT REGARDING SEQUENCE LISTING [002] The Sequence Listing associated with this application is provided in text format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The name of the text file containing the Sequence Listing is CIBR_007_01WO_ST25.txt. The text file is 95 KB, was created on March 25, 2016, and is being submitted electronically via EFS- Web. BACKGROUND OF THE INVENTION [003] Immunotherapies are becoming attractive alternatives to chemotherapies, including immunotherapies that use adoptive transfer of genetically modified T cells to "reteach" the immune system to recognize and eliminate malignant tumor cells. Genetically modified T cells express chimeric antigen receptors, which generally consist of a signaling endodomain, a CD3-zeta transmembrane domain and an extracellular single-chain variable fragment (scFv) derived from a monoclonal antibody which gives the receptor specificity for a tumor-associated antigen on a target malignant cell. Upon binding the tumor-associated antigen via the chimeric antigen receptor, the chimeric antigen receptor expressing T cell (CAR T-cell) mounts an immune response that is cytotoxic to the malignant cell. Such therapies can circumvent chemotherapy resistance and have been shown to be active against relapsed/refractory disease, resulting in sustained remissions for some chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL) patients. However, these therapies require further investigation and optimization, as they caused undesirable effects such as toxic lymphophenia, chronic hypogammaglobulinemia for hematological targets, fatal off-target cytolysis for solid tumor targets, persistent B cell aplasia with the use of anti-CD 19 antibody expressing CAR T-cells, and, in some cases, death. [004] Introduction of a switch, which controls the activity of the CAR T-cell, would allow CAR T-cell activity and associated immune responses to be turned off after neoplastic cells are eliminated and would allow B cells to reproliferate, or potentially taper cytokine storm. Recent preclinical studies have demonstrated that CAR T-cell systems can be controlled through an antibody-based switch, wherein the antibody binds the target cell (e.g., cancer cell), blocking the CAR T-cell from binding the target cell and "switching off CAR -T activity. While these systems conceptually allow for switchable targeting of tumors using CAR T-cells, they may suffer from a series of limitations. In the case of hapten-scFv mediated switches, non-specific labeling of antibodies using cysteines or lysines produces heterogeneous products, which include variants that may be non-functional, have unpredictable pharmacokinetics and/or immunogenicity, and that may be difficult to optimize. SUMMARY OF THE INVENTION [005] In some embodiments, the present invention provides chimeric receptors comprising: a non-antibody extracellular domain that interacts with a chimeric receptor binding partner, wherein the chimeric receptor binding partner is located on a switch that interacts with a target cell; a transmembrane domain; and an intracellular signaling domain, wherein the intracellular signaling domain signals to an effector cell on which the chimeric receptor is expressed when the non-antibody extracellular domain interacts with the chimeric receptor binding partner. The chimeric receptor binding partner may be present on a switch, wherein the switch comprises the chimeric receptor binding partner and a targeting moiety. [006] In some embodiments, the present invention provides chimeric receptors comprising: a non-antibody extracellular domain that interacts with a chimeric receptor binding partner, wherein the chimeric receptor binding partner is present on a switch that comprises the chimeric receptor binding partner and a targeting moiety; a transmembrane domain; and an intracellular signaling domain, wherein the intracellular signaling domain signals to an effector cell on which the chimeric receptor is expressed when the non-antibody extracellular domain interacts with the chimeric receptor binding partner. [007] In some embodiments, the chimeric receptor binding partner comprises a chimeric receptor binding protein. In some embodiments, the chimeric receptor binding protein is selected from an antibody and an antibody fragment. In some embodiments the chimeric receptor binding protein is not selected from an antibody and an antibody fragment. In some embodiments, the chimeric receptor binding partner comprises a chimeric receptor binding peptide. In some embodiments, the chimeric receptor binding partner consists essentially of a chimeric receptor binding peptide. In some embodiments, the chimeric receptor binding peptide comprises a peptide epitope tag. In some embodiments, the targeting moiety is selected from a targeting small molecule, a targeting peptide, a targeting protein, a targeting antibody, and a targeting antibody fragment. In some embodiments, the chimeric receptor binding partner comprises a small molecule. In some embodiments, the targeting moiety is selected from a targeting small molecule, a targeting peptide, and a targeting protein. In some embodiments, the targeting peptide and the targeting protein are not selected from an antibody and an antibody fragment. [008] In some embodiments, the chimeric receptor binding partner or the non- antibody extracellular domain is selected from a naturally occurring protein, a naturally occurring peptide, portions thereof, homologs thereof, and combinations thereof. In some embodiments, the chimeric receptor binding partner and the non-antibody extracellular domain is selected from a naturally occurring protein, a naturally occurring peptide, portions thereof, homologs thereof, and combinations thereof. In some embodiments, the chimeric receptor binding partner or the non-antibody extracellular domain is selected from a nuclease, a ribonuclease, a transmembrane protein, a cell surface molecule, a cell adhesion molecule, a fibrous protein, an enzyme, and portions thereof. In some embodiments, the chimeric receptor binding partner or the non-antibody extracellular domain is derived from an organism selected form a eukaryote and a prokaryote. In some embodiments, the chimeric receptor binding partner or the non-antibody extracellular domain comprises a non-naturally occurring synthetic peptide. In some embodiments, the chimeric receptor binding partner and the non- antibody extracellular domain form a covalent protein-protein interaction.
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