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WO 2015/057852 Al 23 April 2015 (23.04.2015) P O P C T

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WO 2015/057852 Al 23 April 2015 (23.04.2015) 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 2015/057852 Al 23 April 2015 (23.04.2015) P O P C T (51) International Patent Classification: Unit 715, San Diego, CA 92122 (US). PINKERTON, C07K 16/28 (2006.01) C07K 19/00 (2006.01) Stephanie; 3535 Monair Drive, Unit D, San Diego, CA 921 17 (US). SCHULTZ, Peter, G.; 1650 La Jolla Rancho (21) International Application Number: Road, La Jolla, CA 92037 (US). PCT/US20 14/0607 13 (74) Agent: HARDT, Ingo, H.; Wilson Sonsini Goodrich & (22) International Filing Date: Rosati, 650 Page Mill Road, Palo Alto, CA 94304 (US). 15 October 2014 (15.10.2014) (81) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of national protection available): AE, AG, AL, AM, (26) Publication Language: English AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (30) Priority Data: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 61/891,347 15 October 2013 (15. 10.2013) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 61/895,704 25 October 2013 (25. 10.2013) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 62/009,056 6 June 2014 (06.06.2014) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (71) Applicants: THE CALIFORNIA INSTITUTE FOR PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, BIOMEDICAL RESEARCH [US/US]; 11119 North SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, Torrey Pines Road, Suite 100, La Jolla, CA 92037 (US). TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. THE SCRIPPS RESEARCH INSTITUTE [US/US]; (84) Designated States (unless otherwise indicated, for every 10550 North Torrey Pines Road, La Jolla, CA 92037 (US). kind of regional protection available): ARIPO (BW, GH, (72) Inventors: KIM, Chanhyuk; 9434 Twin Trails Drive, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Apt. 103, San Diego, CA 92129 (US). YOUNG, Travis; TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 8012 El Paseo Grande, La Jolla, CA 92037 (US). CAO, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Yu; 7689 Palmilla Drive, Apt. 1115, San Diego, CA 92 122 DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (US). MA, Jennifer; 8680 Via Mallorca, Unit E, La Jolla, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, CA 92037 (US). KIM, Minsoo; 7255 Charmant Drive, [Continued on nextpage] (54) Title: CHIMERIC ANTIGEN RECEPTOR T CELL SWITCHES AND USES THEREOF FIG. 4A anti-CD19 pAcF - pedf cai y incorporated in anti-CD19 " "chemistry (ICD1 9-FITC switch ∞ © (57) Abstract: Disclosed herein are switches for regulating the activity of a chimeric antigen receptor effector cells (CAR-ECs). The switches generally comprise a chimeric antigen receptor-interacting domain (CAR-ID) and a target interacting domain (TID). The switch may furthercomprise a linker. Further disclosed herein are methods of using the switches for the treatment of one or more conditions or diseases in a subject in need thereof. w o 2015/057852 A llll II II 11III II I III I III II 111III II I II SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Published: CHIMERIC ANTIGEN RECEPTOR T CELL SWITCHES AND USES THEREOF CROSS-REFERENCE [001] This application claims the benefit of U.S. provisional application Ser. No. 61/891,347, filed October 15, 2013; U.S. provisional application Ser. No. 61/895,704, filed October 25, 2013; and US provisional application Ser. No. 62/009,056, filed June 6, 2014, which are all incorporated by reference in their entirety. BACKGROUND OF THE INVENTION [002] Immunotherapies, once considered "magic bullets" by Nobel laureate Paul Ehrlich, are rapidly becoming attractive alternatives to chemotherapies. Specifically, immunotherapies that use genetically modified T cells to "reteach" the immune system to recognize and eliminate malignant tumor cells are producing exciting results in early stage clinical trials. Such gene therapy circumvents many mechanisms of chemotherapy resistance and is active against relapsed/refractory disease, offering a realistic hope for a curative therapy. However, gene therapy techniques have encountered significant risks in the clinic including chronic immune dysregulation and even death. In the search for improved immunotherapies we have established a method of selectively activating and deactivating genetically modified T cells, which is both safer and more versatile than effector therapies currently being tested in the clinic. [003] Adoptive transfer of genetically engineered chimeric antigen receptor T cells (CAR-Ts) equips the immune system with the ability to recognize and eliminate tumor cells. This therapy has achieved sustained remissions in clinical trials for chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL) patients, and is rapidly emerging as a powerful alternative to chemotherapy. Despite these successes, this therapy suffers from serious safety concerns due to persistent activity of the CAR-Ts leading to toxic lymphophenia, and chronic hypogammaglobulinemia for hematological targets, and fatal off-target cytolysis for solid tumor targets. SUMMARY OF THE INVENTION [004] Disclosed herein are chimeric antigen receptor-effector cell (CAR-EC) switches comprising: (a) a chimeric antigen receptor-interacting domain (CAR-ID) comprising a small molecule; and (b) a target interacting domain (TID) comprising an unnatural amino acid. The CAR-ID may interact with a chimeric antigen receptor (CAR) on an effector cell. The effector cell may be a chimeric antigen receptor-effector cell (CAR-EC). The target interacting domain (TID) may interact with a surface molecule on a target cell. The CAR-ID may be attached to the TID. The CAR-ID may be site-specifically linked to the TID. The CAR-ID may be site- specifically linked to the unnatural amino acid of the TID. The TID may comprise an antibody or antibody fragment. The antibody fragment may be comprise a Fab. The antibody or antibody fragment may comprise at least a portion of an immunoglobulin. The CAR-EC switches may further comprise a linker. The linker may attach the CAR-ID to the TID. The linker may site- specifically link the CAR-ID to the TID. The linker may site-specifically link the CAR-ID to the unnatural amino acid of the TID. The linker may link the CAR-ID to the TID through one or more chemical groups. The chemical group may be selected from the group consisting of oxime, triazole, cyclooctyne, tetrazine, cyclopropene, norbornene, trans-cyclooctene, and selenocysteine. The chemical group may be formed between the linker and the TID. Alternatively, or additionally, the chemical group may be formed between the linker and the CAR-ID. The CAR-EC switches may further comprise one or more additional linkers. The one or more additional linkers may link an additional TID to the CAR-ID. Alternatively, or additionally, the one or more additional linkers may link an additional CAR-ID to the TID. The one or more additional linkers may be conjugated to the TID. Alternatively, the one or more additional linkers may be conjugated to the CAR-ID. The one or more additional linkers may connect the CAR-ID to a linker that is attached to the TID. The linker may possess a length of about 25 A. The linker may provide a distance between the CAR-ID and TID of about 2.5 A to about 100 A. The CAR-ID may be a hapten. The CAR-ID may comprise FITC or derivatives thereof. The CAR-ID may be selected from DOTA, dinitrophenol, biotin and derivatives thereof. The TID may comprise a polypeptide comprising the unnatural amino acid. The polypeptide may be based on or derived from an antibody or fragment thereof. The unnatural amino acid may replace an amino acid residue of the antibody or fragment from which the polypeptide is based on or derived. The polypeptide may be based on or derived light chain of the antibody. The unnatural amino acid may replace an amino acid of the light chain of the antibody from which the polypeptide is based on or derived. For example, the unnatural amino acid may replace a serine residue of the antibody light chain. The unnatural amino acid may replace serine 202 of the antibody light chain or a homologue thereof. The unnatural amino acid may replace a glycine residue of the antibody light chain. The unnatural amino acid may replace glycine 68 of the antibody light chain or a homologue thereof. The unnatural amino acid may replace a threonine residue of the antibody light chain. The unnatural amino acid may replace threonine 109 of the antibody light chain or a homologue thereof. The polypeptide may be based on or derived from a heavy chain of the antibody. The unnatural amino acid may replace a lysine residue of the antibody heavy chain. The unnatural amino acid may replace lysine 136 of the antibody heavy chain or a homologue thereof. The unnatural amino acid may replace an alanine residue of the antibody heavy chain. The unnatural amino acid may replace alanine 123 of the antibody heavy chain or a homologue thereof. The unnatural amino acid may replace serine residue of the antibody heavy chain. The unnatural amino acid may replace serine 74 of the antibody heavy chain or a homologue thereof. The unnatural amino acid may replace an amino acid residue of the antibody light chain and an amino acid residue of the antibody heavy chain.
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