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WO 2016/014553 Al 28 January 2016 (28.01.2016) P O P C T

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WO 2016/014553 Al 28 January 2016 (28.01.2016) 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 2016/014553 Al 28 January 2016 (28.01.2016) P O P C T (51) International Patent Classification: (74) Agent: KOYFMAN, Hannah, R.; Lando & Anastasi LLP, C07K 19/00 (2006.01) C12N 15/87 (2006.01) Riverfront Office Park, One Main Street, Suite 1100, Cam C12N 15/52 (2006.01) C12N 9/16 (2006.01) bridge, MA 02142 (US). C12N 15/62 (2006.01) C12N 9/52 (2006.01) (81) Designated States (unless otherwise indicated, for every C12N 15/63 (2006.01) 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/US2015/041363 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, 2 1 July 20 15 (21 .07.2015) 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. PCT/CN20 14/082600 2 1 July 2014 (21 .07.2014) CN (84) Designated States (unless otherwise indicated, for every PCT/CN20 14/090503 kind of regional protection available): ARIPO (BW, GH, 6 November 2014 (06. 11.2014) CN GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicants: NOVARTIS AG [CH/CH]; Lichtstrasse 35, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 4056 Basel (CH). THE TRUSTEES OF THE UNIVER¬ TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, SITY OF PENNSYLVANIA [US/US]; 3160 Chestnut DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Street, Suite 200, Philadelphia, PA 19104 (US). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventors; and GW, KM, ML, MR, NE, SN, TD, TG). (71) Applicants (for US only): BROGDON, Jennifer [US/US]; Novartis Institutes for Biomedical Research, Inc., Declarations under Rule 4.17: 250 Massachusetts Avenue, Cambridge, MA 02139 (US). — as to applicant's entitlement to apply for and be granted a GUIMARAES, Carla [PT/US]; Novartis Institutes for patent (Rule 4.1 7(H)) Biomedical Research, Inc., 250 Massachusetts Avenue, — as to the applicant's entitlement to claim the priority of the Cambridge, MA 02139 (US). HASTEWELL, John earlier application (Rule 4.1 7(in)) [US/US]; Novartis Institutes for Biomedical Research, Inc., 250 Massachusetts Avenue, Cambridge, MA 02139 (US). Published: LOEW, Andreas [DE/US]; Novartis Institutes for Bio — with international search report (Art. 21(3)) medical Research, Inc., 250 Massachusetts Avenue, Cam bridge, MA 02139 (US). — with sequence listing part of description (Rule 5.2(a)) © v o (54) Title: SORTASE SYNTHESIZED CHIMERIC ANTIGEN RECEPTORS (57) Abstract: Sortase molecules and methods described herein allow for the construction of a CAR or CAR member, e.g., in situ, on a CARX, e.g., CART, cell. For example, sortase mediated transfer of an antigen binding domain, e.g., a scFv, onto a CAR mem ber having a sortase acceptor motif in place of an antigen binding domain can provide for a complete CAR member on a cell wherein the cell does not comprise nucleic acid that encodes the complete CAR member. SORTASE SYNTHESIZED CHIMERIC ANTIGEN RECEPTORS This application claims priority to International Application PCT/CN2014/082600 filed Jul 21, 2014, and International Application PCT/CN2014/090503 filed November 6, 2014, the contents of which are incorporated herein by reference in their entireties. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on July 21, 2015, is named N2067-7054WO3_SL.txt and is 380,675 bytes in size. FIELD OF THE INVENTION The invention relates generally to a Chimeric Antigen Receptors (CARS) and cells expressing CARs, as well as sortase-based method of making and using the same, e.g., to target and inactivate or kill target cells, e.g., cancer cells. BACKGROUND Adoptive cell transfer (ACT) therapy with autologous T-cells, especially with T- cells transduced with Chimeric Antigen Receptors (CARs), are useful in treating cancer. SUMMARY Sortase molecules and methods described herein allow for the construction of a CAR or CAR member, e.g., in situ, on a CARX, e.g., CART, cell. E.g., sortase mediated transfer of an antigen binding domain, e.g., a scFv, onto a CAR member having a sortase acceptor motif in place of an antigen binding domain can provide for a complete CAR member on a cell wherein the cell does not comprise nucleic acid that encodes the complete CAR member. Because the gene encoding the antigen binding domain is not comprised in the genome of a CARX cell, the number of antigen binding domain comprising CAR members attached to the CARX surface will decrease over time, e.g., due to each cell division or membrane protein turnover. This imposes a time limit to the activity of CARXs, e.g., CARTs. Thus, sortase mediated transfer can be used to couple an extracellular domain, herein provide for inclusion of a "safety mechanism" in CARX cells, e.g., CART cells. In one aspect, a sortase acceptor member described herein comprises: (i) a sortase acceptor motif; (ii) a transmembrane domain; and optionally (iii) an intracellular signaling domain or (iv) a switch domain. In an embodiment, the components of the sortase acceptor member, in order of N terminal to C terminal, is (i), (ii), and (iii) or (iv). In an embodiment, the sortase acceptor member comprises an intracellular signaling domain. In an embodiment, the sortase acceptor member comprises a switch domain. In an embodiment, the sortase acceptor member comprises a moiety, e.g., an amino acid residue, e.g., a Gly or Ala residue, which accepts transfer of a moiety by a sortase. In an embodiment, the sortase acceptor member comprises a moiety, e.g., an amino acid residue, e.g., a Gly or Ala residue, which accepts transfer of a moiety mediated by nucleophilic attack. In an embodiment, the sortase acceptor motif comprises, consists of, or consists essentially of, Gly-, Gly-Gly-, Gly-Gly-Gly-, Gly-Gly-Gly-Gly- (SEQ ID NO: 31), or Gly-Gly-Gly-Gly-Gly- (SEQ ID ON: 32). In an embodiment, the sortase acceptor motif comprises, Gly-, Gly-Gly-, Gly-Gly-Gly-, Gly-Gly-Gly-Gly- (SEQ ID NO: 31), or Gly- Gly-Gly-Gly-Gly- (SEQ ID NO: 32). In an embodiment, the sortase acceptor motif comprises, Gly-. In an embodiment, the sortase acceptor motif comprises, consists of, or consists essentially of, Ala-, Ala-Ala -, Ala-Ala-Ala-, Ala-Ala-Ala-Ala- (SEQ ID NO: 33), Ala- Ala-Ala-Ala-Ala- (SEQ ID NO: 34). In an embodiment, the sortase acceptor motif comprises Ala-, Ala-Ala -, Ala-Ala-Ala-, Ala-Ala-Ala-Ala- (SEQ ID NO: 33), Ala-Ala- Ala-Ala-Ala- (SEQ ID NO: 34). In an embodiment, the sortase acceptor motif comprises, Ala-. As is discussed herein, a sortase acceptor member can provide a substrate useful, e.g., for making CARs, e.g., as substrate for the in situ formation of a CAR on an immune effector cell. In an embodiment a sortase acceptor member comprises the transmembrane and intracellular elements of a CAR. In an embodiment, the sortase acceptor member comprises, e.g., in the N terminal to C terminal direction: (i) a sortase acceptor motif; (ii) a transmembrane domain; and (iii) an intracellular signaling domain. As is discussed herein, embodiments of a sortase acceptor member can comprise one or more intracellular signaling domains. Embodiments of such members, and intracellular signaling domains, are described in the section following immediately hereafter, sometimes referred to herein as the Intracellular Signaling domain Module. In an embodiment, the intracellular signaling domain comprises a primary intracellular signaling domain, selected, e.g., from the list in Table 8. In an embodiment, the primary intracellular signaling domain comprises a CD3zeta domain. In an embodiment, the intracellular signaling domain comprises a costimulatory signaling domain, e.g., selected from the list in Table 9. In an embodiment, the intracellular signaling domain comprises a 4-IBB domain. In an embodiment, the intracellular signaling domain comprises a domain from Table 13. In an embodiment, the sortase acceptor member comprises a second intracellular signaling domain. In an embodiment, the second intracellular signaling domain comprises a primary intracellular signaling domain, e.g., selected from the list in Table 8. In an embodiment, the second intracellular signaling domain comprises a costimulatory domain, e.g., selected from the list in Table 9. In an embodiment, a first and second intracellular signaling domains comprise: a primary intracellular signaling domain and a costimulatory signaling domain. In an embodiment, a first and second intracellular signaling domains comprise: a 4-1BB domain and a CD3zeta domain. In an embodiment, a first and second intracellular signaling domains comprise: a CD28 domain and a 4-1BB domain. In an embodiment, the sortase acceptor member comprises a third intracellular signaling domain.
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