Chimeric antigen receptors specific for G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D)

Abstract

Provided are chimeric antigen receptors (CARs), which contain antibody portions specific to G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D) and polynucleotides that encode CARs specific for GPRC5D. The disclosure further relates to genetically engineered cells, containing such GPRCSD-binding receptors, and uses thereof in adoptive cell therapy.

Description

CHIMERIC ANTIGEN RECEPTORS SPECIFIC FOR G PROTEIN-COUPLED RECEPTOR CLASS C GROUP 5§ MEMBER D (GPRC5D) Cross-Reference to Related Applications

[0001] This application claims priority to U.S. provisional applications: 62 / 754,576, filed November 1, 2018, entitled “CHIMERIC ANTIGEN RECEPTORS SPECIFIC FOR G PROTEIN-COUPLED RECEPTOR CLASS C GROUP 5 MEMBER D (GPRCSD)™; 62 / 774,159, filed November 30, 2018, entitled “CHIMERIC ANTIGEN RECEPTORS SPECIFIC FOR G PROTEIN-COUPLED RECEPTOR CLASS C GROUP 5 MEMBER D (GPRC5D)"; 62 / 819,422 filed March 15, 2019, entitled “CHIMERIC ANTIGEN RECEPTORS SPECIFIC FOR G PROTEIN-COUPLED RECEPTOR CLASS C GROUP 5 MEMBER D (GPRC5D)”; 62 / 904,197 filed September 23, 2019, entitled “CHIMERIC ANTIGEN RECEPTORS SPECIFIC FOR G PROTEIN-COUPLED RECEPTOR CLASS C GROUP 5 MEMBER D (GPRCSD)™; and 62 / 904,187, filed September 23, 2019, entitled “BICISTRONIC POLYNUCLEOTIDE CONSTRUCTS ENCODING CHIMERIC ANTIGEN RECEPTORS,” the contents of which are incorporated by reference in their entirety for all purposes. Incorporation by Reference of Sequence Listing

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 735042013740SeqList. TXT, created October 31, 2019, which is 294 kilobytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety. Field

[0003] The present disclosure relates in some aspects to chimeric antigen receptors (CARs), which contain antibody portions specific to G Protein-Coupled Receptor Class C Group 5 Member D (GPRCSD) and polynucleotides that encode CARs specific for GPRCS5D. The disclosure further relates to genetically engineered cells, containing such GPRC5D-binding receptors, and uses thereof in adoptive cell therapy. Background

[0004] G-protein coupled receptor class C group 5 member D (GPRC5D) is a G-protein coupled receptor, the specific function of which has not yet been determined. The expression of GPRC5D is high in bone marrow samples of patients with multiple myeloma (MM) compared to the minimal expression of GPRC5D in bone marrow samples of patients with other hematological malignancies. Based on its expression, GPRC5D could be a marker of MM tumors and a therapeutic target. Various GPRC5D- binding chimeric antigen receptors (CARs), and cells expressing such CARs, are available. However, there remains a need for improved GPRC5D-binding CARs and engineered GPRC5D-CAR expressing targeting cells, such as for use in adoptive cell therapy. Provided herein are embodiments that meet such needs. Summary

[0005] Provided herein are chimeric antigen receptors containing: (1) an extracellular antigen- binding domain that specifically binds human G-protein coupled receptor class C group 5 member D (GPRCS5D), wherein the extracellular antigen-binding domain contains: (i) a variable heavy chain (Vi) region containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vu region amino acid sequence set forth in any of SEQ ID NO:21, 23,25,27,29, 31 or 33; and (ii) a variable light chain (V1) region containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in any of SEQ ID NO:22, 24,2 6, 28, 30, 32 or 34; (2) a spacer of at least 125 amino acids in length; (3) a transmembrane domain; and (4) an intracellular signaling region.

[0006] Also provided are chimeric antigen receptors containing: (1) an extracellular antigen-binding domain that specifically binds human G-protein coupled receptor class C group 5 member D (GPRC5D), wherein the extracellular antigen-binding domain contains: (i) a variable heavy chain (Vg) containing a CDR-HI, CDR-H2 and CDR-H3 contained within the Vi region amino acid sequence selected from any one of SEQ ID NOs: 21, 23, 25, 27, 29, 31 or 33; and (ii) a variable light chain (V1) region containing a CDR-L1, CDR-L2 and CDR-L3 contained within the Vy region amino acid sequence selected from any one of SEQ ID NOs: 22, 24,2 6, 28, 30, 32 or 34; (2) a spacer of at least 125 amino acids in length; (3) a transmembrane domain; and (4) an intracellular signaling region.

[0007] Also provided are chimeric antigen receptors containing: (1) an extracellular antigen-binding domain that specifically binds human G-protein coupled receptor class C group 5 member D (GPRC5D) wherein the extracellular antigen-binding domain contains:(i) a variable heavy chain (Vg) containing a heavy chain complementarity determining region 1 (CDR-H1) containing the amino acid sequence selected from any one of SEQ ID NOs: 75, 78, 80, 82, 90, 93, 95, 97, 105, 108, 110, 112, 120, 123, 125, 127, 135, 138, 140, 142, 135, 152, 162, 165, 167 or 169; (b) a heavy chain complementarity determining region 2 (CDR-H2) containing the amino acid sequence selected from any one of SEQ ID NOs: 76, 79, 81, 83,91, 94, 96, 98, 106, 109, 111, 113, 121, 124, 126, 128, 136, 139, 141, 143, 150, 153, 154, 155, 163, 166, 169 or 170; and (c) a heavy chain complementarity determining region 3 (CDR-H3) containing the amino acid sequence selected from any one of SEQ ID NOs: 77, 84, 92, 99, 107, 114, 133, 129, 137, 144, 151, 156, 164 or 171; and (ii) a variable light chain (V1) region containing a light chain complementarity determining region 1 (CDR-L1) containing the amino acid sequence selected from any one of SEQ ID NOs: 85, 88, 100, 103, 115, 118, 130, 133, 145, 148, 157, 160, 172 or 174; (b) a light chain complementarity determining region 2 (CDR-L2) containing the amino acid sequence selected from any one of SEQ ID NOs: 86, 89, 101, 104, 116, 119, 131, 134, 146, 149, 158 or 161; and (c) a light chain complementarity determining region 3 (CDR-L3) containing the amino acid sequence selected from any one of SEQ ID NOs: 87, 102, 117, 132, 147, 159, 173, 175, or 297; (2) a spacer of at least 125 amino acids in length; (3) a transmembrane domain; and (4) an intracellular signaling region.

[0008] In some of any of the provided embodiments, the extracellular antigen-binding domain of the chimeric antigen receptor contains:(i) a variable heavy chain (Vg) containing: an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vy region amino acid sequence set forth in any of SEQ ID NO:21, 23, 25, 27, 29, 31 or 33; and (ii) a variable light chain (V1) region containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vy region amino acid sequence set forth in any of SEQ ID NO:22, 24, 26, 28, 30, 32 or 34.

[0009] In some of any of the provided embodiments, the spacer has a length from or from about 125 to 300 amino acids in length, 125 to 250 amino acids in length, 125 to 230 amino acids in length, 125 to 200 amino acids in length, 125 to 180 amino acids in length, 125 to 150 amino acids in length, 150 to 300 amino acids in length, 150 to 250 amino acids in length, 150 to 230 amino acids in length, 150 to 200 amino acids in length, 150 to 180 amino acids in length, 180 to 300 amino acids in length, 180 to 250 amino acids in length, 180 to 230 amino acids in length, 180 to 200 amino acids in length, 200 to 300 amino acids in length, 200 to 250 amino acids in length, 200 to 230 amino acids in length, 230 to 300 amino acids in length, 230 to 250 amino acids in length or 250 to 300 amino acids in length. In some of any of the provided embodiments, the spacer is at least or at least about or is or is about 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 221, 222, 223, 224, 225, 226, 227, 228 or 229 amino acids in length, or has a length between any of the foregoing.

[0010] In some of any of the provided embodiments, the spacer is derived from an immunoglobulin. In some of any of the provided embodiments, the spacer contains a sequence of a hinge region, a CH2 and CH3 region. In some of any of the provided embodiments, one of more of the hinge, CH2 and CH3 is derived all or in part from IgG4 or IgG2, optionally human IgG4 or human IgG2. In some of any of the provided embodiments, the hinge, CH2 and CH3 is derived from IgG4. In some of any of the provided embodiments, one or more of the hinge, CH2 and CH3 is chimeric and contains a sequence derived from IgG4 and IgG2. In some of any of the provided embodiments, the spacer contains an IgG4 / 2 chimeric hinge or a modified IgG4 containing at least one amino acid replacement compared to human IgG4, an IgG2 / 4 chimeric CH2, and an IgG4 CH3 region.

[0011] In some of any of the provided embodiments, the spacer is or contains (i) the sequence set forth in SEQ ID NO: 17; (ii) a functional variant of SEQ ID NO:17 that has at least 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:17; or (iii) a contiguous portion of (i) or (ii) that is at least 125 amino acids in length. In some of any of the provided embodiments, the spacer is or contains the sequence set forth in SEQ ID NO:17. In some of any of the provided embodiments, the spacer is or contains a sequence encoded by the sequence of nucleotides set forth in SEQ ID NO:48 (also set forth in SEQ ID NO:74).

[0012] In some of any of the provided embodiments, the Vy region and the Vy regions contain the amino acid sequence set forth in SEQ ID NOs:21 and 22, respectively, or a sequence of amino acids having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NOS:21 and 22, respectively; the Vy region and the Vi regions contain the amino acid sequence set forth in SEQ ID NOs:23 and 24, respectively, or a sequence of amino acids having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NOS:23 and 24, respectively; the Vy region and the Vi regions contain the amino acid sequence set forth in SEQ ID NOs:25 and 26, respectively, or a sequence of amino acids having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NOS:25 and 26, respectively; the Vu region and the Vi regions contain the amino acid sequence set forth in SEQ ID NOs:27 and 28, respectively, or a sequence of amino acids having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NOS:27 and 28, respectively; the Vi region and the Vi regions contain the amino acid sequence set forth in SEQ ID NOs:29 and 30, respectively, or a sequence of amino acids having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NOS:29 and 30, respectively; the Vu region and the Vyregions contain the amino acid sequence set forth in SEQ ID NOs:31 and 32, respectively, or a sequence of amino acids having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NOS:31 and 32, respectively; or the Vg region and the Vi regions contain the amino acid sequence set forth in SEQ ID NOs:33 and 34, respectively, or a sequence of amino acids having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NOS:33 and 34, respectively.

[0013] In some of any of the provided embodiments, the Vi region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:80, 81 and 77, respectively, and the Vyregion contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:85, 86 and 87, respectively; the Vy region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:82, 83 and 84, respectively, and the VL_region contains a CDR- L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:88, 89 and 87, respectively; the Vi region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:95, 96, 92, respectively, and the Vy region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:100, 101 and 102, respectively; the Vi region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:97, 98 and 99, respectively, and the Vi region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:103, 104 and 102, respectively; the Vu region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:110, 111 and 107, respectively, and the Vy region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:115, 116 and 117, respectively; the Vy region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:112, 113 and 114, respectively, and the Vy region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:118, 119 and 117, respectively; the Vy region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:125, 126 and 122, respectively, and the Vy region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively; the Vy region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:127, 128 and 129, respectively, and the Vi region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:133, 134 and 132, respectively; the Vg region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:140, 141 and 137, respectively, and the Vi region contains a CDR- L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:145, 146 and 147, respectively; the Vu region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:142, 143 and 144, respectively, and the Vi region contains a CDR-L1, CDR- L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:148, 149 and 147, respectively; the Vy region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:140, 154 and 151, respectively, and the Vi region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:157, 158 and 159, respectively; the Vu region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:142, 155 and 156, respectively, and the Vi region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:160, 161 and 159, respectively; the Vx region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:167, 168 and 164, respectively, and the Vy region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:172, 86, 173, respectively; the Vg region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:169, 170 and 171, respectively, and the Vp. region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:174, 89 and 175, respectively; or the Vy region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:169, 170 and 171, respectively, and the Vi region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:174, 89 and 297, respectively.

[0014] In some of any of the provided embodiments, the Vg region and the Vy regions contain the amino acid sequence set forth in SEQ ID NOs:21 and 22, respectively; the Vi region and the Vi regions contain the amino acid sequence set forth in SEQ ID NOs:23 and 24, respectively; the Vi region and the Viregions contain the amino acid sequence set forth in SEQ ID NOs:25 and 26, respectively; the Vu region and the V_regions contain the amino acid sequence set forth in SEQ ID NOs:27 and 28, respectively; the Vi region and the Vi regions contain the amino acid sequence set forth in SEQ ID NOs:29 and 30, respectively; the Vu region and the Vi regions contain the amino acid sequence set forth in SEQ ID NOs:31 and 32, respectively; or the Vy region and the Vi regions contain the amino acid sequence set forth in SEQ ID NOs:33 and 34, respectively.

[0015] In some of any of the provided embodiments, the Vg region and the Vy regions contain the amino acid sequence set forth in SEQ ID NOs:21 and 22, respectively, or a sequence of amino acids having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NOS:21 and 22, respectively; the Vu region and the Vi regions contain the amino acid sequence set forth in SEQ ID NOs:23 and 24, respectively, or a sequence of amino acids having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NOS:23 and 24, respectively; the Vu region and the Vy regions contain the amino acid sequence set forth in SEQ ID NOs:27 and 28, respectively, or a sequence of amino acids having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NOS:27 and 28, respectively; or the Vg region and the Vy regions contain the amino acid sequence set forth in SEQ ID NOs:31 and 32, respectively, or a sequence of amino acids having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%. 98%, or 99% identity to SEQ ID NOS:31 and 32, respectively.

[0016] In some of any of the provided embodiments, the Vy region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:80, 81 and 77, respectively, and the Viregion contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:85, 86 and 87, respectively; the Vy region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:82, 83 and 84, respectively, and the Vy region contains a CDR- L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:88, 89 and 87, respectively; the Vu region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:95, 96, 92, respectively, and the Vy region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:100, 101 and 102, respectively; the Vu region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:97, 98 and 99, respectively, and the Vi region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:103, 104 and 102, respectively; the Vy region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:125, 126 and 122, respectively, and the Vi region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively; the Vu region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:127, 128 and 129, respectively, and the Vy region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:133, 134 and 132, respectively; the Vy region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:140, 154 and 151, respectively, and the Vyregion contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:157, 158 and 159, respectively; or the Vi region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:142, 155 and 156, respectively, and the Vi region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:160, 161 and 159, respectively.

[0017] In some of any of the provided embodiments, the Vg region and the Vy regions contain the amino acid sequence set forth in SEQ ID NOs:21 and 22, respectively; the Vy region and the Vi regions contain the amino acid sequence set forth in SEQ ID NOs:23 and 24, respectively; the Vi region and the Viregions contain the amino acid sequence set forth in SEQ ID NOs:27 and 28, respectively; or the Vu region and the Vy regions contain the amino acid sequence set forth in SEQ ID NOs:31 and 32, respectively.

[0018] In some of any of the provided embodiments, the extracellular antigen-binding domain is cross-reactive or binds mouse GPRC5D and / or is cross-reactive or binds cynomolgus GPRC5D. In some of any of the provided embodiments, the extracellular antigen-binding domain is not cross-reactive to or does not bind mouse GPRC5D or cynomolgus GPRC5D.

[0019] In some of any of the provided embodiments, the Vi region and the Vy region contain the amino acid sequences set forth in SEQ ID NOs:27 and 28, respectively, or a sequence of amino acids having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, or 99% identity to SEQ ID NOS:27 and 28, respectively.

[0020] In some of any of the provided embodiments, the chimeric antigen receptor contains a variable heavy chain (Vy) containing a CDR-H1, CDR-H2 and CDR-H3 contained within the Vy region amino acid sequence set forth in SEQ ID NO: 27; and a variable light chain (V1) region containing a CDR-L1, CDR-L2 and CDR-L3 contained within the Vy region amino acid sequence set forth in SEQ ID NO: 28. In some of any of the provided embodiments, the Vg region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:125, 126 and 122, respectively, and the Vp region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively. In some of any of the provided embodiments, the Vy region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:127, 128 and 129, respectively, and the Vi region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:133, 134 and 132, respectively. In some of any of the provided embodiments, the Vi region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:120, 121 and 122, respectively, and the Vy region contains a CDR-L1, CDR- L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively. In some of any of the provided embodiments, the Vu region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:123, 124 and 122, respectively, and the Vi region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively. In some of any of the provided embodiments, the Vy region and the Vy regions contain the amino acid sequence set forth in SEQ ID NOs:27 and 28, respectively.

[0021] In some of any of the provided embodiments, the extracellular antigen-binding domain is a single chain antibody fragment. In some of any of the provided embodiments, the fragment is or contains a single chain variable fragment (scFv).

[0022] In some of any of the provided embodiments, the Vi region and the Vy. region are joined by a flexible linker. In some of any of the provided embodiments, the Vy region and the Vy region are joined by a linker containing the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO:52). In some of any of the provided embodiments, the Vy region and the Vy region are joined by a flexible linker. In some of any of the provided embodiments, the Vi region and the Vy region are joined by a linker containing the amino acid sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID N0O:320).

[0023] In some of any of the provided embodiments, the Vy region is amino-terminal to the Vi. region. In some of any of the provided embodiments, the antigen-binding domain contains the amino acid sequence selected from any one of SEQ ID NOs: 1, 3, 5,7, 9, 11 or 13 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%. or 99% sequence identity to the amino acid sequence selected from any one of SEQ ID NOs: 1, 3, 5,7, 9, 11 or 13. In some of any of the provided embodiments, the antigen-binding domain contains the amino acid sequence selected from any one of SEQID NOs: 1, 3,5,7,9, 11 or 13. In some of any of the provided embodiments, the antigen-binding domain contains the amino acid sequence selected from any one of SEQ ID NOs: 1, 3,7 or 11 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence selected from any one of SEQ ID NOs: 1,3, 7or 11. In some of any of the provided embodiments, the antigen-binding domain contains the amino acid sequence selected from any one of SEQ ID NOs: 1, 3, 7 or 11. In some of any of the provided embodiments, the antigen-binding domain contains the amino acid sequence set forth in SEQ ID NO: 7 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 7. In some of any of the provided embodiments, the antigen-binding domain contains the amino acid sequence set forth in SEQ ID NO: 7.

[0024] In some of any of the provided embodiments, the Vi region is carboxy-terminal to the VL region. In some of any of the provided embodiments, the antigen-binding domain contains the amino acid sequence selected from any one of SEQ ID NOs: 2, 4, 6, 8, 10, 12 or 14 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence selected from any one of SEQ ID NOs: 2, 4, 6, 8, 10, 12 or 14. In some of any of the provided embodiments, the antigen-binding domain contains the amino acid sequence selected from any one of SEQ ID NOs: 2, 4, 6, 8, 10, 12 or 14. In some of any of the provided embodiments, the antigen-binding domain contains the amino acid sequence selected from any one of SEQ ID NOs: 2, 4, 8 or 12 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence selected from any one of SEQ ID NOs: 2, 4, 8 or 12. In some of any of the provided embodiments, the antigen-binding domain contains the amino acid sequence selected from any one of SEQ ID NOs: 2, 4, 8 or 12. In some of any of the provided embodiments, the antigen-binding domain contains the amino acid sequence set forth in SEQ ID NO: 8 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 8. In some of any of the provided embodiments, the antigen-binding domain contains the amino acid sequence set forth in SEQ ID NO: 8. In some of any of the provided embodiments, the antigen-binding domain is encoded by the nucleotide sequence set forth in SEQ ID NO:264.

[0025] In some of any of the provided embodiments, the intracellular signaling region contains an intracellular cytoplasmic signaling domain. In some of any of the provided embodiments, the intracellular signaling domain is capable of inducing a primary activation signal in a T cell, is a T cell receptor (TCR) component and / or contains an immunoreceptor tyrosine-based activation motif ITAM). In some of any of the provided embodiments, the intracellular signaling domain is or contains a cytoplasmic signaling domain of a zeta chain of a CD3-zeta (CD3() chain or a functional variant or signaling portion thereof.

[0026] In some of any of the provided embodiments, the intracellular signaling domain is human or is derived from a human protein. In some of any of the provided embodiments, the intracellular signaling domain is or contains the sequence set forth in SEQ ID NO:20 or a sequence of amino acids that has at least 90%, 91%, 92%. 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:20.

[0027] In some of any of the provided embodiments, the intracellular signaling region further contains a costimulatory signaling region. In some of any of the provided embodiments, the costimulatory signaling region contains an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof. In some of any of the provided embodiments, the costimulatory signaling region contains an intracellular signaling domain of a CD28, a 4-1BB or an ICOS or a signaling portion thereof. In some of any of the provided embodiments, the costimulatory signaling region contains an intracellular signaling domain of a 4-1BB or a signaling portion thereof. In some of any of the provided embodiments, the costimulatory signaling region is human or is derived from a human protein. In some of any of the provided embodiments, the costimulatory signaling region contains an intracellular signaling domain of CD28, such as an intracellular signaling domain of human CD28.

[0028] In some of any of the provided embodiments, the costimulatory signaling region is or contains the sequence set forth in SEQ ID NO:46 or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 46. In some of any of the provided embodiments, the costimulatory signaling region contains an intracellular signaling domain of 4-1BB. In some of any of the provided embodiments, the costimulatory signaling region is or contains the sequence set forth in SEQ ID NO:19 or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 19.

[0029] In some of any of the provided embodiments, the costimulatory signaling region is between the transmembrane domain and the intracellular signaling region. In some of any of the provided embodiments, the transmembrane domain is or contains a transmembrane domain derived from CD4, CD28, or CD8. In some of any of the provided embodiments, the transmembrane domain is or contains a transmembrane domain derived from a CD28. In some of any of the provided embodiments, the transmembrane domain is human or is derived from a human protein. In some of any of the provided embodiments, the transmembrane domain is or contains the sequence set forth in SEQ ID NO:18 or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:18.

[0030] Also provided are chimeric antigen receptors containing: (1) an extracellular antigen-binding domain that specifically binds human G-protein coupled receptor (GPRCSD), wherein the extracellular antigen-binding domain contains: (i) a variable heavy chain (Vy) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vy region amino acid sequence set forth in SEQ ID NO: 27; and (ii) a variable light chain (V1) region containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vy region amino acid sequence set forth in any of SEQ ID NO: 28; (2) a spacer set forth in SEQ ID NO:17; (3) a transmembrane domain derived from a human CD28; and (4) an intracellular signaling region containing a cytoplasmic signaling domain of a zeta chain of a CD3-zeta (CD3{) chain and an intracellular signaling domain of a T cell costimulatory molecule.

[0031] In some of any of the provided embodiments, the Vi region contains a CDR-H1, CDR-H2 and CDR-H3 contained within the Vy region amino acid sequence set forth in SEQ ID NO: 27; and the Viregion contains a CDR-L1, CDR-L2 and CDR-L3 contained within the Vi region amino acid sequence set forth in SEQ ID NO: 28; or the Vu region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:125, 126 and 122, respectively, and the Vi region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively; the Vu region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:127, 128 and 129, respectively, and the Vi region contains a CDR- L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:133, 134 and 132, respectively; the Vi region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:120, 121 and 122, respectively, and the Vi region contains a CDR-L1, CDR- L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively; or the Vy region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:123, 124 and 122, respectively, and the Vi region contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively. In some of any of the provided embodiments, the Vy region contains a CDR-H1, CDR-H2 and CDR-H3 contained within the Vy region amino acid sequence set forth in SEQ ID NO: 27; and the Vy region contains a CDR-L1, CDR-L2 and CDR-L3 contained within the Vi region amino acid sequence set forth in SEQ ID NO: 28; or the Vy region contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:125, 126 and 122, respectively, and the Vi region contains a CDR-L1, CDR-L2, and CDR- L3 containing the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively.

[0032] Also provided are chimeric antigen receptors containing: (1) an extracellular antigen-binding domain that specifically binds human G-protein coupled receptor (GPRC5D), wherein the extracellular antigen-binding domain contains: a variable heavy (Vu) region containing a CDR-H1, CDR-H2 and CDR-H3 contained within the Va region amino acid sequence set forth in SEQ ID NO: 27; and a variable light (V1) region containing a CDR-L1, CDR-L2 and CDR-L3 contained within the Vi region amino acid sequence set forth in SEQ ID NO: 28; or a Vy region containing a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:125, 126 and 122, respectively, and a Vi region containing a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively; a Vg region containing a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:127, 128 and 129, respectively, and a Vi region containing a CDR- L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:133, 134 and 132, respectively; a Vy region containing a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:120, 121 and 122, respectively, and a Vi region containing a CDR-L1, CDR- L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively; or a Vu region containing a CDR-HI, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:123, 124 and 122, respectively, and a Vy region containing a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively; (2) a spacer set forth in SEQ ID NO:17; (3) a transmembrane domain derived from a human CD28; and (4) an intracellular signaling region containing a cytoplasmic signaling domain of a zeta chain of a human CD3- zeta (CD3() chain and an intracellular signaling domain of a human CD28 or a human 4-1BB.

[0033] Also provided are chimeric antigen receptors containing: (1) an extracellular antigen-binding domain that specifically binds human G-protein coupled receptor (GPRCSD), wherein the extracellular antigen-binding domain contains: a variable heavy (Vu) region containing a CDR-H1, CDR-H2 and CDR-H3 contained within the Vy region amino acid sequence set forth in SEQ ID NO: 27; and a variable light (V1) region containing a CDR-L1, CDR-L2 and CDR-L3 contained within the Vy region amino acid sequence set forth in SEQ ID NO: 28; or a Vy region containing a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:125, 126 and 122, respectively, and a Vi region containing a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively; (2) a spacer set forth in SEQ ID NO:17; (3) a transmembrane domain derived from a human CD28; and (4) an intracellular signaling region containing a cytoplasmic signaling domain of a zeta chain of a human CD3-zeta (CD3() chain and an intracellular signaling domain of a human CD28. Also provided are chimeric antigen receptors containing: (1) an extracellular antigen-binding domain that specifically binds human G-protein coupled receptor (GPRCSD), wherein the extracellular antigen-binding domain contains: a variable heavy (Vu) region containing a CDR-H1, CDR-H2 and CDR-H3 contained within the Vg region amino acid sequence set forth in SEQ ID NO: 27; and a variable light (V1) region containing a CDR-L1, CDR-L2 and CDR-L3 contained within the Vi region amino acid sequence set forth in SEQ ID NO: 28; or a Vy region containing a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:125, 126 and 122, respectively, and a Vi region containing a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively; (2) a spacer set forth in SEQ ID NO:17; (3) a transmembrane domain derived from a human CD28; and (4) an intracellular signaling region containing a cytoplasmic signaling domain of a zeta chain of a human CD3-zeta (CD3{) chain and an intracellular signaling domain of a human 4- 1BB.

[0034] In some of any of the provided embodiments, the extracellular antigen-binding domain contains the Vy region amino acid sequence set forth in SEQ ID NO:27 and the Vy region amino acid sequence set forth in SEQ ID NO:28; and / or in some of any of the provided embodiments, the extracellular antigen-binding domain contains an scFv set forth in SEQ ID NO:7 or SEQ ID NO:8. In some of any of the provided embodiments, the extracellular antigen-binding domain contains the Vy region amino acid sequence set forth in SEQ ID NO:27 and the Vy region amino acid sequence set forth in SEQ ID NO:28; and the extracellular antigen-binding domain contains an scFv set forth in SEQ ID NO:7. In some of any of the provided embodiments, the extracellular antigen-binding domain contains the Vg region amino acid sequence set forth in SEQ ID NO:27 and the Vy region amino acid sequence set forth in SEQ ID NO:28; and the extracellular antigen-binding domain contains an scFv set forth in SEQ ID NO:8.

[0035] In some of any of the provided embodiments, the transmembrane domain is or contains the sequence set forth in SEQ ID NO:18 or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:18. In some of any of the provided embodiments, the transmembrane domain is or contains the sequence set forth in SEQ ID NO:18.

[0036] In some of any of the provided embodiments, the intracellular signaling region contains the sequence set forth in SEQ ID NO:20 or a sequence of amino acids that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:20 and the sequence set forth in SEQ ID NO:46 or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 46. In some of any of the provided embodiments, the intracellular signaling region is or contains the sequences set forth in SEQ ID NO:20 and SEQ ID NO:46. In some of any of the provided embodiments, the intracellular signaling region contains the sequence set forth in SEQ ID NO:20 or a sequence of amino acids that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:20 and the sequence set forth in SEQ ID NO:19 or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 19. In some of any of the provided embodiments, the intracellular signaling region is or contains the sequences set forth in SEQ ID NO:20 and SEQ ID NO:19.

[0037] In some of any of the provided embodiments, the chimeric antigen receptor contains from its N to C terminus in order: the antigen-binding domain, the spacer, the transmembrane domain and the intracellular signaling region.

[0038] Also provided are polynucleotides containing a sequence of nucleotides encoding any of the chimeric antigen receptors provided herein.

[0039] In some of any of the provided embodiments, the nucleic acid encoding the spacer contains at least one modified splice donor and / or splice acceptor site, said modified splice donor and / or acceptor site containing one or more nucleotide modifications corresponding to a reference splice donor site and / or reference splice acceptor site contained in the sequence set forth in SEQ ID NO:73. In some of any of the provided embodiments, the one or more nucleotide modifications contain an amino acid substitution. In some of any of the provided embodiments, the reference splice donor and / or reference splice acceptor sites are canonical, non-canonical, or cryptic splice sites. In some of any of the provided embodiments, the reference splice donor and / or reference splice acceptor site(s) has a splice site prediction score of at least or about 0.4, 0.5, 0.6, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 0.99, or 1.0; and / or the reference splice donor and / or reference splice acceptor site(s) is / are predicted to be involved in a splice event with a probability of at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%.

[0040] In some of any of the provided embodiments, the reference splice donor site contains the sequence aatctaagtacggac (SEQ ID NO: 176), tcaactggtacgtgg (SEQ ID NO:177), acaattagtaaggca (SEQ ID NO:178) and / or accacaggtgtatac (SEQ ID NO:179); and / or the reference splice acceptor site contains the sequence aagtttcttictgtattccaggctgaccgtggataaatcte (SEQ ID NO: 180) and / or gggcaacgtgttctettgeagtgteatgeacgaageectge (SEQ ID NO:181).

[0041] In some of any of the provided embodiments, the reference splice donor and / or reference splice acceptor site(s) has a splice site prediction score of at least or about 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 0.99, or 1.0; and / or In some of any of the provided embodiments, the reference splice donor and / or reference splice acceptor site(s) is / are predicted to be involved in a splice event with a probability of at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%.

[0042] In some of any of the provided embodiments, the reference splice donor site contains the sequence tcaactggtacgtgg (SEQ ID NO:177); and / or the reference splice acceptor site contains the sequence aagtttctttctgtattccaggetgaccgtggataaatcte (SEQ ID NO:180).

[0043] In some of any of the provided embodiments, at least one of the one or more nucleotide modifications are within 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 residues of the splice site junction of the reference splice acceptor and / or reference splice donor site.

[0044] In some of any of the provided embodiments, the one or more nucleotide modifications is silent and / or results in a degenerate codon compared to SEQ ID NO:73 and / or does not change the amino acid sequence of the encoded spacer.

[0045] In some of any of the provided embodiments, the modified splice donor site is set forth in agtctaaatacggac (SEQ ID NO:182), tcaactggtatgtgg (SEQ ID NO:183), accatctccaaggee (SEQ ID NO:184) and / or gececaggtttacac (SEQ ID NO:185); and / or the modified splice acceptor site is set forth in cagtttettectgtatagtagactcacegtggataaatcaa (SEQ ID NO: 186), gggeaacgtgttcagetgeagegtgatgeacgaggeectge (SEQ ID NO: 187) and / or cgecttgteeteettgtecegetecteetgttgeeggacet (SEQ ID NO:188). In some of any of the provided embodiments, the modified splice donor site is set forth in tcaactggtatgtgg (SEQ ID NO:183) and / or the modified acceptor site is set forth in cagtttcttcctgtatagtagactcacegtggataaatcaa (SEQ ID NO:186) and / or cgecttgtectecttgtcecgetectectgttgecggaccet (SEQ ID NO: 188).

[0046] In some of any of the provided embodiments, the spacer is encoded by a sequence of nucleotide set forth in SEQ ID NO:74 (also set forth in SEQ ID NO:48) or a portion thereof. In some of any of the provided embodiments, the spacer is encoded by a sequence of nucleotide set forth in SEQ ID NO:73 or a portion thereof. In some of any of the provided embodiments, the spacer is encoded by a sequence of nucleotide set forth in SEQ ID NO:74 or a portion thereof. In some of any of the provided embodiments, the spacer is encoded by a sequence of nucleotide set forth in SEQ ID NO:283 or a portion thereof. In some of any of the provided embodiments, the spacer is encoded by a sequence of nucleotide set forth in SEQ ID NO:284 or a portion thereof. In some of any of the provided embodiments, the spacer is encoded by a sequence of nucleotide set forth in SEQ ID NO:305 or a portion thereof.

[0047] In some of any of the provided embodiments, upon expression of the polynucleotide in a cell, the transcribed RNA, optionally messenger RNA (mRNA), from the polynucleotide, exhibits at least 70%, 75%, 80%, 85%, 90%, or 95% RNA homogeneity.

[0048] In some of any of the provided embodiments, upon expression in a cell, the transcribed RNA, optionally messenger RNA (mRNA), from the polynucleotide exhibits reduced heterogeneity compared to the heterogeneity of the mRNA transcribed from a reference polynucleotide, said reference polynucleotide encoding the same amino acid sequence as the polynucleotide, wherein the reference polynucleotide differs by the presence of one or more splice donor site and / or one or more splice acceptor site in the nucleic acid encoding the spacer and / or contains one or more nucleotide modifications compared to the polynucleotide and / or contains the spacer set forth in SEQ ID NO:73. In some of any of the provided embodiments, the RNA heterogeneity is reduced by greater than or greater than about 10%, 15%, 20%, 25%, 30%, 40%, 50% or more. In some of any of the provided embodiments, the transcribed RNA, optionally messenger RNA (mRNA), from the reference polynucleotide exhibits greater than or greater than about 10%, 15%, 20%, 25%, 30%, 40%, 50% or more RNA heterogeneity. In some of any of the provided embodiments, the RNA homogeneity and / or heterogeneity is determined by agarose gel electrophoresis, chip-based capillary electrophoresis, analytical ultracentrifugation, field flow fractionation, or liquid chromatography.

[0049] In some of any of the provided embodiments, the polynucleotide is codon-optimized for expression in a human cell.

[0050] In some of any of the provided embodiments, the chimeric receptor is a first chimeric receptor and the polynucleotide further contains a sequence of nucleotides encoding a second chimeric antigen receptor. Thus, also provided herein are polynucleotides that encode a first chimeric receptor that is directed against GPRCSD, including any as provided herein, and a second chimeric receptor. In some of any of the provided embodiments, the first and second chimeric receptors are separated by one or more multicistronic element(s). In some of any of the provided embodiments, the one or more multicistronic element is or contains a ribosome skip sequence. In some embodiments, the ribosome skip sequence is a T2A, aP2A, an E2A, or an F2A element. In some of any of the provided embodiments, the one or more multicistronic element contains the amino acid sequence set forth in SEQ ID NO:37. In some of any of the provided embodiments, the one or more multicistronic element is encoded by a nucleotide sequence selected from among SEQ ID NOS: 44, 45, and 319. In some of any of the provided embodiments, the nucleotide sequence encoding the one or more multicistronic element is codon diverged. In some of any of the provided embodiments, nucleotide sequence encoding the multicistronic element is or comprises the sequence set forth in SEQ ID NO:319.

[0051] In some of any of the provided embodiments, the second chimeric receptor contains an extracellular antigen binding domain that specifically binds a second antigen, such as other than GPRCS5D, expressed on or associated with multiple myeloma. In some of any of the provided embodiments, the second CAR contains an extracellular antigen binding domain that binds the second antigen, a spacer, a transmembrane domain, and an intracellular signaling region. In some of any of the provided embodiments, the second antigen is selected from B cell maturation antigen (BCMA), CD38, CD138, CS-1, BAFF-R, TACI or FcRHS. In some of any of the provided embodiments, the second antigen is BCMA.

[0052] In some of any of the provided embodiments, the second CAR contains: (1) an extracellular antigen-binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain contains: (i) a variable heavy chain (Vg) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vy region amino acid sequence set forth in any of SEQ ID NOs: 189, 191, 193, 195 or 197; and (ii) a variable light chain (V1) region containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vi region amino acid sequence set forth in any of SEQ ID NO: 190, 192, 194, 196 or 198; (2) a spacer; (3) a transmembrane; and (4) an intracellular signaling region. In some of any of the provided embodiments, the Vy region of the second CAR contains a CDR-H1, CDR-H2 and CDR-H3 contained within the Vg region amino acid sequence set forth in any of SEQ ID NOs: 189, 191, 193, 195 or 197; and the Vy region contains a CDR-L1, CDR-L2 and CDR-L3 contained within the Vi. region amino acid sequence set forth in any of SEQ ID NOs: 190, 192, 194, 196 or 198.

[0053] In some of any of the provided embodiments, the second CAR contains: (1) an extracellular antigen-binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain contains: (i) a variable heavy chain (Vy) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vy region amino acid sequence set forth in SEQ ID NO: 197; and (ii) a variable light chain (V1) region containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vy region amino acid sequence set forth in any of SEQ ID NO:198; (2) a spacer; (3) a transmembrane domain; and (4) an intracellular signaling region. In some of any of the provided embodiments, the second CAR contains: (1) an extracellular antigen-binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain contains: (i) a variable heavy chain (Vu) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vu region amino acid sequence set forth in SEQ ID NO: 197; and (ii) a variable light chain (V1) region containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vi region amino acid sequence set forth in any of SEQ ID NO:198; (2) a spacer set forth in SEQ ID NO: 17; (3) a transmembrane domain derived from a human CD28; and (4) an intracellular signaling region containing a cytoplasmic signaling domain of a zeta chain of a human CD3-zeta (CD3() chain and an intracellular signaling domain of a human 4-1BB. In some of any of the provided embodiments, the Vu region of the second CAR contains a CDR-H1, CDR-H2 and CDR-H3 contained within the Vy region amino acid sequence set forth in any of SEQ ID NOs: 197; and the Vi region contains a CDR-L1, CDR-L2 and CDR-L3 contained within the Vy region amino acid sequence set forth in any of SEQ ID NOs:198. In some of any of the provided embodiments, the second CAR is or comprises the amino acid sequence set forth in SEQ ID NO:251. In some of any of the provided embodiments, the second CAR is encoded by the nucleotide sequence set forth in SEQ ID NO:246.

[0054] In some of any of the provided embodiments, the second CAR contains: (1) an extracellular antigen-binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain contains: (i) a variable heavy chain (Vu) containing a heavy chain complementarity determining region 1 (CDR-H1) containing the amino acid sequence selected from any one of SEQ ID NOs: 199, 202, 206, 209, 212 or 215; (b) a heavy chain complementarity determining region 2 (CDR-H2) containing the amino acid sequence selected from any one of SEQ ID NOs: 200, 203, 207, 210, 213 or 216; and (c) a heavy chain complementarity determining region 3 (CDR-H3) containing the amino acid sequence selected from any one of SEQ ID NOs: 201, 204, 205, 208, 211, 214 or 217; and (ii) a variable light chain (V1) region containing a light chain complementarity determining region 1 (CDR-L1) containing the amino acid sequence selected from any one of SEQ ID NOs: 218, 221, 224, 227, 230, 233 or 235; (b) a light chain complementarity determining region 2 (CDR-L2) containing the amino acid sequence selected from any one of SEQ ID NOs: 219, 222, 225, 228, 231, 234 or 236; and (c) a light chain complementarity determining region 3 (CDR-L3) containing the amino acid sequence selected from any one of SEQ ID NOs: 220, 223, 226, 229 or 232; (2) a spacer; (3) a transmembrane domain; and (4) an intracellular signaling region.

[0055] In some of any of the provided embodiments, the Vi region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:199, 200 and 201, respectively, and the Vy region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:218, 219 and 220, respectively; the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:202, 203, 204, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:221, 222 and 223, respectively; the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:199, 200, 205, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:224, 225, and 226, respectively; the Vi region of the second CAR contains a CDR-HI1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:206, 207, 208, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:227, 228 and 229, respectively; the Vy region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Vy region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively; the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:212, 213 and 214, respectively, and the Vy region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:233, 234 and 229, respectively; or the Vi region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:215, 216 and 217, respectively, and the Vo region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:235, 236 and 232, respectively.

[0056] In some of any of the provided embodiments, the Vu region of the encoded second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR- L3 containing the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively; or the Vy region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:215, 216 and 217, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:235, 236 and 232, respectively. In some of any of the provided embodiments, the Vu region of the encoded second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR- L3 containing the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively. In some of any of the provided embodiments, the Vy region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:215, 216 and 217, respectively, and the V1. region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:235, 236 and 232, respectively.

[0057] In some of any of the provided embodiments, the Vy region and Vy region of the encoded second CAR contains the amino acid sequences set forth in SEQ ID NO:189 and SEQ ID NO:190, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:189 and SEQ ID NO:190; the Vy region and Vi region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:191 and SEQ ID NO:192, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:191 and SEQ ID NO:192; the Vy region and Vy region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:193 and SEQ ID NO:194, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:193 and SEQ ID NO:194; the Vu region and Vy region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:195 and SEQ ID NO:196, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% , or 99% sequence identity to SEQ ID NO:195 and SEQ ID NO:196; or the Vu region and Vi region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:197 and SEQ ID NO:198.

[0058] In some of any of the provided embodiments, the Vy region and Vy region of the encoded second CAR contains the amino acid sequences set forth in SEQ ID NO:189 and SEQ ID NO:190, respectively; the Vi region and Vy region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:191 and SEQ ID NO:192; the Vy region and Vy region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:193 and SEQ ID NO:194; the Vu region and Vy region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:195 and SEQ ID NO:196; or the Vy region and Vy region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO: 198, respectively. In some of any of the provided embodiments, the Vg region and Vy region of the encoded second CAR contain the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively.

[0059] In some of any of the provided embodiments, the extracellular antigen-binding domain of the encoded second CAR is a single chain antibody fragment. In some of any of the provided embodiments, the encoded fragment is or contains a single chain variable fragment (scFv). In some of any of the provided embodiments, the Vi region and the V1 region of the encoded second CAR are joined by a flexible linker. In some of any of the provided embodiments, the scFv of the encoded second CAR contains a linker containing the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO:52). In some of any of the provided embodiments, the scFv of the encoded second CAR contains a linker containing the amino acid sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO:320). In some of any of the provided embodiments, the Vy region is amino-terminal to the Vi region in the encoded second CAR. In some of any of the provided embodiments, the Vy region is carboxy-terminal to the VL. region in the encoded second CAR.

[0060] In some of any of the provided embodiments, the antigen-binding domain of the encoded second CAR contains the amino acid sequence selected from any one of SEQ ID NOs: 227, 238, 239, 240 or 241 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence selected from any one of SEQ ID NOs: 227, 238, 239, 240 or 241. In some of any of the provided embodiments, the antigen-binding domain of the encoded second CAR contains the amino acid sequence selected from any one of SEQ ID NOs: 227, 238, 239, 240 or 241. In some of any of the provided embodiments, the antigen-binding domain of the encoded second CAR contains the amino acid sequence set forth in SEQ ID NO: 241 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 241. In some of any of the provided embodiments, the antigen-binding domain of the encoded second CAR contains the amino acid sequence set forth in SEQ ID NO: 241.

[0061] In some of any of the provided embodiments, the Vi region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Vy region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively; or the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:215, 216 and 217, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:235, 236 and 232, respectively; and / or the Vy region and VL region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively; and / or the antigen-binding domain of the second CAR contains the amino acid sequence set forth in SEQ ID NO: 241 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO:241. In some of any of the provided embodiments, the Vi region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR- L3 containing the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively; and / or the Vu region and VL region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively; and / or the antigen-binding domain of the second CAR contains the amino acid sequence set forth in SEQ ID NO: 241 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO:241. In some of any of the provided embodiments, the Vy region of the second CAR contains a CDR-HI1, CDR- H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:215, 216 and 217, respectively, and the Vy region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:235, 236 and 232, respectively; and / or the Vu region and VL region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively; and / or the antigen-binding domain of the second CAR contains the amino acid sequence set forth in SEQ ID NO: 241 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO:241.

[0062] In some of any of the provided embodiments, the transmembrane domain of the encoded second CAR is or contains a transmembrane domain derived from CD4, CD28, or CD8, optionally from a human CD4, a human CD28 or a human CDS.

[0063] In some of any of the provided embodiments, the transmembrane domain of the encoded second CAR is or contains a transmembrane domain derived from a human CD28 and / or is or contains the sequence set forth in SEQ ID NO:18 or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:18. In some of any of the provided embodiments, the transmembrane domain of the encoded second CAR is or contains the sequence set forth in SEQ ID NO:18.

[0064] In some of any of the provided embodiments, the intracellular signaling region of the encoded second CAR contains an intracellular signaling domain. In some of any of the provided embodiments, the intracellular signaling domain of the encoded second CAR is capable of inducing a primary activation signal in a T cell, is a T cell receptor (TCR) component and / or contains an immunoreceptor tyrosine-based activation motif (ITAM). In some of any of the provided embodiments, the intracellular signaling domain of the encoded second CAR is or contains a cytoplasmic signaling domain of a zeta chain of a CD3-zeta (CD3() chain or a functional variant or signaling portion thereof, optionally a human CD3 zeta chain. In some of any of the provided embodiments, the intracellular signaling region of the encoded second CAR contains the sequence set forth in SEQ ID NO:20 or a sequence of amino acids that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:20.

[0065] In some of any of the provided embodiments, the intracellular signaling region of the encoded second CAR further contains a costimulatory signaling region. In some of any of the provided embodiments, the costimulatory signaling region of the encoded second CAR contains an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof. In some of any of the provided embodiments, the costimulatory signaling region of the encoded second CAR contains an intracellular signaling domain of a CD28, a 4-1BB or an ICOS or a signaling portion thereof, optionally a human CD28, a human 4-1BB, or a human ICOS. In some of any of the provided embodiments, the costimulatory signaling region of the encoded second CAR contains an intracellular signaling domain of a 4-1BB or a signaling portion thereof. In some of any of the provided embodiments, at least one of the first chimeric antigen receptor and the second chimeric antigen receptor contains an intracellular signaling region containing an intracellular signaling domain of 4-1BB or a signaling portion thereof, optionally of human 4-1BB.

[0066] In some of any of the provided embodiments, the costimulatory signaling region of the encoded second CAR contains: an intracellular signaling domain of a human CD28; and / or the sequence set forth in SEQ ID NO:46 or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 46.

[0067] In some of any of the provided embodiments, the costimulatory signaling region of the encoded second CAR contains: an intracellular signaling domain of a human 4-1BB; and / or the sequence set forth in SEQ ID NO:19 or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 19.

[0068] In some of any of the provided embodiments, the encoded second chimeric antigen receptor contains from its N to C terminus in order: the antigen-binding domain, the spacer, the transmembrane domain and the intracellular signaling region.

[0069] In some of any of the provided embodiments, at least one of the polynucleotide sequence encoding the first chimeric antigen receptor and the polynucleotide sequence encoding the second chimeric antigen receptor is codon diverged. In some of any of the provided embodiments, the polynucleotide sequence encoding the first chimeric antigen receptor and the polynucleotide sequence encoding the second chimeric antigen receptor have no more than about 30, no more than about 20, or no more than about 10 consecutive base pairs of sequence homology.

[0070] In some of any of the provided embodiments, the sequence of nucleotides encoding the CAR is operably linked to a promoter to control expression of the encoded CAR when expressed from a cell introduced with the polynucleotide, optionally wherein the promoter is a heterologous promoter, optionally wherein the heterologous promoter is or contains a human elongation factor 1 alpha (EFla) promoter or an MND promoter or a variant thereof.

[0071] In some of any of the provided embodiments, wherein the polynucleotide encodes two CARs, the sequence of nucleotides encoding the first CAR is operably linked to a first promoter to control expression of the first CAR when expressed from a cell introduced with the polynucleotide and the sequence of nucleotides encoding the second CAR is operably linked to a second promoter to control expression of the second CAR when expressed from a cell introduced with the polynucleotide. In some embodiments, the first and second promoter independently is a heterologous promoter, such as wherein the heterologous promoter is or contains a human elongation factor 1 alpha (EF1c) promoter or an MND promoter or a variant thereof. In some of such embodiments, the first and second promoters are the same. In some of such embodiments, the first and second promoter are different.

[0072] Also provided are vectors containing any of the provided polynucleotides. In some of any of the provided embodiments, the vector is a viral vector. In some of any of the provided embodiments, the viral vector is a lentiviral vector or a retroviral vector.

[0073] Also provided are engineered cells containing any of the chimeric antigen receptors provided herein. In some of any of the provided embodiments, the engineered cell contains a chimeric antigen receptor provided herein and further contains a polynucleotide containing a sequence of nucleotides encoding a second chimeric antigen receptor.

[0074] Also provided are engineered cells containing any of the polynucleotides provided herein.

[0075] In some of any of the provided embodiments, the second chimeric receptor of the provided cell contains an extracellular antigen binding domain that specifically binds a second antigen expressed on or associated with multiple myeloma. In some of any of the provided embodiments, the second CAR contains the extracellular antigen binding domain that binds the second antigen, a spacer, a transmembrane domain, and an intracellular signaling region. In some of any of such embodiments, the second antigen is selected from B cell maturation antigen (BCMA), CD38, CD138, CS-1, BAFF-R, TACI or FcRHS. In some of any of the provided embodiments, the second antigen is BCMA.

[0076] In some of any of the provided embodiments of engineered cells, the second CAR contains: (1) an extracellular antigen-binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain contains: (i) a variable heavy chain (Vu) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vy region amino acid sequence set forth in any of SEQ ID NOs: 189, 191, 193, 195 or 197; and (ii) a variable light chain (V1) region containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vy region amino acid sequence set forth in any of SEQ ID NO: 190, 192, 194, 196 or 198; (2) a spacer; (3) a transmembrane; and (4) an intracellular signaling region. In some of such embodiments, the Vx region contains a CDR-H1, CDR-H2 and CDR- H3 contained within the Vi region amino acid sequence set forth in any of SEQ ID NOs: 189, 191, 193, 195 or 197; and the Vy region contains a CDR-L1, CDR-L2 and CDR-L3 contained within the Vy region amino acid sequence set forth in any of SEQ ID NOs: 190, 192, 194, 196 or 198.

[0077] In some of any of the provided embodiments of engineered cells, the second CAR contains: (1) an extracellular antigen-binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain contains: (i) a variable heavy chain (Vy) containing a heavy chain complementarity determining region 1 (CDR-H1) containing the amino acid sequence selected from any one of SEQ ID NOs: 199, 202, 206, 209, 212 or 215; (b) a heavy chain complementarity determining region 2 (CDR-H2) containing the amino acid sequence selected from any one of SEQ ID NOs: 200, 203, 207, 210, 213 or 216; and (c) a heavy chain complementarity determining region 3 (CDR-H3) containing the amino acid sequence selected from any one of SEQ ID NOs: 201, 204, 205, 208, 211, 214 or 217; and (ii) a variable light chain (V1) region containing a light chain complementarity determining region 1 (CDR-L1) containing the amino acid sequence selected from any one of SEQ ID NOs: 218, 221, 224, 227, 230, 233 or 235; (b) a light chain complementarity determining region 2 (CDR-L2) containing the amino acid sequence selected from any one of SEQ ID NOs: 219, 222, 225, 228, 231, 234 or 236; and (c) a light chain complementarity determining region 3 (CDR-L3) containing the amino acid sequence selected from any one of SEQ ID NOs: 220, 223, 226, 229 or 232; (2) a spacer; (3) a transmembrane domain; and (4) an intracellular signaling region.

[0078] In some of any of the provided embodiments of engineered cells, the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:199, 200 and 201, respectively, and the Vy region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:218, 219 and 220, respectively; the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:202, 203, 204, respectively, and the Vr region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:221, 222 and 223, respectively; the Vu region of the second CAR contains a CDR-HI1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:199, 200, 205, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:224, 225, and 226, respectively; the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:206, 207, 208, respectively, and the Vyregion of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:227, 228 and 229, respectively; the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Vy region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively; the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:212, 213 and 214, respectively, and the Viregion of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:233, 234 and 229, respectively; or the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:215, 216 and 217, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:235, 236 and 232, respectively.

[0079] In some of any of the provided embodiments of engineered cells, the Vg region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the V_region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively; or the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:215, 216 and 217, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:235, 236 and 232, respectively.

[0080] In some of any of the provided embodiments of engineered cells, the Vx region and Vi region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:189 and SEQ ID NO: 190, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:189 and SEQ ID NO:190; the Vy region and Vy, region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:191 and SEQ ID NO:192, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%. or 99% sequence identity to SEQ ID NO:191 and SEQ ID NO:192; the Vy region and Vy region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:193 and SEQ ID NO:194, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:193 and SEQ ID NO:194; the Vu region and Vi region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:195 and SEQ ID NO:196, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:195 and SEQ ID NO:196; or the Vg region and V1 region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%. or 99% sequence identity to SEQ ID NO:197 and SEQ ID NO:198.

[0081] In some of any of the provided embodiments of engineered cells, the Vx region and Vi. region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:189 and SEQ ID NO:190, respectively; the Vy region and Vy region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:191 and SEQ ID NO:192; the Vy region and Vy region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:193 and SEQ ID NO:194; the Vi region and Vi region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:195 and SEQ ID NO:196; or the Vy region and Vi. region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO: 198, respectively.

[0082] In some of any of the provided embodiments of engineered cells, the extracellular antigen- binding domain of the second CAR is a single chain antibody fragment. In some of any of such embodiments, the fragment is or contains a single chain variable fragment (scFv).

[0083] In some of any of the provided embodiments of engineered cells, the Vy region and the Vi. region of the second CAR are joined by a flexible linker. In some of such embodiments, the linker contains the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO:52). In some of such embodiments, the linker contains the amino acid sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO:320).

[0084] In some of any of the provided embodiments of engineered cells, the Vg region is amino- terminal to the Vy region in the second CAR. In some of any of the provided embodiments of engineered cells, the Vi region is carboxy-terminal to the Vi region in the second CAR. In some of any of the provided embodiments of engineered cells, the antigen-binding domain of the second CAR contains the amino acid sequence selected from any one of SEQ ID NOs: 227, 238, 239, 240 or 241 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence selected from any one of SEQ ID NOs: 227, 238, 239, 240 or 241.

[0085] In some of any of the provided embodiments of engineered cells, the antigen-binding domain of the second CAR contains the amino acid sequence selected from any one of SEQ ID NOs: 227, 238, 239, 240 or 241. In some of any of the provided embodiments of engineered cells, the Vy region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Vy region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively; or the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:215, 216 and 217, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:235, 236 and 232, respectively; and / or the Vi region and VL region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively; and / or the antigen-binding domain of the second CAR contains the amino acid sequence set forth in SEQ ID NO: 241 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO:241.

[0086] In some of any of the provided embodiments of engineered cells, the antigen-binding domain of the second CAR contains the amino acid set forth in SEQ ID NO: 241. In some of any of the provided embodiments of engineered cells, the Vi region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Vi. region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively; and / or the Vy region and VL region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively; and / or the antigen-binding domain of the second CAR contains the amino acid sequence set forth in SEQ ID NO: 241 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO:241.

[0087] In some of any of the provided embodiments of engineered cells, the transmembrane domain of the second CAR is or contains a transmembrane domain derived from CD4, CD28, or CD8, optionally from a human CD4, a human CD28 or a human CD8. In some of any of the provided embodiments of engineered cells, the transmembrane domain of the second CAR is or contains a transmembrane domain derived from a human CD28; and / or the transmembrane domain is or contains the sequence set forth in SEQ ID NO:18 or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:18. In some of any of the provided embodiments of engineered cells, the transmembrane domain of the second CAR is or contains the sequence set forth in SEQ ID NO:18.

[0088] In some of any of the provided embodiments of engineered cells, the intracellular signaling region of the second CAR contains an intracellular signaling domain.

[0089] In some of any of the provided embodiments of engineered cells, the intracellular signaling domain of the second CAR is capable of inducing a primary activation signal ina T cell, is a T cell receptor (TCR) component and / or contains an immunoreceptor tyrosine-based activation motif ITAM). In some of any of the provided embodiments of engineered cells, the intracellular signaling domain of the second CAR is or contains a cytoplasmic signaling domain of a zeta chain of a CD3-zeta (CD3() chain or a functional variant or signaling portion thereof, optionally a human CD3 zeta chain. In some of any of the provided embodiments of engineered cells, the intracellular signaling region of the second CAR contains the sequence set forth in SEQ ID NO:20 or a sequence of amino acids that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:20.

[0090] In some of any of the provided embodiments of engineered cells, the intracellular signaling region of the second CAR further contains a costimulatory signaling region. In some of any of the provided embodiments of engineered cells, the costimulatory signaling region of the second CAR contains an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof. In some of any of the provided embodiments of engineered cells, the costimulatory signaling region of the second CAR contains an intracellular signaling domain of a CD28, a 4-1BB or an ICOS or a signaling portion thereof, optionally a human CD28, a human 4-1BB, or a human ICOS. In some of any of the provided embodiments of engineered cells, the costimulatory signaling region of the second CAR contains an intracellular signaling domain of 4-1BB or a signaling portion thereof. In some of any of the provided embodiments, at least one of the first chimeric antigen receptor and the second chimeric antigen receptor contains an intracellular signaling region containing an intracellular signaling domain of 4-1BB or a signaling portion thereof, optionally of human 4-1BB.

[0091] In some of any of the provided embodiments of engineered cells, the costimulatory signaling region of the second CAR contains: an intracellular signaling domain of a human CD28; and / or the sequence set forth in SEQ ID NO:46 or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 46.

[0092] In some of any of the provided embodiments of engineered cells, the costimulatory signaling region of the second CAR contains: an intracellular signaling domain of a human 4-1BB; and / or the sequence set forth in SEQ ID NO:19 or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 19.

[0093] In some of any of the provided embodiments of engineered cells, the encoded second chimeric antigen receptor contains from its N to C terminus in order: the antigen-binding domain, the spacer, the transmembrane domain and the intracellular signaling region.

[0094] In some of any of the provided embodiments, the engineered cell is a lymphocyte. In some of any of the provided embodiments, the engineered cell is an NX cell or a T cell. In some of any of the provided embodiments, the engineered cell is a T cell and the T cell is a CD4+ or a CD8+ T cell.

[0095] In some of any of the provided embodiments, the engineered cell was engineered from a primary cell obtained from a subject.

[0096] In some of any of the provided embodiments, the engineered cell is among a plurality of the engineered cells, where less than or less than about 10%, 9%, 8%, 7%, 5%, 4%, 3%, 2% or 1% of the cells in the plurality contain a chimeric antigen receptor that exhibits tonic signaling and / or antigen- independent activity or signaling.

[0097] Also provided are compositions containing any of the chimeric receptors provided herein. Also provided are compositions containing any of the engineered cells provided herein. In some of any of the provided embodiments, the composition contains CD4+ and CD8+ T cells and the ratio of CD4+ to CD8+ T cells is from or from about 1:3 to 3:1, optionally 1:2 to 2:1. In some of any of the provided embodiments, the composition contains CD4+ and CD8+ T cells and the ratio of CD4+ to CD8+ T cells is about 1:1.

[0098] Also provided are compositions containing: a plurality of first engineered cells containing a first chimeric antigen receptor that is any of the chimeric antigen receptors provided herein or encoded by any of the polynucleotides provided herein; and a plurality of second engineered cells containing a second chimeric antigen receptor. In some of any of the provided embodiments, among a plurality of the first engineered cells, less than or less than about 10%, 9%, 8%, 7%, 5%, 4%, 3%, 2% or 1% of the cells in the plurality contain a chimeric antigen receptor that exhibits tonic signaling and / or antigen independent activity or signaling. In some of any of the provided embodiments, among a plurality of the second engineered cells, less than or less than about 10%, 9%, 8%, 7%, 5%, 4%, 3%, 2% or 1% of the cells in the plurality contain a chimeric antigen receptor that exhibits tonic signaling and / or antigen independent activity or signaling.

[0099] In some of any of the provided embodiments, the second chimeric receptor in the plurality of second engineered cells in the composition contains an extracellular antigen binding domain that specifically binds a second antigen expressed on or associated with multiple myeloma. In some of any of the provided embodiments, the second CAR in the plurality of second engineered cells in the composition contains the extracellular antigen binding domain that binds the second antigen, a spacer, a transmembrane domain, and an intracellular signaling region. In some of any of the provided embodiments, the second antigen in the plurality of second engineered cells in the composition is selected from B cell maturation antigen (BCMA), CD38, CD138, CS-1, BAFF-R, TACI or FcRHS5. In some of any of the provided embodiments, the second antigen in the plurality of second engineered cells in the composition is BCMA.

[0100] In some of any of the provided embodiments, the second CAR in the plurality of second engineered cells in the composition contains: (1) an extracellular antigen-binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain contains: (i) a variable heavy chain (Vg) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vg region amino acid sequence set forth in any of SEQ ID NOs: 189, 191, 193, 195 or 197; and (ii) a variable light chain (V1) region containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the VL region amino acid sequence set forth in any of SEQ ID NO: 190, 192, 194, 196 or 198; (2) a spacer; (3) a transmembrane; and (4) an intracellular signaling region. In some of such embodiments, the Vu region contains a CDR-H1, CDR-H2 and CDR-H3 contained within the Vg region amino acid sequence set forth in any of SEQ ID NOs: 189, 191, 193, 195 or 197; and the Vi region contains a CDR-L1, CDR-L2 and CDR-L3 contained within the Vy region amino acid sequence set forth in any of SEQ ID NOs: 190, 192, 194, 196 or 198.

[0101] In some of any of the provided embodiments, the second CAR in the plurality of second engineered cells in the composition contains: (1) an extracellular antigen-binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain contains: (i) a variable heavy chain (Vg) containing a heavy chain complementarity determining region 1 (CDR-H1) containing the amino acid sequence selected from any one of SEQ ID NOs: 199, 202, 206, 209, 212 or 215; (b) a heavy chain complementarity determining region 2 (CDR-H2) containing the amino acid sequence selected from any one of SEQ ID NOs: 200, 203, 207, 210, 213 or 216; and (c) a heavy chain complementarity determining region 3 (CDR-H3) containing the amino acid sequence selected from any one of SEQ ID NOs: 201, 204, 205, 208, 211, 214 or 217; and (ii) a variable light chain (V1) region containing a light chain complementarity determining region 1 (CDR-L1) containing the amino acid sequence selected from any one of SEQ ID NOs: 218, 221, 224, 227, 230, 233 or 235; (b) a light chain complementarity determining region 2 (CDR-L2) containing the amino acid sequence selected from any one of SEQ ID NOs: 219, 222, 225, 228, 231, 234 or 236; and (c) a light chain complementarity determining region 3 (CDR-L3) containing the amino acid sequence selected from any one of SEQ ID NOs: 220, 223, 226, 229 or 232; (2) a spacer; (3) a transmembrane domain; and (4) an intracellular signaling region.

[0102] In some of any of the provided embodiments, the Vg region of the second CAR of the composition contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:199, 200 and 201, respectively, and the Viregion of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:218, 219 and 220, respectively; the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:202, 203, 204, respectively, and the Vpregion of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:221, 222 and 223, respectively; the Vi region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:199, 200, 205, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:224, 225, and 226, respectively; the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:206, 207, 208, respectively, and the Vyregion of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:227, 228 and 229, respectively; the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Vy region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively; the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:212, 213 and 214, respectively, and the Vy region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:233, 234 and 229, respectively; or the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:215, 216 and 217, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:235, 236 and 232, respectively.

[0103] In some of any of the provided embodiments, the Vu region of the second CAR in the composition contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively; or the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:215, 216 and 217, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:235, 236 and 232, respectively.

[0104] In some of any of the provided embodiments, the Vy region and Vy region of the second CAR in the composition contains the amino acid sequences set forth in SEQ ID NO:189 and SEQ ID NO: 190, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:189 and SEQ ID NO:190; the Vy region and Vy region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:191 and SEQ ID NO:192, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:191 and SEQ ID NO:192; the Vu region and Vy region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:193 and SEQ ID NO:194, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:193 and SEQ ID NO:194; the Vy region and Vy region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:195 and SEQ ID NO:196, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%. or 99% sequence identity to SEQ ID NO:195 and SEQ ID NO:196; or the Vy region and Vy region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:197 and SEQ ID NO: 198.

[0105] In some of any of the provided embodiments, the Vg region and Vy region of the second CAR in the composition contains the amino acid sequences set forth in SEQ ID NO:189 and SEQ ID NO:190, respectively; the Vi region and Vy region of the second CAR in the composition contains the amino acid sequences set forth in SEQ ID NO:191 and SEQ ID NO:192; the Vu region and Vi region of the second CAR in the composition contains the amino acid sequences set forth in SEQ ID NO:193 and SEQ ID NO:194; the Vg region and V1 region of the second CAR in the composition contains the amino acid sequences set forth in SEQ ID NO:195 and SEQ ID NO:196; or the Vy region and Vy region of the second CAR in the composition contains the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively.

[0106] In some of any of the provided embodiments, the extracellular antigen-binding domain of the second CAR in the composition is a single chain antibody fragment. In some of such embodiments, the fragment is or contains a single chain variable fragment (scFv). In some of any of the provided embodiments, the Vy region and the Vi. region in the second CAR in the composition are joined by a flexible linker. In some of any of the provided embodiments, the linker in the second CAR in the composition contains the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO:52). In some of any of the provided embodiments, the linker in the second CAR in the composition contains the amino acid sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO:320).

[0107] In some of any of the provided embodiments, the Vu region is amino-terminal to the VL region in the second CAR in the composition. In some of any of the provided embodiments, the Vi region is carboxy-terminal to the Vi region in the second CAR in the composition. In some of any of the provided embodiments, the antigen-binding domain in the second CAR in the composition contains the amino acid sequence selected from any one of SEQ ID NOs: 227, 238, 239, 240 or 241 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence selected from any one of SEQ ID NOs: 227, 238, 239, 240 or 241. In some of any of the provided embodiments, the antigen-binding domain in the second CAR in the composition contains the amino acid sequence selected from any one of SEQ ID NOs: 227, 238, 239, 240 or 241.

[0108] In some of any of the provided embodiments, the Vg region of the second CAR in the composition contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Vy region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively; or the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:215, 216 and 217, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:235, 236 and 232, respectively; and / or the Vg region and VL region of the second CAR in the composition contains the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively; and / or the antigen-binding domain of the second CAR in the composition contains the amino acid sequence set forth in SEQ ID NO: 241 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO:241. In some of any of the provided embodiments, the Vi region of the second CAR in the composition contains a CDR-H1, CDR- H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Vy region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively; and / or the Vu region and VL region of the second CAR in the composition contains the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively; and / or the antigen-binding domain of the second CAR in the composition contains the amino acid sequence set forth in SEQ ID NO: 241 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO:241.

[0109] In some of any of the provided embodiments, the transmembrane domain of the second CAR in the composition is or contains a transmembrane domain derived from CD4, CD28, or CDS, optionally from a human CD4, a human CD28 or a human CD8. In some of any of the provided embodiments, the transmembrane domain of the second CAR in the composition is or contains a transmembrane domain derived from a human CD28; and / or the transmembrane domain of the second CAR in the composition is or contains the sequence set forth in SEQ ID NO:18 or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:18. In some of any of the provided embodiments, the transmembrane domain of the second CAR in the composition is or contains the sequence set forth in SEQ ID NO:18.

[0110] In some of any of the provided embodiments, the intracellular signaling region of the second CAR in the composition contains an intracellular signaling domain. In some of any of the provided embodiments, the intracellular signaling domain of the second CAR in the composition is capable of inducing a primary activation signal in a T cell, is a T cell receptor (TCR) component and / or contains an immunoreceptor tyrosine-based activation motif (ITAM). In some of any of the provided embodiments, the intracellular signaling domain of the second CAR in the composition is or contains a cytoplasmic signaling domain of a zeta chain of a CD3-zeta (CD3() chain or a functional variant or signaling portion thereof, optionally a human CD3 zeta chain. In some of any of the provided embodiments, the intracellular signaling region of the second CAR in the composition contains the sequence set forth in SEQ ID NO:20 or a sequence of amino acids that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:20.

[0111] In some of any of the provided embodiments, the intracellular signaling region of the second CAR in the composition further contains a costimulatory signaling region. In some of any of the provided embodiments, the costimulatory signaling region of the second CAR in the composition contains an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof. In some of any of the provided embodiments, the costimulatory signaling region of the second CAR in the composition contains an intracellular signaling domain of a CD28, a 4-1BB or an ICOS or a signaling portion thereof, optionally a human CD28, a human 4-1BB, or a human ICOS. In some of any of the provided embodiments, the costimulatory signaling region of the second CAR in the composition contains an intracellular signaling domain of a 4-1BB or a signaling portion thereof, optionally a human 4-1BB. In some of any of the provided embodiments, at least one of the first chimeric antigen receptor and the second chimeric antigen receptor contains an intracellular signaling region containing an intracellular signaling domain of 4-1BB or a signaling portion thereof, optionally of human 4-1BB. In some of any of the provided embodiments, the costimulatory signaling region of the second CAR in the composition contains: an intracellular signaling domain of a human CD28; and / or the sequence set forth in SEQ ID NO:46 or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 46. In some of any of the provided embodiments, the costimulatory signaling region of the second CAR in the composition contains: an intracellular signaling domain of a human 4-1BB; and / or the sequence set forth in SEQ ID NO:19 or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 19.

[0112] In some of any of the provided embodiments, the encoded second chimeric antigen receptor of the composition contains from its N to C terminus in order: the antigen-binding domain, the spacer, the transmembrane domain and the intracellular signaling region.

[0113] In some of any of the provided embodiments, the plurality of first engineered cells in the composition contains T cells, optionally wherein the T cells include CD4+ and CD8+ T cells, optionally wherein the ratio of CD4+ to CD8+ T cells is from or from about 1:3 to 3:1, optionally 1:2 to 2:1. In some of any of the provided embodiments, the plurality of first engineered cells in the composition contains T cells, optionally wherein the T cells include CD4+ and CD8+ T cells, optionally wherein the ratio of CD4+ to CD8+ T cells is about 1:1.

[0114] In some of any of the provided embodiments, the plurality of second engineered cells in the composition contains T cells, optionally wherein the T cells include CD4+ and CD8+ T cells, optionally wherein the ratio of CD4+ to CD8+ T cells is from or from about 1:3 to 3:1, optionally 1:2 to 2:1. In some of any of the provided embodiments, the plurality of second engineered cells in the composition contains T cells, optionally wherein the T cells include CD4+ and CD8+ T cells, optionally wherein the ratio of CD4+ to CD8+ T cells is about 1:1.

[0115] In some of any of the provided embodiments, the composition contains a ratio of the first plurality of engineered cells and the second plurality of engineered cells that is from or from about 1:3 to 3:1, optionally 1:2 to 2:1, optionally is or is about 1:1. In some of any of the provided embodiments, the composition contains the first plurality of cells expressing the first chimeric antigen receptor and the second plurality of cells expressing the second chimeric antigen receptor at a ratio that is from about 1:3 to 3:1, optionally about 1:2 to 2:1. In particular embodiments, the ratio of the first plurality of engineered cells and the second plurality of engineered cells in the composition is or is about 1:1. In some of any of the provided embodiments, the composition further contains a pharmaceutically acceptable excipient. In some of any of the provided embodiments, the composition is sterile.

[0116] Also provided herein are uses of any of the compositions provided herein. In some of any of the provided embodiments, the composition is for use in treating a subject with a disease or condition. In some of any of the provided embodiments, the disease or condition is a cancer. In some of any of the provided embodiments, the disease or condition is multiple myeloma, optionally relapsed / refractory multiple myeloma. The provided uses and compositions for use provided herein can be for treating a subject in accord with aspects of any of the provided methods.

[0117] Also provided herein are methods of treatment, containing administering any of the compositions provided herein containing any of the engineered cells provided herein or any of the compositions provided herein containing any of the chimeric antigen receptors provided herein to a subject having a disease or disorder. In some of any of the provided embodiments, the dose of cells contains between at or about 1.0 x 10” CAR-expressing T cells and 1.2 x 10° CAR-expressing T cells, between about 1.25 x 107 CAR-expressing T cells and 1.2 x 10° CAR-expressing T cells, between about 1.5 x 107 CAR-expressing T cells and 1.2 x 10° CAR-expressing T cells, between about 5.0 x 107 CAR- expressing T cells and 4.5 x 10° CAR-expressing T cells, between about 1.5 x 108 CAR-expressing T cells and 3.0 x 108 CAR-expressing T cells. In some of any of the provided embodiments, the dose of cells contains between at or about 2.5 x 10” CAR-expressing T cells and 1.2 x 10° CAR-expressing T cells, between at or about 5.0 x 10” CAR-expressing T cells and 4.5 x 10® CAR-expressing T cells, between at or about 1.5 x 10% CAR-expressing T cells and 3.0 x 10° CAR-expressing T cells.

[0118] In some of any embodiments, the dose of cells contains between at or about 1 x 107 CAR- expressing T cells and at or about 2 x 10° CAR-expressing T cells. In some of any embodiments, the dose of cells contains between at or about 2.5 x 10” CAR-expressing T cells and at or about 1.2 x 10° CAR- expressing T cells, between at or about 5.0 x 107 CAR-expressing T cells and at or about 4.5 x 10° CAR- expressing T cells, or between at or about 1.5 x 108 CAR-expressing T cells and at or about 3.0 x 10% CAR-expressing T cells. In some of any embodiments, the dose of cells contains at or about 1.0 x 107, at or about 1.5 x 107, at or about 2.5 x 107, at or about 5.0 x 107, at or about 7.5 x 107, at or about 1.5 x 108, at or about 2.25 x 10%, at or about 3.0 x 108, at or about 4.5 x 10%, at or about 6.0 x 10%, at or about 8.0 x 10%, or at or about 1.2 x 10° CAR-expressing T cells. In some of any embodiments, the dose of cells contains at or about 5.0 x 107, at or about 1.5 x 10%, at or about 3.0 x 10% or at or about 4.5 x 10° CAR- expressing T cells. In some of any embodiments, the dose of cells contains at or about 5.0 x 107, at or about 1.5 x 10%, at or about 3.0 x 10% or at or about 4.5x 10% CAR-expressing T cells. In some of any embodiments, the dose of cells contains at or about 5.0 x 10” CAR-expressing T cells.

[0119] Also provided herein are uses of a first composition containing a plurality of first engineered cells containing a first chimeric antigen receptor that is any chimeric antigen receptor provided herein or encoded by any of the polynucleotides provided herein and a second composition containing a plurality of second engineered cells containing a second chimeric antigen receptor. In some of any of the provided embodiments, the compositions are used together for use in treating a subject with a disease or condition. In some of any of the provided embodiments, the disease or condition is a cancer. In some of any of the provided embodiments, the disease or condition is multiple myeloma, optionally relapsed / refractory multiple myeloma. The provided uses and compositions for use provided herein can be for treating a subject in accord with aspects of any of the provided methods.

[0120] Also provided here in are methods of treatment, that include: administering a composition containing a plurality of first engineered cells containing a first chimeric antigen receptor that is any chimeric antigen receptor provided herein or encoded by any of the polynucleotides provided herein to a subject having a disease or disorder; and administering to the subject a composition containing a plurality of second engineered cells containing a second chimeric antigen receptor. In some of any of the provided embodiments, the dose of the plurality of first engineered cells and the dose of the plurality of second engineered cells independently contain between at or about 1.0 x 10” CAR-expressing T cells and 1.5 x 10° CAR-expressing T cells, between at or about 1.25 x 10” CAR-expressing T cells and 0.6 x 10° CAR- expressing T cells, between at or about 2.5 x 107 CAR-expressing T cells and 2.25 x 108 CAR-expressing T cells, between at or about 7.5 x 107 CAR-expressing T cells and 1.5 x 10® CAR-expressing T cells, between at or about 2.5 x 10” CAR-expressing T cells and 1.2 x 10° CAR-expressing T cells, between at or about 5.0 x 107 CAR-expressing T cells and 4.5 x 10% CAR-expressing T cells, between at or about 1.5 x 10° CAR-expressing T cells and 3.0 x 10° CAR-expressing T cells. In some of any embodiments, the dose of the plurality of first engineered cells and the dose of the plurality of second engineered cells independently contain between at or about 1 x 10” CAR-expressing T cells and at or about 2 x 10° CAR- expressing T cells. In some of any embodiments, the dose of cells contains between at or about 2.5 x 107 CAR-expressing T cells and at or about 1.2 x 10° CAR-expressing T cells, between at or about 5.0 x 107 CAR-expressing T cells and at or about 4.5 x 108 CAR-expressing T cells, or between at or about 1.5 x 108 CAR-expressing T cells and at or about 3.0 x 10% CAR-expressing T cells. In some of any embodiments, the dose of cells contains at or about 1.5 x 107, at or about 2.5 x 107, at or about 5.0 x 107, at or about 7.5 x 107, at or about 1.5 x 10%, at or about 2.25 x 108, at or about 3.0 x 10%, at or about 4.5 x 108, at or about 6.0 x 108, at or about 8.0 x 10%, or at or about 1.2 x 10° CAR-expressing T cells. In some of any embodiments, the dose of cells contains at or about 5.0 x 107, at or about 1.5 x 108, at or about 3.0 x 10° or at or about 4.5x 10° CAR-expressing T cells. In some of any embodiments, the dose of cells contains at or about 5.0 x 107, at or about 1.5 x 108, at or about 3.0 x 10% or at or about 4.5 x 10° CAR- expressing T cells. In some of any embodiments, the dose of cells contains at or about 5.0 x 10” CAR- expressing T cells.

[0121] In some of any of the provided embodiments, the composition containing the plurality of first engineered cells and the composition containing the plurality of second engineered cells are administered simultaneously, sequentially or intermittently. In some of any of the provided embodiments, the composition containing the plurality of first engineered cells and the composition containing the plurality of second engineered cells are administered sequentially in any order.

[0122] In some of any of the provided embodiments, among a plurality of the first engineered cells of compositions in the provided methods of treatment or for uses in treating, less than or less than about 10%, 9%, 8%, 1%, 5%, 4%, 3%, 2% or 1% of the cells in the plurality contain a chimeric antigen receptor that exhibits tonic signaling and / or antigen independent activity or signaling.

[0123] In some of any of the provided embodiments, among a plurality of the second engineered cells of compositions in the provided methods of treatment or for uses in treating, less than or less than about 10%, 9%, 8%, 7%, 5%, 4%, 3%, 2% or 1% of the cells in the plurality contain a chimeric antigen receptor that exhibits tonic signaling and / or antigen independent activity or signaling.

[0124] In some of any of the provided embodiments, the second chimeric receptor in engineered cells of compositions in the methods of treatment or for uses in treating contains an extracellular antigen binding domain that specifically binds a second antigen expressed on or associated with multiple myeloma.

[0125] In some of any of the provided embodiments, the second CAR in engineered cells of compositions in the provided methods or for uses in treating contains the extracellular antigen binding domain that binds the second antigen, a spacer, a transmembrane domain, and an intracellular signaling region.

[0126] In some of any of the provided embodiments, the second antigen targeted by the second CAR in engineered cells of compositions in the provided methods or for uses in treating contains is selected from B cell maturation antigen (BCMA), CD38, CD138, CS-1, BAFF-R, TACI or FcRHS. In some of any of the provided embodiments, the second antigen in the provided methods contains is BCMA.

[0127] In some of any of the provided embodiments, the second CAR in engineered cells of compositions in the provided methods or for uses in treating contains: (1) an extracellular antigen- binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain contains: (i) a variable heavy chain (Vg) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vu region amino acid sequence set forth in any of SEQ ID NOs: 189, 191, 193, 195 or 197; and (ii) a variable light chain (V1) region containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vy region amino acid sequence set forth in any of SEQ ID NO: 190, 192, 194, 196 or 198; (2) a spacer; (3) a transmembrane; and (4) an intracellular signaling region. In some of any of the provided embodiments, the Vu region of the second CAR in the provided methods contains a CDR-HI, CDR-H2 and CDR-H3 contained within the Vi region amino acid sequence set forth in any of SEQ ID NOs: 189, 191, 193, 195 or 197; and the V_region contains a CDR-L1, CDR-L2 and CDR-L3 contained within the Vi region amino acid sequence set forth in any of SEQ ID NOs: 190, 192, 194, 196 or 198.

[0128] In some of any of the provided embodiments, the second CAR in engineered cells of compositions in the provided methods or for uses in treating contains: (1) an extracellular antigen- binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain contains: (i) a variable heavy chain (Vy) containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the Vy region amino acid sequence set forth in SEQ ID NO: 197; and (ii) a variable light chain (V1) region containing an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the V1 region amino acid sequence set forth in SEQ ID NO: 198; (2) a spacer; (3) a transmembrane; and (4) an intracellular signaling region. In some of any of the provided embodiments, the Vy region of the second CAR in the provided methods contains a CDR-H1, CDR-H2 and CDR-H3 contained within the Vu region amino acid sequence set forth in SEQ ID NO: 197; and the Viregion contains a CDR-L1, CDR-L2 and CDR-L3 contained within the Vi region amino acid sequence set forth in SEQ ID NO: 198.

[0129] In some of any of the provided embodiments, the second CAR in engineered cells of compositions in the provided methods or for uses in treating contains: (1) an extracellular antigen- binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain contains: (i) a variable heavy chain (Vg) containing a heavy chain complementarity determining region 1 (CDR-H1) containing the amino acid sequence selected from any one of SEQ ID NOs: 199, 202, 206, 209, 212 or 215; (b) a heavy chain complementarity determining region 2 (CDR-H2) containing the amino acid sequence selected from any one of SEQ ID NOs: 200, 203, 207, 210, 213 or 216; and (¢) a heavy chain complementarity determining region 3 (CDR-H3) containing the amino acid sequence selected from any one of SEQ ID NOs: 201, 204, 205, 208, 211, 214 or 217; and (ii) a variable light chain (V1) region containing a light chain complementarity determining region 1 (CDR-L1) containing the amino acid sequence selected from any one of SEQ ID NOs: 218, 221, 224, 227, 230, 233 or 235; (b) a light chain complementarity determining region 2 (CDR-L2) containing the amino acid sequence selected from any one of SEQ ID NOs: 219, 222, 225, 228, 231, 234 or 236; and (c) a light chain complementarity determining region 3 (CDR-L3) containing the amino acid sequence selected from any one of SEQ ID NOs: 220, 223, 226, 229 or 232; (2) a spacer; (3) a transmembrane domain; and (4) an intracellular signaling region.

[0130] In some of any of the provided embodiments, the second CAR in engineered cells of compositions in the provided methods or for uses in treating contains an extracellular antigen-binding domain in which the Vy region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:199, 200 and 201, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:218, 219 and 220, respectively; the Vu region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:202, 203, 204, respectively, and the Viregion of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:221, 222 and 223, respectively; the Vi region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:199, 200, 205, respectively, and the Vy region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:224, 225, and 226, respectively; the Vy region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:206, 207, 208, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:227, 228 and 229, respectively; the Vi region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively; the Vy region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:212, 213 and 214, respectively, and the Viregion of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:233, 234 and 229, respectively; or the Vi region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:215, 216 and 217, respectively, and the Vy region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:235, 236 and 232, respectively.

[0131] In some of any of the provided embodiments, the second CAR in engineered cells of compositions in the provided methods or for uses in treating contains an extracellular antigen-binding domain in which the Vy region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively; or the Vi region of the second CAR in the provided methods contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:215, 216 and 217, respectively, and the Vy region of the second CAR contains a CDR-L1, CDR-L2, and CDR- L3 containing the amino acid sequence of SEQ ID NOS:235, 236 and 232, respectively. In some of any of the provided embodiments, the second CAR in engineered cells of compositions in the provided methods or for uses in treating contains an extracellular antigen-binding domain in which the Vy region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Vo region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively.

[0132] In some of any of the provided embodiments, the second CAR in engineered cells of compositions in the provided methods or for uses in treating contains an extracellular antigen-binding domain in which the Vy region and VL region contains the amino acid sequences set forth in SEQ ID NO:189 and SEQ ID NO:190, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%. or 99% sequence identity to SEQ ID NO:189 and SEQ ID NO:190; the Vu region and VL region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:191 and SEQ ID NO:192, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:191 and SEQ ID NO:192; the Vg region and VL region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:193 and SEQ ID NO:194, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%. 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:193 and SEQ ID NO:194; the Vy region and VL region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:195 and SEQ ID NO:196, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:195 and SEQ ID NO:196; or the Vy region and VL region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:197 and SEQ ID NO:198.

[0133] In some of any of the provided embodiments, the second CAR in engineered cells of compositions in the provided methods or for uses in treating contains an extracellular antigen-binding domain in which the Vg region and VL region contains the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively, or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:197 and SEQ ID NO:198.

[0134] In some of any of the provided embodiments, the second CAR in engineered cells of compositions in the provided methods or for uses in treating contains an extracellular antigen-binding domain in which the Vy region and VL region contains the amino acid sequences set forth in SEQ ID NO:189 and SEQ ID NO:190, respectively; the Vi region and VL region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:191 and SEQ ID NO:192; the Vu region and VL region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:193 and SEQ ID NO:194; the Vu region and VL region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:195 and SEQ ID NO:196; or the Vg region and VL region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively. In some of any of the provided embodiments, the second CAR in engineered cells of compositions in the provided methods or for uses in treating contains an extracellular antigen-binding domain in which the Vy region and VL region contains the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively.

[0135] In some of any of the provided embodiments, the extracellular antigen-binding domain of the second CAR in engineered cells in compositions in in the provided methods or for uses in treating is a single chain antibody fragment. In some of any of the provided embodiments, the fragment is or contains a single chain variable fragment (scFv).

[0136] In some of any of the provided embodiments of the provided methods or for uses in treating, the Vg region and the V1 region of the extracellular antigen-binding domain of the second CAR in engineered cells in compositions are joined by a flexible linker. In some of any of the provided embodiments, the linker of the second CAR in engineered cells in compositions contains the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO:52). In some of any of the provided embodiments, the linker of the second CAR in engineered cells in compositions contains the amino acid sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO:320).

[0137] In some of any of the provided embodiments of the provided methods or for uses in treating, the Vy region is amino-terminal to the Vi region in the extracellular antigen-binding domain of the second CAR. In some of any of the provided embodiments of the provided methods, the Vu region is carboxy-terminal to the Vi region in the second CAR.

[0138] In some of any of the provided embodiments of the provided methods or for uses in treating, the extracellular antigen-binding domain of the second CAR contains the amino acid sequence selected from any one of SEQ ID NOs: 227, 238, 239, 240 or 241 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence selected from any one of SEQ ID NOs: 227, 238, 239, 240 or 241. In some of any of the provided embodiments of the provided methods, the antigen-binding domain of the second CAR contains the amino acid sequence selected from any one of SEQ ID NOs: 227, 238, 239, 240 or 241. In some of any of the provided embodiments of the provided methods or for uses in treating, the extracellular antigen- binding domain of the second CAR contains the amino acid sequence set forth in SEQ ID NO: 241 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:241. In some of any of the provided embodiments of the provided methods, the antigen-binding domain of the second CAR contains the amino acid sequence set forth in SEQ ID NO: 241.

[0139] In some of any of the provided embodiments of the provided methods or for uses in treating, the extracellular antigen-binding domain of the second CAR has a Vy region and a Vy region in which the Vg region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Viregion of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively; or the Vy region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:215, 216 and 217, respectively, and the Vi region of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:235, 236 and 232, respectively; and / or the Vu region and VL region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively; and / or the antigen-binding domain of the second CAR contains the amino acid sequence set forth in SEQ ID NO: 241 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO:241. In some of any of the provided embodiments of the provided methods or for uses in treating, the extracellular antigen-binding domain of the second CAR has a Vy region and a Vy region in which the Vi region of the second CAR contains a CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Vyregion of the second CAR contains a CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively; and / or the Vi region and VL region of the second CAR contains the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively; and / or the antigen-binding domain of the second CAR contains the amino acid sequence set forth in SEQ ID NO: 241 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO:241.

[0140] In some of any of the provided embodiments of the provided methods or for uses in treating, the transmembrane domain of the second CAR is or contains a transmembrane domain derived from CD4, CD28, or CDS, optionally from a human CD4, a human CD28 or a human CD8. In some of any of the provided embodiments of the provided methods, the transmembrane domain of the second CAR is or contains a transmembrane domain derived from a human CD28; and / or the transmembrane domain is or contains the sequence set forth in SEQ ID NO:18 or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:18. In some of any of the provided embodiments of the provided methods, the transmembrane domain of the second CAR is or contains the sequence set forth in SEQ ID NO:18.

[0141] In some of any of the provided embodiments of the provided methods or for uses in treating, the intracellular signaling region of the second CAR contains an intracellular signaling domain. In some of any of the provided embodiments of the provided methods, the intracellular signaling domain of the second CAR is capable of inducing a primary activation signal in a T cell, is a T cell receptor (TCR) component and / or contains an immunoreceptor tyrosine-based activation motif (ITAM). In some of any of the provided embodiments of the provided methods, the intracellular signaling domain of the second CAR is or contains a cytoplasmic signaling domain of a zeta chain of a CD3-zeta (CD3() chain or a functional variant or signaling portion thereof, optionally a human CD3 zeta chain. In some of any of the provided embodiments of the provided methods, the intracellular signaling region of the second CAR contains the sequence set forth in SEQ ID NO:20 or a sequence of amino acids that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:20.

[0142] In some of any of the provided embodiments of the provided methods or for uses in treating, the intracellular signaling region of the second CAR further contains a costimulatory signaling region. In some of any of the provided embodiments of the provided methods, the costimulatory signaling region of the second CAR contains an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof. In some of any of the provided embodiments of the provided methods, the costimulatory signaling region of the second CAR contains an intracellular signaling domain of a CD28, a 4-1BB or an ICOS or a signaling portion thereof, optionally a human CD28, a human 4-1BB, or a human ICOS. In some of any of the provided embodiments of the provided methods, the costimulatory signaling region of the second CAR contains an intracellular signaling domain of a 4-1BB or a signaling portion thereof, optionally a human 4-1BB. In some of any of the provided embodiments, at least one of the first chimeric antigen receptor and the second chimeric antigen receptor contains an intracellular signaling region containing an intracellular signaling domain of 4-1BB or a signaling portion thereof, optionally of human 4-1BB.

[0143] In some of any of the provided embodiments of the provided methods or for uses in treating, the costimulatory signaling region of the second CAR contains: an intracellular signaling domain of a human CD28; and / or the sequence set forth in SEQ ID NO:46 or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 46.

[0144] In some of any of the provided embodiments of the provided methods or for uses in treating, the costimulatory signaling region of the second CAR contains: an intracellular signaling domain of a human 4-1BB; and / or the sequence set forth in SEQ ID NO:19 or a sequence of amino acids that exhibits at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the sequence set forth in SEQ ID NO: 19.

[0145] In some of any of the provided embodiments of the provided methods or for uses in treating, the encoded second chimeric antigen receptor contains from its N to C terminus in order: the antigen- binding domain, the spacer, the transmembrane domain and the intracellular signaling region.

[0146] Among polynucleotides provided herein are polynucleotides containing (i) a first nucleic acid sequence encoding a first chimeric antigen receptor (CAR) containing a first antigen binding domain; and (ii) a second nucleic acid sequence encoding a second chimeric antigen receptor (CAR) containing a second antigen binding domain; wherein the first CAR and second CAR each contain the following: (a) the first antigen binding domain or the second antigen binding domain, (b) a spacer, (c) a transmembrane domain, and (d) an intracellular signaling region comprising an intracellular signaling domain and a costimulatory signaling region; wherein one or more of (b) through (d) in the first CAR and the same one or more of (b) through (d) in the second CAR contains the identical amino acid sequence; and wherein the nucleotide sequence(s) encoding the one or more of (b) through (d) in the first CAR differs in sequence from the nucleotide sequence(s) encoding the same one or more of (b) through (d) in the second CAR.

[0147] Also provided here are polynucleotides containing (i) a first nucleic acid sequence encoding a first chimeric antigen receptor (CAR) containing a first antigen binding domain capable of binding to one of GPRC5D or BCMA and (ii) a second nucleic acid sequence encoding a second chimeric antigen receptor (CAR) containing a second antigen binding domain capable of binding to the other of GPRC5D or BCMA; wherein the first CAR and second CAR each contain the following: (a) the first antigen binding domain or the second antigen binding domain, (b) a spacer, (c) a transmembrane domain, and (d) an intracellular signaling region comprising an intracellular signaling domain and a costimulatory signaling region; wherein one or more of (b) through (d) in the first CAR and the same one or more of (b) through (d) in the second CAR contains the identical amino acid sequence; and wherein the nucleotide sequence(s) encoding the one or more of (b) through (d) in the first CAR differs in sequence from the nucleotide sequence(s) encoding the same one or more of (b) through (d) in the second CAR.

[0148] In some of any of the provided embodiments, the first and second antigen binding domains bind to the same antigen. In some of any of the provided embodiments, the first and second antigen binding domains bind different epitopes of the same antigen. In some of any of the provided embodiments, the first and second antigen binding domains bind to different antigens. In some of any of the provided embodiments, the first antigen binding domain binds a first antigen expressed by or associated with cells of a disease or condition and the second antigen binding domains binds a second antigen expressed by or associated with cells of the same disease or condition.

[0149] In some of any of the provided embodiments, the disease or condition is a cancer. In some of any of the provided embodiments, the disease or condition is a GPRC5D-expressing cancer. In some of any of the provided embodiments, the disease or condition is a BCMA-expressing cancer. In some of any of the provided embodiments, the disease or condition is a BCMA-expressing and GPRC5D-expressing cancer. In some of any of the provided embodiments, the cancer is a plasma cell malignancy and the plasma cell malignancy is multiple myeloma (MM) or plasmacytoma. In some of any of the provided embodiments, the cancer is multiple myeloma. In some of any of the provided embodiments, the cancer is relapsed / refractory multiple myeloma.

[0150] In some of any of the provided embodiments, the first and second antigen binding domain independently bind to an antigen selected from the group consisting of GPRC5D, BCMA, CD38, CD138, CS-1, BAFF-R, TACI and FcRHS. In some of any of the provided embodiments, the first antigen binding domain binds to B cell maturation antigen (BCMA). In some of any of the provided embodiments, the first antigen binding domain bind to G protein-coupled receptor class C group 5 member D (GPRCSD). In some of any of the provided embodiments, the second antigen binding domain binds to BCMA. In some of any of the provided embodiments, the second antigen binding domain binds to GPRC5D.

[0151] In some of any of the provided embodiments, (a) is or contains the first antigen binding domain or the second antigen binding domain, (b) is or contains a spacer, (c) is or contains a transmembrane domain, and (d) is or contians an intracellular signaling region containing an intracellular signaling domain and a costimulatory signaling region. In some of any of the provided embodiments, the one or more of (b) through (d) is one of (b) through (d). In some of any of the provided embodiments, the one or more of (b) through (d) is two of (b) through (d). In some of any of the provided embodiments, the one or more of (b) through (d) is each of (b) through (d).

[0152] In some of any of the provided embodiments, (a) is or contains the first antigen binding domain or the second antigen binding domain, (b) is or contains a spacer, (c) is or contains a transmembrane domain, and (d) is or contains an intracellular signaling region containing an intracellular signaling domain and a costimulatory signaling region. In some of any of the provided embodiments, the nucleotide sequence(s) encoding the one or more of (a) through (d) in the first CAR and the nucleotide sequence(s) encoding the same one or more of (a) through (d) in the second CAR comprises no more than about 20 consecutive base pairs of sequence homolog; and / or the first nucleic acid sequence encoding the first CAR and the second nucleic acid sequence encoding the second CAR contain no more than about 20 consecutive base pairs of sequence homology. In some of any of the provided embodiments, the nucleotide sequence(s) encoding the one or more of (a) through (d) in the first CAR and the nucleotide sequence(s) encoding the same one or more of (a) through (d) in the second CAR contains no more than between about 5 and about 15 consecutive base pairs of sequence homology; and / or the first nucleic acid sequence encoding the first CAR and the second nucleic acid sequence encoding the second CAR contain no more than about 5 and about 15 consecutive base pairs of sequence homology. In some of any of the prvided embodiments, the nucleotide sequence(s) encoding the one or more of (a) through (d) in the first CAR and the nucleotide sequence(s) encoding the same one or more of (a) through (d) in the second CAR contain no more than about 10 consecutive base pairs of homology; and / or the first nucleic acid sequence encoding the first CAR and the second nucleic acid sequence encoding the second CAR contain no more than about 10 consecutive base pairs of sequence homology.

[0153] In some of any of the provided embodiments, the first nucleic acid encoding the first CAR and the second nucleic acid encoding the second CAR are separated by a nucleotide sequence encoding a multicistronic element, optionally wherein the multicistronic element is a bicistronic element. In some of any of the provided embodiments, the multicistronic element is an IRES or is a ribosome skip sequence or self-cleaving peptide. In some of any of the provided embodiments, the multicistronic element is a ribosome skip sequence or self-cleaving peptide and the ribosome skip sequence or self-cleaving peptide is a T2A, a P2A, an E2A, or an F2A element. In some of any of the provided embodiments, the nucleotide sequence encoding the one or more multicistronic element is codon diverged. In some of any of the provided embodiments, the nucleotide sequence encoding the T2A is codon diverged. In some of any of the provided embodiments, nucleotide sequence encoding the T2A is or contains the sequence set forth in SEQ ID NO:319.

[0154] In some of any of the provided embodiments, the first nucleic acid sequence encoding the first CAR is codon optimized for expression in a human cell. In some of any of the provided embodiments, the second nucleic acid sequence encoding the second CAR is codon optimized for expression in a human cell. In some of any of the provided embodiments, the polynucleotide is codon optimized for expression in a human cell. In some of any of the provided embodiments, following transcription of the polynucleotide in a human cell, optionally a human T cell, the transcribed mRNA, optionally messenger RNA, from the polynucleotide, exhibits at least about 70%, 75%, 80%, 85%, 90%, or 95% RNA homogeneity. In some of any of the provided embodiments, following transcription of the first nucleic acid encoding the first CAR of the polynucleotide in a human cell, optionally a human T cell, the transcribed mRNA, optionally messenger RNA, from the first nucleic acid exhibits at least about 70%, 75%, 80%, 85%, 90%, or 95% RNA homogeneity. In some of any of the provided embodiments, following transcription of the second nucleic acid encoding the second CAR of the polynucleotide in a human cell, optionally a human T cell, the transcribed mRNA, optionally messenger RNA, from the second nucleic acid exhibits at least about 70%, 75%, 80%, 85%, 90%, or 95% RNA homogeneity.

[0155] In some of any of the provided embodiments, any potential splice donor and / or splice acceptor site present in the first nucleic acid encoding the first CAR exhibits a splice prediction score of about or at least about less than 0.70, 0.65, 0.60, 0.55, 0,50, 0.45, 0.40, 0.35, 0.30, 0.25, 0.20 and / or is predicted to be involved in a splice event with a probability of less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%; less than 30%, less than 25%, or less than 20%. In some of any of the provided embodiments, any potential splice donor or acceptor site in the second nucleic acid encoding the second CAR exhibits a splice prediction score of about or at least about less than 0.70, 0.65, 0.60, 0.55, 0,50, 0.45, 0.40, 0.35, 0.30, 0.25, 0.20 and / or is predicted to be involved in a splice event with a probability of less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, or less than 20%. In some of any of the provided embodiments, any potential splice donor or acceptor sites in the polynucleotide exhibits a splice prediction score of about or at least about less than 0.70, 0.65, 0.60, 0.55, 0,50, 0.45, 0.40, 0.35, 0.30, 0.25, 0.20 and / or is predicted to be involved in a splice event with a probability of less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, or less than 20%.

[0156] In some of any of the provided embodiments, the first and / or second antigen binding domain of (a) is a single chain antibody fragment. In some of any of the provided embodiments, the first and / or second antigen binding domain of (a) is or contains a single chain variable fragment (scFv). In some of any of the provided embodiments, the first and / or second antigen binding domain of (a) contains a variable heavy chain (VH) region and a variable light chain (VL) region.

[0157] In some of any of the provided embodiments, the first antigen binding domain or the second antigen binding domain contains a VH region that contains a CDR-HI as set forth in SEQ ID NO:209, a CDR-H2 as set forth in SEQ ID NO:210, and a CDR-H3 as set forth in SEQ ID NO:211 and a VL region that contains a CDR-L1 as set forth in SEQ ID N0O:230, a CDR-L2 as set forth in SEQ ID NO:231, and a CDR-L3 as set forth in SEQ ID NO:232. In some of any of the provided embodiments, one of the first antigen binding domain or the second antigen binding domain contain a VH region and a VL region that contain the amino acid sequences set forth in SEQ ID NOS:197 and 198, respectively. In any of the provided embodiments, the first antigen binding domain or the second antigen binding domain contains the amino acid sequence set forth in SEQ ID NO:241 or a sequence of amino acids that exhibits at least at or about 90%, at least about or about 91%, at least at or about 92%, at least at or about 93%, at least at or about 94%, at least at or about 95%, at least at or about 96%, at least at or about 97%, at least at or about 98%, at least at or about 99% sequence identity to SEQ ID NO:241.

[0158] In any of the provided embodiments, one of the first antigen binding domain or the second antigen binding domain contains a VH region contains a CDR-H1 as set forth in SEQ ID NO:125, a CDR-H2 as set forth in SEQ ID NO:126, and a CDR-H3 as set forth in SEQ ID NO:127 and a VL region that contains a CDR-L1 as set forth in SEQ ID NO:130, a CDR-L2 as set forth in SEQ ID NO:131, and a CDR-L3 as set forth in SEQ ID NO:132. In any of the provided embodiments, one of the first antigen binding domain or the second antigen binding domain contain a VH region and VL region that contain the amino acid sequences set forth in SEQ ID NOS:27 and 28, respectively. In any of the provided embodiments, one of the first antigen binding domain or the second antigen binding domain contain the amino acid sequence set forth in SEQ ID NO:8 or a sequence of amino acids that exhibits at least at or about 90%, at least about or about 91%, at least at or about 92%, at least at or about 93%, at least at or about 94%, at least at or about 95%, at least at or about 96%, at least at or about 97%, at least at or about 98%, at least at or about 99% sequence identity to SEQ ID NO:8.

[0159] In any of the provided embodiments, one of the first antigen binding domain or the second antigen binding domain contains a VH region that contains a CDR-HI as set forth in SEQ ID NO:209, a CDR-H2 as set forth in SEQ ID NO:210, and a CDR-H3 as set forth in SEQ ID NO:211 and a VL region that contains a CDR-L1 as set forth in SEQ ID NO:230, a CDR-L2 as set forth in SEQ ID NO:231, and a CDR-L3 as set forth in SEQ ID NO:232; and the other of the first antigen binding domain or the second antigen binding domain contains a CDR-HI as set forth in SEQ ID NO:125, a CDR-H2 as set forth in SEQ ID NO:126, and a CDR-H3 as set forth in SEQ ID NO:127 and a VL region that contains a CDR-L1 as set forth in SEQ ID NO:130, a CDR-L2 as set forth in SEQ ID NO:131, and a CDR-L3 as set forth in SEQ ID NO:132. In some of any of the provided embodiments, one of the first antigen binding domain or the second antigen binding domain contain a VH region and a VL region that contain the amino acid sequences set forth in SEQ ID NOS:197 and 198, respectively; and the other of the first antigen binding domain or the second antigen binding domain contains a VH region and VL region that contain the amino acid sequences set forth in SEQ ID NOS:27 and 28, respectively. In some of any of the provided embodiments, one of the first or second antigen binding domain contains the amino acid sequence set forth in SEQ ID NO:241 and the other of the first or second antigen binding domain contains the amino acid sequence set forth in SEQ ID NO:8.

[0160] In some of any of the provided embodiments, one of the first or second antigen binding domain is encoded by the nucleotide sequence set forth in SEQ ID NO:310. In some of any of the provided embodiments, one of the first or second antigen binding domain is encoded by a nucleotide sequence set forth in SEQ ID NO:264 or SEQ ID NO: 311. In some of any of the provided embodiments, the first or second antigen binding domain is encoded by the nucleotide sequence set forth in SEQ ID NO:310, and the other of the first or second antigen binding domain is encoded by the nucleotide sequence set forth in SEQ ID NO:311

[0161] In some of any of the provided embodiments, (b) is or contains a spacer. In some of any of the provided embodiments, (b) contains a portion of an immunoglobulin. In some of any of the provided embodiments, (b) contains a sequence of a hinge region, a CH2 and CH3 region. In some of any of the provided embodiments, the hinge region contains all or a portion of an IgG4 hinge region and / or an IgG2 hinge region, wherein the IgG4 hinge region is optionally a human IgG4 hinge region and the IgG2 hinge region is optionally a human IgG2 hinge region; the Cu2 region contains all or a portion of an IgG4 C2 and / or an IgG2 Cu2, wherein the IgG4 Cy2 is optionally a human IgG4 Cy2 and the IgG2 Ca2 is optionally a human IgG2 Cu2; and / or the Cr3 region contains all or a portion of an IgG4 Cu3 and / or an 1gG2 Cw3, wherein the IgG4 Cu3 is optionally a human IgG4 Cg3 and the IgG2 Cr3 is optionally a human IgG2 Cg3. In some of any of the provided embodiments, the hinge region, CH2 and CH3 contains all or a portion of a hinge, all or a portion of a Cy2 and all or a portion of a Cy3 from human IgG4. In some of any of the provided embodiments, one or more of the hinge region, the Cu2 and the Cu3 is chimeric and contains a hinge, Cg2 and Cg3 from human IgG4 and human IgG2. In some of any of the provided embodiments, (b) contains an IgG4 / 2 chimeric hinge region or a modified IgG4 hinge region containing at least one amino acid replacement compared to a human IgG4 hinge; an IgG2 / 4 chimeric Cy2 region; and an IgG4 Cy3 region.

[0162] In some of any of the provided embodiments, (b) is or contains a spacer. In some of any of the provided embodiments (b) has a length from or from about 125 to 300 amino acids in length, 125 to 250 amino acids in length, 125 to 230 amino acids in length, 125 to 200 amino acids in length, 125 to 180 amino acids in length, 125 to 150 amino acids in length, 150 to 300 amino acids in length, 150 to 250 amino acids in length, 150 to 230 amino acids in length, 150 to 200 amino acids in length, 150 to 180 amino acids in length, 180 to 300 amino acids in length, 180 to 250 amino acids in length, 180 to 230 amino acids in length, 180 to 200 amino acids in length, 200 to 300 amino acids in length, 200 to 250 amino acids in length, 200 to 230 amino acids in length, 230 to 300 amino acids in length, 230 to 250 amino acids in length or 250 to 300 amino acids in length, optionally wherein the spacer is at or about 224, at or about 225, at or about 226, at or about 227, at or about 228 or at or about 229 amino acids in length. In some of any of the provided embodiments, (b) is or contains the amino acid sequence set forth in SEQ ID NO:17. In some of any of the provided embodiments, (b) in one of the first CAR or the second CAR is encoded by the nucleotide sequence set forth in SEQ ID NO:48 and (b) in the other of the first CAR or the second CAR is encoded by the nucleotide sequence set forth in SEQ ID NO:305.

[0163] In some of any of the provided embodiments, (c) is or contains a transmembrane domain. In some of any of the provided embodiments, (c) is or contains a transmembrane domain of CD4, CD28, or CD8, optionally a transmembrane domain from human CD4, human CD28 or human CD8. In some of any of the provided embodiments, (c) is or contains a human CD28 transmembrane domain. In some of any of the provided embodiments, (c) is or contains the amino acid sequence set forth in SEQ ID NO:18. In some of any of the provided embodiments, (c) in one of the first CAR or the second CAR is encoded by the nucleotide sequence set forth in SEQ ID NOS:56 and (c) in the other of the first CAR or second CAR is encoded by the nucleotide sequence set forth in SEQ ID NO: 307.

[0164] In some of any of the provided embodiments, (d) is or contains an intracellular signaling region containing an intracellular signaling domain and a costimulatory signaling region. In some of any of the provided embodiments, the intracellular signaling domain of (d) is capable of inducing a primary activation signal in a T cell, is a T cell receptor (TCR) component and / or contains an immunoreceptor tyrosine-based activation motif (ITAM). In some of any of the provided embodiments, the intracellular signaling domain of (d) is or contains a cytoplasmic signaling domain of a CD3-zeta (CD3() chain or a functional variant or signaling portion thereof, optionally a human CD3 zeta chain.). In some of any of the provided embodiments, the intracellular signaling domain of (d) is or contains the amino acid sequence set forth in SEQ ID NO:20. In some of any of the provided embodiments, the intracellular signaling domain of (d) in one of the first CAR or the second CAR is encoded by the nucleotide sequence set forth in SEQ ID NO:58 and the intracellular signaling domain of (d) in the other of the first CAR or the second CAR is encoded by the nucleotide sequence set forth in SEQ ID NO:309.In some of any of the provided embodiments, (d) is or contains an intracellular signaling region containing an intracellular signaling domain and a costimulatory signaling region. In some of any of the provided embodiments, the costimulatory signaling region of (d) contains an intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof. In some of any of the provided embodiments, the costimulatory signaling region of (d) contains an intracellular signaling domain of CD28, 4-1BB, or ICOS, or a signaling portion thereof, optionally of human CD28, human 4-1BB, or human ICOS. In some of any of the provided embodiments, the costimulatory signaling region of (d) contains an intracellular signaling domain of 4-1BB. In some of any of the provided embodiments, the costimulatory signaling region of (d) is or contains the amino acid sequence set forth in SEQ ID NO:19. In some of any of the provided embodiments, the costimulatory signaling region of (d) in one of the first CAR or the second CAR is encoded by the nucleotide sequence set forth in SEQ ID NOS:60 and the costimulatory signaling region of (d) in the other of the first CAR or the second CAR is encoded by the nucleotide sequence set forth in SEQ ID NO:308.

[0165] In some of any of the provided embodiments, (a) is or contains the first antigen binding domain or the second antigen binding domain, (b) is or contains a spacer, (c) is or contains a transmembrane domain, and (d) is or contains an intracellular signaling region containing an intracellular signaling domain and a costimulatory signaling region. In some of any of the provided embodiments, one of the first CAR or the second CAR contains (a) a first antigen binding domain that binds to GPRC5D, optionally wherein the first antigen binding domain is encoded by the nucleotide sequence set forth in SEQ ID NO:311, (b) a spacer encoded by the nucleotide set forth in SEQ ID NO:305, (c) a transmembrane domain encoded by the nucleotide sequence set forth in SEQ ID NO:307, and (d) an intracellular signaling region containing an intracellular signaling domain encoded by the nucleotide sequence set forth in SEQ ID NO:309 and a co-stimulatory signaling region encoded by the nucleotide sequence set forth in SEQ ID NO:308; the other of the first CAR or the second CAR contains (a) an antigen binding domain that binds to BCMA, optionally wherein the antigen binding domain is encoded by the nucleotide sequence set forth in SEQ ID NO:310, (b) a spacer encoded by the nucleotide set forth in SEQ ID NO:48, (c) a transmembrane domain encoded by the nucleotide sequence set forth in SEQ ID NO:56, and (d) an intracellular signaling region containing an intracellular signaling domain encoded by the nucleotide sequence set forth in SEQ ID NO:58 and a co-stimulatory signaling domain region encoded by the nucleotide sequence set forth in SEQ ID NO:60.

[0166] In some of any of the provided embodiments, the first nucleic acid sequence encoding the first CAR is located toward the 5° end of the polynucleotide, relative to the second nucleic acid sequence encoding the first CAR. In some of any of the provided embodiments, the first CAR contains an antigen binding domain that binds to GPRC5D and the second CAR contains an antigen binding domain that binds to BCMA. In some of any of the provided embodiments, the first CAR contains an antigen binding domain that binds to BCMA and the second CAR contains an antigen binding domain that binds to GPRCS5D.

[0167] Also provided herein are polynucleotides containing (i) a first nucleic acid sequence encoding a first chimeric antigen receptor (CAR), (ii) a second nucleic acid sequence encoding a second chimeric antigen receptor (CAR) and (iii) a nucleotide sequence encoding a multicistronic element, wherein the first nucleic acid encoding the first CAR and the second nucleic acid encoding the second CAR are separated by the multicistronic element; wherein the first CAR contains a first antigen binding domain that binds to GPRC5D, optionally wherein the first antigen binding domain is encoded by the nucleotide sequence set forth in SEQ ID NO:311; a spacer encoded by the nucleotide set forth in SEQ ID NO:305; a transmembrane domain encoded by the nucleotide sequence set forth in SEQ ID NO:307; and an intracellular signaling region containing an intracellular signaling domain encoded by the nucleotide sequence set forth in SEQ ID NO:309 and a co-stimulatory signaling region encoded by the nucleotide sequence set forth in SEQ ID NO:308; wherein the second CAR contains a second antigen binding domain that binds to BCMA optionally wherein the second antigen binding domain is encoded by the nucleotide sequence set forth in SEQ ID NO:310; a spacer encoded by the nucleotide set forth in SEQ ID NO:48; a transmembrane domain encoded by the nucleotide sequence set forth in SEQ ID NO:56; and an intracellular signaling region containing an intracellular signaling domain encoded by the nucleotide sequence set forth in SEQ ID NO:58 and a co-stimulatory signaling domain region encoded by the nucleotide sequence set forth in SEQ ID NO:60; and wherein the first nucleic acid sequence encoding the first CAR is located toward the 5° end of the polynucleotide relative to the second nucleic acid sequence encoding the second CAR.

[0168] Also provided herein are polynucleotides containing (i) a first nucleic acid sequence encoding a first chimeric antigen receptor (CAR), (ii) a second nucleic acid sequence encoding a second chimeric antigen receptor (CAR), and (iii) a nucleotide sequence encoding a multicistronic element, wherein the first nucleic acid encoding the first CAR and the second nucleic acid encoding the second CAR are separated by the multicistronic element; wherein the first CAR contains a first antigen binding domain that binds to BCMA, optionally wherein the first antigen binding domain is encoded by the nucleotide sequence set forth in SEQ ID NO:310, a spacer encoded by the nucleotide set forth in SEQ ID NO:48, a transmembrane domain encoded by the nucleotide sequence set forth in SEQ ID NO:56, and an intracellular signaling region containing an intracellular signaling domain encoded by the nucleotide sequence set forth in SEQ ID NO:58 and a co-stimulatory signaling domain region encoded by the nucleotide sequence set forth in SEQ ID NO:60 wherein the second CAR contains a second antigen binding domain that binds to GPRC5D, optionally wherein the second antigen binding domain is encoded by the nucleotide sequence set forth in SEQ ID NO:311, a spacer encoded by the nucleotide set forth in SEQ ID NO:305, a transmembrane domain encoded by the nucleotide sequence set forth in SEQ ID NO:307, and an intracellular signaling region containing an intracellular signaling domain encoded by the nucleotide sequence set forth in SEQ ID NO:309 and a co-stimulatory signaling region encoded by the nucleotide sequence set forth in SEQ ID NO:308; wherein the first nucleic acid encoding the first CAR is located toward the 5° end of the polynucleotide relative to the second nucleic acid sequence encoding the second CAR.

[0169] In some of any of the provided embodiments, the multicistronic element contains the amino acid sequence set forth in SEQ ID NO:37. In some of any of the provided embodiments, the multicistronic element is encoded by a nucleotide sequence set forth in SEQ ID NOS:44 or SEQ ID NO: 45. In some of any of the provided embodiments, the multicistronic element is encoded by a nucleotide sequence set forth in SEQ ID NO:44. In some of any of the provided embodiments, the multicistronic element is encoded by a nucleotide sequence set forth in SEQ ID NO:45. In some of any of the provided embodiments, the multicistronic element is encoded by a nucleotide sequence set forth in SEQ ID NO:319.

[0170] In some of any of the provided embodiments, the polynucleotide contains the nucleotide sequence set forth in SEQ ID NO:299. In some of any of the provided embodiments, the polynucleotide encodes sequence set forth in SEQ ID NO:298.

[0171] In some of any of the provided embodiments, the polynucleotide contains the nucleotide sequence set forth in SEQ ID NO:302. In some of any of the provided embodiments, the polynucleotide encodes the sequence set forth in SEQ ID NO:301.

[0172] In some of any of the provided embodiments, the polynucleotide contains the nucleotide sequence set forth in SEQ ID NO:315. In some of any of the provided embodiments, the polynucleotide contains the nucleotide sequence set forth in SEQ ID NO:316.

[0173] Also provided herein are polynucleotides, wherein a polynucleotide encodes a GPRC5D- binding domain, a BCMA-binding domain, and an intracellular signaling region containing an intracellular signaling domain of a 4-1BB. In some of any of the provided embodiments, the polynucleotide contains the nucleotide sequence set forth in SEQ ID NO:317.

[0174] Also provided are vectors containing any of the provided polynucleotides. In some of any of the provided embodiments, the vector is a viral vector. In some of any of the provided embodiments, the viral vector is a lentiviral vector or a retroviral vector.

[0175] Also provided are engineered cells containing any of the chimeric antigen receptors provided herein. In some of any of the provided embodiments, the engineered cell contains a chimeric antigen receptor provided herein and further contains a polynucleotide containing a sequence of nucleotides encoding a second chimeric antigen receptor.

[0176] Also provided are engineered cells containing any of the polynucleotides provided herein.

[0177] In some of any of the provided embodiments, the engineered cell is a lymphocyte. In some of any of the provided embodiments, the engineered cell is an NX cell or a T cell. In some of any of the provided embodiments, the engineered cell is a T cell and the T cell is a CD4+ or a CD8+ T cell.

[0178] In some of any of the provided embodiments, the engineered cell was engineered from a primary cell obtained from a subject.

[0179] In some of any of the provided embodiments, the engineered cell is among a plurality of the engineered cells, where less than or less than about 10%, 9%, 8%, 7%, 5%, 4%, 3%, 2% or 1% of the cells in the plurality contain a chimeric antigen receptor that exhibits tonic signaling and / or antigen- independent activity or signaling.

[0180] Also provided are compositions containing any of the chimeric receptors provided herein. In some of any of the provided embodiments, the composition contains CD4+ and CD8+ T cells and the ratio of CD4+ to CD8+ T cells is from or from about 1:3 to 3:1. In some embodiments, the ratio of CD4+ and CD8+ T cells in the composition is 1:2 to 2:1. In some embodiments, the ratio of CD4+ and CD8+ T cells in the composition is 1:1. In some of any of the provided embodiments, the composition further contains a pharmaceutically acceptable excipient. In some of any of the provided embodiments, the composition is sterile.

[0181] Also provided herein are methods of treatment, including administering any of the compositions provided herein containing any of the engineered cells provided herein or any of the compositions provided herein containing any of the chimeric antigen receptors provided herein to a subject having a disease or disorder. In some of any of the provided embodiments, the dose of cells contains contain between at or about 2.5 x 10” CAR-expressing T cells and 1.2 x 10° CAR-expressing T cells, between at or about 5.0 x 10’ CAR-expressing T cells and 4.5 x 10% CAR-expressing T cells, between at or about 1.5 x 10® CAR-expressing T cells and 3.0 x 10° CAR-expressing T cells. In some of any embodiments, the dose of cells contains between at or about 1 x 10” CAR-expressing T cells and at or about 2 x 10° CAR-expressing T cells. In some of any embodiments, the dose of cells contains between at or about 2.5 x 10” CAR-expressing T cells and at or about 1.2 x 10° CAR-expressing T cells, between at or about 5.0 x 10” CAR-expressing T cells and at or about 4.5 x 10° CAR-expressing T cells, or between at or about 1.5 x 10% CAR-expressing T cells and at or about 3.0 x 108 CAR-expressing T cells. In some of any embodiments, the dose of cells contains at or about 1.5 x 107, at or about 2.5 x 107, at or about 5.0 x 107, at or about 7.5 x 107, at or about 1.5 x 10%, , at or about 2.25 x 10°, at or about 3.0 x 10%, at or about 4.5 x 10%, at or about 6.0 x 10°, at or about 8.0 x 10° or at or about 1.2 x 10° CAR- expressing T cells. In some of any embodiments, the dose of cells contains at or about 5.0 x 10’, at or about 1.5 x 10%, at or about 3.0 x 10% or at or about 4.5x 10° CAR-expressing T cells. In some of any embodiments, the dose of cells contains at or about 5.0 x 107, at or about 1.5 x 10°, at or about 3.0 x 10° or at or about 4.5x 10% CAR-expressing T cells. In some of any embodiments, the dose of the cells contains at or about 5.0 x 10” CAR-expressing T cells.

[0182] Also provided herein are methods of treatment, including administering any of the compositions provided herein containing any of the engineered cells provided herein or any of the compositions provided herein containing any of the chimeric antigen receptors provided herein to a subject having a disease or disorder. In some of any of the provided embodiments, the dose of cells contains contain between at or about 1.0 x 10” CAR-expressing T cells and 1.2 x 10° CAR-expressing T cells, between at or about 1.5 x 10” CAR-expressing T cells and 4.5 x 10® CAR-expressing T cells, between at or about 2.0 x 107 CAR-expressing T cells and 3.0 x 10° CAR-expressing T cells.

[0183] Also provided here in are methods of treatment, that include: administering a composition containing a plurality of engineered cells containing a first chimeric antigen receptor and a second chimeric antigen receptor, wherein each is any chimeric antigen receptor provided herein or encoded by any of the polynucleotides provided herein, to a subject having a disease or disorder; and administering to the subject a composition containing a plurality of second engineered cells containing a second chimeric antigen receptor. In some of any of the provided embodiments, the dose of the plurality of first engineered cells and the dose of the plurality of second engineered cells independently contain between at or about 1.0 x 107 CAR-expressing T cells and 1.5 x 10° CAR-expressing T cells, between at or about 1.25 x 10” CAR-expressing T cells and 0.6 x 10% CAR-expressing T cells, between at or about 2.5 x 107 CAR-expressing T cells and 2.25 x 10° CAR-expressing T cells, between at or about 7.5 x 10” CAR- expressing T cells and 1.5 x 10% CAR-expressing T cells, between at or about 2.5 x 10” CAR-expressing T cells and 1.2 x 10° CAR-expressing T cells, between at or about 5.0 x 107 CAR-expressing T cells and 4.5 x 108 CAR-expressing T cells, between at or about 1.5 x 108 CAR-expressing T cells and 3.0 x 10° CAR-expressing T cells.

[0184] In some of any of the provided embodiments of the provided methods, the disease or disorder is associated with expression of G protein-coupled receptor class C group 5 member D (GPRC5D).

[0185] In some of any of the provided embodiments of the provided methods, the disease or disorder is further associated with expression of B cell maturation antigen (BCMA).

[0186] In some of any of the provided embodiments of the provided methods, the disease or disorder is a B cell-related disorder. In some of any of the provided embodiments of the provided methods, the disease or disorder associated with BCMA is an autoimmune disease or disorder. In some of any of the provided embodiments of the provided methods, the autoimmune disease or disorder is systemic lupus erythematosus (SLE), lupus nephritis, inflammatory bowel disease, rheumatoid arthritis, ANCA associated vasculitis, idiopathic thrombocytopenia purpura (ITP), thrombotic thrombocytopenia purpura (TTP), autoimmune thrombocytopenia, Chagas’ disease, Grave's disease, Wegener's granulomatosis, poly-arteritis nodosa, Sjogren's syndrome, pemphigus vulgaris, scleroderma, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, vasculitis, diabetes mellitus, Reynaud’s syndrome, anti-phospholipid syndrome, Goodpasture’s disease, Kawasaki disease, autoimmune hemolytic anemia, myasthenia gravis, or progressive glomerulonephritis.

[0187] In some of any of the provided embodiments of the provided methods, the disease or disorder is a cancer. In some of any of the provided embodiments of the provided methods, the cancer is a GPRC5D-expressing cancer. In some of any of the provided embodiments of the provided methods, the cancer is a plasma cell malignancy and the plasma cell malignancy is multiple myeloma (MM) or plasmacytoma. In some of any of the provided embodiments of the provided methods, the cancer is multiple myeloma (MM). In some of any of the provided embodiments of the provided methods, the cancer is a relapsed / refractory multiple myeloma.

[0188] In some of any of the provided embodiments of the provided methods, the subject is refractory to or has relapsed following administration of a BCMA-targeted therapy, optionally following administration of T cells comprising a CAR that specifically binds BCMA. In some of any of the provided embodiments of the provided methods, a subject is selected for treatment that is refractory to or has relapsed following administration of a BCMA-targeted therapy, optionally following administration T cells comprising a CAR that specifically binds BCMA. In some of any of the provided embodiments of the provided methods, prior to the administration of the dose of cells, the subject has previously received administration of a BCMA-targeted therapy for treating the disease or disorder. In some of any of the provided embodiments of the provided methods, prior to the administration of the first dose of cells and the second dose of cells, the subject has previously received administration of a BCMA-targeted therapy for treating the disease or disorder.

[0189] In some of any of the provided embodiments of the provided methods, the BCMA-targeted therapy comprises a composition comprising T cells comprising a CAR that specifically binds BCMA. In some of any of the provided embodiments of the provided methods, the subject is refractory to or has relapsed following administration of the BCMA-targeted therapy, optionally following administration of T cells comprising a CAR that specifically binds BCMA. In some of any of the provided embodiments of the provided methods, the subject comprises multiple myeloma cells exhibiting BCMA antigen or epitope loss, BCMA downregulation amd / or BCMA -negative tumor cells following a previous administration. Brief Description of the Drawings

[0190] FIG. 1A shows Cancer Cell Line Encyclopedia CD138 mRNA expression data (logscale). Type of cancer, from left to right: upper aerodigestive (32); esophagus (25); prostate (7); multiple myeloma (30); bile duct (8); lung (131); pancreas (44); kidney (34); breast (58); colorectal (61); stomach (38); meningioma (3); liver (28); glioma (62); osteosarcoma (10); thyroid (12); endometrium (27); soft tissue (21); mesothelioma (11); ovary (51); chondrosarcoma (4); small cell lung (53); melanoma (61); neuroblastoma (17); medulloblastoma (4); Ewing sarcoma (12); Hodgkin lymphoma (12); DLBCL (18); other lymphoma (28); B-cell (15); CML (15); Burkitt lymphoma (11); T-cell (16); AML (34); other leukemia (1).

[0191] FIG. 1B shows mRNA expression of GPRCS5D in malignant cell lines [n=1036; Cancer Cell Line Encyclopedia (CCLE)]. RMA, robust multi-array average; DLBCL, diffuse large B cell lymphoma; CML, chronic myeloid leukemia; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; NSC, non-small cell. Type of cancer, from left to right: multiple myeloma (30); other leukemia (1); DLBCL (18); CML (15); meningioma (3); other lymphoma (28); Burkitt lymphoma (11); Hodgkin lymphoma (12); T-cell (16); B-cell (15);bile duct (8); AML (34); pancreas (44); thyroid (12); colorectal (61); kidney (34); osteosarcoma (10); urinary tract (27); breast (58); neuroblastoma (17); non-small cell lung (131); Ewing sarcoma (12); prostate (7); melanoma (61); upper aerodigestive (32); endometrium (27); medulloblastoma (4); liver (28); ovary (51); stomach (38); glioma (62); small cell lung (53); mesothelioma (11); esophagus (25); other (150); chondrosarcoma (4).

[0192] FIG. 2A shows CD138 GTEx RNASeq expression data for various organs. Type of tissue, from left to right: cerebellum, cerebral hemisphere, anterior cingulate cortex, frontal cortex, cortex, amygdala, hippocampus, nucleus accumbens, caudate, putamen, sigmoid colon, tibial nerve, skeletal muscle, uterus, muscularis of esophagus, gastroesophagal junction of esophagus, hypothalamus, adipose, cervix, coronary artery, cervical spinal cord, substantia nigra, ovary, tibial artery, mammary tissue, fallopian tube, adipose, kidney, left ventricle, cervix, adrenal gland, bladder, whole blood, skin (sun exposed), skin (not sun exposed), aortic artery, tonsil, small intestine, pancrease, liver, atrial appendage, vagina, stomach, prostate, spleen, cord blood, thyroid, transverse colon, pituitary, mucosa of esophagus, testis, minor salivary gland, lung, bone marrow.

[0193] FIG. 2B shows mRNA expression of GPRC5D in normal tissues according to Gtex RNASeq data (Gtex 708 ENSG00000111291.4). Dashed line represents the level of GPRC5D expression in CD138-sorted primary MM cells (Blueprint RNAseq; n=9). FPKM, fragments per kilobase of transcript per million mapped reads. Type of tissue, from left to right: cerebellum, cerebral hemisphere, anterior cingulate cortex, frontal cortex, cortex, amygdala, hippocampus, nucleus accumbens, caudate, putamen, sigmoid colon, tibial nerve, skeletal muscle, uterus, muscularis of esophagus, gastroesophagal junction of esophagus, hypothalamus, adipose, cervix, coronary artery, cervical spinal cord, substantia nigra, ovary, tibial artery, mammary tissue, fallopian tube, adipose, kidney, left ventricle, cervix, adrenal gland, bladder, whole blood, skin (sun exposed), skin (not sun exposed), aortic artery, tonsil, small intestine, pancrease, liver, atrial appendage, vagina, stomach, prostate, spleen, cord blood, thyroid, transverse colon, pituitary, mucosa of esophagus, testis, minor salivary gland, lung, primary MM (bone marrow).

[0194] FIG. 2C shows GPRC5D mRNA expression by Blueprint RNAseq for primary human tissue cell types. FPKM, fragments per kilobase of transcript per million mapped reads.

[0195] FIG. 3A shows Kaplan-Meier curves for progession free survival (PFS) stratified by subjects with MM whose GPRCSD expression by RNA-seq was either above (>) or below (<) median GPRC5D expression. Significance was determined by log-rank test of equal hazards (p=0.0031; n=765).

[0196] FIG. 3B shows international staging system (ISS) scores for subjects with MM, stratified by GPRCS5D expression level (n=369 above median, 374 below median).

[0197] FIGS. 3C-3H show the frequency of common cytogenetic abnormalities among MM subjects, stratified by GPRC5D expression level (n=287-291 above median, 280-282 below median).

[0198] FIG. 4A shows outlier boxplot quantification of GPRCS5D protein on cell lines, following immunohistochemical detection. The outlier boxplots indicate median membrane optical density and interquartile range (IQR); whiskers are 1.5XxIQR. Mean fluorescence intensity (MFI) of GPRCSD expression in K562 cells engineered to express the protein is given by the number following the K562- GPRCS5D designated cell line.

[0199] FIG. 4B shows automated quantitative immunofluorescence in 83 bone marrow samples from MM patients. Each column represents an individual patient sample.

[0200] FIG. 4C shows the percent of patient samples in which greater than 50% of CD138+ cells expressed BCMA, GPRC5D, or BCMA or GPRCS5D as determined by automated quantitative immunofluorescence in 83 bone marrow samples from MM patients.

[0201] FIG. 4D shows the correlation of BCMA and GPRCSD expression on CD138+ cells; R= 0.156.

[0202] FIG. 5 shows linear, conformational, and discontinuous epitope binding of a subset of GPRC5D-targeted scFvs assessed by ELISA-based technology.

[0203] FIGS. 6A and 6B show antigen-independent (tonic) signaling of CARs containing the indicated scFvs and spacers. Jurkat Nur77-RFP reporter cells were transduced with 1 of 42 CAR / GFP bicistronic constructs. 5x10° viable GFP+ Jurkat cells were plated and monitored for RFP expression 11 days after transduction in the absence of target antigen. Expression of both RFP and GFP indicated tonic signaling; expression of GFP alone indicated CAR transduced without tonic signaling.

[0204] FIG. 6C-6E depict antigen-dependent vs. antigen-independent signaling of candidate CARs with long (FIG. 6C), medium (FIG. 6D), and short (FIG. 6E) spacers, measured after culturing Jurkat Nur77-RFP reporter cells 2:1 with MM.1S cells (expressing endogenous GPRC5D) for 20h. Percent CAR T cell signaling determined by: RFP+GFP+ / total GFP+ cells. Data representative of 2 experiments.

[0205] FIG. 6F shows CAR-transduced cells indicated as GFP+ along the y-axis. RFP, a surrogate for Nur77 expression, is shown along the x-axis. Percentages shown are of transduced GFP+ cells only (top quadrants only) that are RFP+.

[0206] FIG. 7A depicts binding of HEK293 cells transiently expressing one of a library of human G-protein coupled receptors (GPCR) with cytoplasmic GFP to co-cultured HEK293 cells transiently expressing anti-GPRC5D scFv clone 203, a long spacer, and cytoplasmic mCherry 761 (both in suspension), quantified by automated flow cytometric analysis. Pre-specified threshold for significance (red line): Z-score 3; p<0.0027.

[0207] FIG. 7B shows binding of anti-GPRCSD scFv clone 203 mIgG2a Fc chimeric antibody to HEK293 cells expressing the indicated cell surface proteins. Shown is confirmation of binding to potential off-target proteins and non-specific binders identified in a microarray screen of >4400 transmembrane proteins. ZsGreenl, transfection control; Isotype, irrelevant scFv-mIgG2a Fe negative control; CTLA-4 / CD86 interaction, positive control.

[0208] FIG. 7C shows results of evaluation of potential off-target proteins PCDH1A or FCGR2A to activate through the GPRC5D (203) CAR. Jurkat Nur77-RFP activation reporter cells expressing a bicistronic plasmid containing a GPRC5D (203) CAR and GFP were co-cultured with K562 cells expressing the indicated antigens, GPRCS5D (positive control), or BCMA (negative control). Activation was determined as %RFP+GFP+ / total GFP+ cells.

[0209] FIG. 7D shows that CRISPR-Cas9-mediated knockout of GPRCSD from a MM cell line abolished activation of GPRC5D (203) CAR-Jurkat Nur77 reporter cells, as assessed by measuring changes in RFP expression by flow cytometry.

[0210] FIG. 8A shows GPRC5D mRNA expression across MM cell lines and primary MM cells (boxed).

[0211] FIG. 8B shows results of GPRCS5D (203)-expressing CAR T cell cytotoxicity against MML1.S, OPM2, and RPMI-8226 target cells after 24 h of co-culture, as indicated by percent lysis, normalized to donor matched, mock-transduced CAR T cells (technical triplicates in each of two donors; mean + SD).

[0212] FIG. 9A shows cell killing of OPM2-ffLuc MM cells induced by CAR T cells incorporating the indicated scFv after 24 h of co-culture, as indicated by ATP-dependent bioluminescence after addition of luciferin; normalized to tumor cell-alone control (pooled data from 2 experiments each performed in triplicate, mean + SEM; p<0.001).

[0213] FIG. 9B and 9C depict flow cytometry analysis depicting killing of primary bone marrow mononuclear cells (BMMCs) from a patient with multiply relapsed MM after overnight co-culture with anti-GPRC5D CAR T cells at a 1:1 ratio CAR+ T cells:BMMCs. MM cells, CD138+ / CD38hi; plots gated on viable, CD3- cells.

[0214] FIG. 9D depicts flow cytometry analysis of primary BMMCs from additional patients, plotted for CD138+ / CD3-.

[0215] FIGS. 10A to 10C show cytokines produced by CAR T cells incorporating the indicated scFv after co-culture 1:1 with OPM2 MM cells, or alone, for 24h, measured in the supernatant by multiplex luminex assay.

[0216] FIGS. 11A and 11B show proliferation and FIGS. 11C and 11D show activation of mock- transduced or GPRC5D (203)-expressing CAR T cells cultured alone, with B-ALL (Nalmé; GPRC5D-), or MM (OPM2; endogenous GPRC5D+) cells at a 1:1 ratio. T cells were stained with CellTrace Violet (CTV) before co-culture, and stained for CD4, CD8, and CD25 after 72 h. (A, B) Proliferation is indicated by dilution of CTV fluorescence. (C, D) Activation is indicated by increased CD25 fluorescence.

[0217] FIG. 12A depicts representative FACS analysis of CAR expression in the CAR T cells, measured using an antibody specific to the spacer.

[0218] FIG. 12B depicts survival of mice treated 14 days post-OPM2 injection with 3x10° 4-1BB containing CAR T cells incorporating the indicated anti-GPRC5D scFv clones (n=8 / arm).

[0219] FIG. 12C depicts mouse tumor volume and survival in an RPMI-8226 xenograft model from one of two experiments; median days of survival 29 vs. 50 (p<0.05; n=>5 / arm, representative of two experiments).

[0220] FIG. 12D depicts mouse tumor volume and CAR T cell expansion in an RPMI-8226 xenograft model, as monitored by flow cytometry of peripheral blood using an antibody to the spacer to detect the CAR (p<0.001; n=10 / arm; both timepoints).

[0221] FIG. 13A depicts survival of mice treated at 21 days post-OPM2 injection with 3x10° T cells gene modified to express a bicistronic construct encoding extGLuc and a CAR incorporating scFv CD19 (SJ25C1) or GPRCS5D (203) and either a 4-1BB or CD28 co-stimulatory domain (n=5 / arm).

[0222] FIGS. 13B, C, and D depict tumor burden (D-luciferin bioluminescence imaging [BLI] of OPM-ffLuc) of mice from FIG. 13A.

[0223] FIG. 13E shows results of CAR T cell homing (coelenterazine BLI of extGLuc CAR T cells) of mice from FIG. 13A performed on day 7 post-CAR T cell treatment.

[0224] FIGS. 14A and 14B show dose response of GPRC5D-targeted and BCMA-targeted CAR T cell therapy, administered 14 days post-OPM2 injection (n=8 mice / arm). In FIG. 14A, tumor burden as assessed by BLI of OPM-ffLuc is shown. In FIG. 14B, percent survival is shown (p-values shown are vs. mock transduced or irrelevantly targeted CAR T cells).

[0225] FIG. 15A-15C depict IFN-gamma (FIG. 15A), TNF-alpha (FIG. 15B), and IL-2 (FIG. 15C) levels following 20 hours co-culture of GPRC5D (203), anti-BCMA, or mock-processed T cells with twenty different normal primary human cell types or OPM2 cells (mean + SD).

[0226] FIG. 15D depicts results from screening of murine and cynomolgus cross-reactive scFv clones for tonic signaling. %RFP+ indicates activation after co-culture at an effector:target ratio of 1:1 (relative to GFP+ CAR-transduced cells).

[0227] FIGS. 16A-C shows body mass change (FIG. 16A), body temperature (FIG. 16B) or BLI of OPM2-ffLuc cells (FIG. 16C) following injection of mice with 3 x 10° human T cells expressing a CAR containing a human / murine cross-reactive anti-GPRC5D scFv (clone 205).

[0228] FIG. 17A shows representative FACs analysis of CAR expression as measured using a truncated receptor surrogate marker in non-human primate (NHP) T cells transduced to express either the cynomolgus cross-reactive GPRC5D CAR or cynomolgus GPRC5D.

[0229] FIG. 17B shows target lysis and FIG. 17C shows IFNy production by NHP T cells transduced to express either the cynomolgus cross-reactive GPRC5D CAR or mock T cells against autologous target antigen presenting cells (tAPCs) at various effector to target (E:T) ratios.

[0230] FIG. 17D shows target lysis and FIG. 17E shows IFNy production by NHP T cells transduced to express either the cynomolgus cross-reactive GPRC5D CAR or mock T cells against target K562 or K562-GPRCS5D cells at various effector to target (E:T) ratios.

[0231] FIG. 18A shows results of PCR for the DNA encoding the CAR as a measure of CAR T cell persistence in the peripheral blood and bone marrow at day 21 after infusion. CAR transduced NHP T cells were used as a positive control.

[0232] FIG. 18B-D show results of pathologic evaluation 1 to 21 days after injection of cynomolgus monkeys with cynomolgus T cells modified to express a CAR containing a human / cynomolgus cross- reactive anti-GPRC5D scFv clone 202. FIG. 18B depicts body temperature, FIG. 18C depicts body mass change, and FIG. 18D depicts body mass.

[0233] FIG. 19A depicts BLI images at days 7 and 15 and FIG. 19B depicts images at day 34 of mice injected on day 0 with 1x10° mixed population of OPM2WT cells and OPM23MAXO (GFP / ffLuc+) cells and injected on days 8 and 16 with 3x10° of the indicated CAR T-cells. n=5 mice / arm, representative of 2 experiments.

[0234] FIGS. 20A and 20B show OPM2 cells in the bone marrow of mice injected with a mixed population OPM2 cells and CAR T-cells as described in FIGS. 19A and 19B. Representative plots of 3 mice per arm. Live / dead gating performed but not shown (n=2 replicate experiments with comparable results).

[0235] FIG. 21A shows minimal tonic signaling through an exemplary anti-BCMA CAR.

[0236] FIG. 21B shows lysis of target cells by primary human T cells expressing the exemplary anti-BCMA CAR.

[0237] FIG. 21C shows IFN-gamma secretion by primary human T cells expressing the exemplary anti-BCMA CAR upon co-culture with target cells.

[0238] FIG. 22A shows a loss of GPRC5D expression or BCMA expression, as assessed by flow cytometry, in OPM2 cells with GPRC5D or BCMA knocked out, respectively.

[0239] FIG. 22B shows antigen-specific activation of exemplary anti-BCMA and anti-GPRC5D CARs.

[0240] FIG. 23 shows BCMA and GPRCS5D gene expression levels in multiple myeloma cell lines.

[0241] FIG. 24 shows BCMA and GPRCSD protein expression levels in multiple myeloma and control cell lines.

[0242] FIGS. 25A and 25B show OPM2 tumor burden in mice injected with either OPM2 WT cells (FIG. 25A), OPM2 BCMA KO cells (FIG. 25B; top panel) or OPM2 GPRC5D KO cells (FIG. 25B; bottom panel). Mice were treated with cell compositions containing cells expressing an anti-BCMA CAR (BCMA) or an anti-GPRCS5D CAR (GPRCSD), or containing a pool of cells generated to contain anti- BCMA CAR-expressing cells and anti-GPRC5D CAR-expressing cells at a 1:1 ratio (GPRC5D and BCMA pooled cells).

[0243] FIG. 26 shows percent survival of mice injected with OPM2 tumor cells and treated with three different doses of cells expressing an anti-GPRC5D CAR (GPRCSD) or an anti-BCMA CAR (BCMA), or a pool of anti-BCMA CAR-expressing cells and anti-GPRC5D CAR-expressing cells (GPRCS5D and BCMA pooled cells).

[0244] FIG.27 shows tumor volume in mice injected with RPMI8226 cells and treated with three different doses of cells expressing an anti-GPRC5D CAR (GPRCSD) or an anti-BCMA CAR (BCMA), or a pool of anti-BCMA CAR-expressing cells and anti-GPRC5D CAR-expressing cells (GPRC5D and BCMA pooled cells).

[0245] FIG. 28 shows percent survival of mice from FIG. 27.

[0246] FIG. 29 depicts anti-BCMA and anti-GPRC5D dual-targeting strategies. (i) and (ii) represent pools of anti-BCMA CAR-expressing cells and anti-GPRC5D CAR-expressing cells (GPRC5D and BCMA pooled cells). (iii) and (iv) represent bicistronic constructs, each containing an anti-BCMA CAR and an anti-GPRC5D CAR separated by a self-cleaving peptide. (v) represents a “single stalk” CAR approach, wherein an anti-BCMA scFv and an anti-GPRC5D scFv are in tandem, separated only by a linker.

[0247] FIG. 30 shows expression of the indicated construct on the surface of cells, following retroviral transduction of cells with the respective constructs from FIG. 29.

[0248] FIG. 31 shows the retroviral transduction efficiency of each of the constructs depicted in FIG. 29, as assess by flow cytometric analysis.

[0249] FIG. 32A depicts the cytotoxicity of T cells expressing the constructs depicted in FIG. 29 upon co-culture with a wild-type OPM2 multiple myeloma cell line, as indicated by the percentage of lysed tumor cells. CAR-expressing T cells and target cells were cultured at increasing E:T ratios.

[0250] FIG. 32B depicts the cytotoxicity of cells expressing the constructs depicted in FIG. 29 upon co-culture with a BCMA knockout OPM2 cell line, as indicated by the percentage of lysed tumor cells. CAR-expressing T cells and target cells were cultured at increasing E:T ratios.

[0251] FIG. 33A shows the ability of T cells expressing the indicated CAR constructs to secrete various cytokines when co-cultured with BCMA- and GPRC5D-expressing target cells for 24 hours.

[0252] FIG. 33B shows the ability of T cells expressing the indicated CAR constructs to secrete various cytokines when co-cultured with BCMA-expressing, GPRC5D-negative target cells for 24 hours.

[0253] FIG. 33C shows the ability of T cells expressing the indicated CAR constructs to secrete various cytokines when co-cultured with GPRC5D-expressing, BCMA-negative target cells for 24 hours.

[0254] FIG. 34A depicts the survival of mice injected with OPM2 wild-type cells, following treatment with T cells expressing the indicated CAR(s).

[0255] FIG. 34B depicts the survival of mice from FIG. 34A after a second injection with BCMA knockout OPM2 cells, following treatment with T cells expressing the indicated CAR(s).

[0256] FIGS. 35A-C depict tumor growth, as assessed via bioluminescence imaging, in mice 30 days (FIG. 35A) or 105 days (FIG. 35B) after an initial injection with BCMA knockout OPM2 cells (2 x 10%), or 36 days (FIG. 35C) following a second injection with BCMA knockout OPM2 cells (3 x 10°), following treatment with 3 x 106 CAR-expressing T cells.

[0257] FIG. 36 shows the survival of mice treated with a lower dose (5 x 10°) of cells expressing the indicated CAR(s), following injection with 2 x 106 wild-type OPM2 cells.

[0258] FIGS. 37A-C depict tumor burden in mice, as assessed via bioluminescence imaging, injected with wild-type OPM2 cells, following 0 days (FIG. 37A), 15 days (FIG. 37B), or 22 days (Fig. 37C) of treatment with cells expressing the indicated CAR(s).

[0259] FIG. 38 depicts tumor burden in mice injected with a mixed composition of wild-type and 5- 10% BCMA knockout OPM2 cells, as assessed via bioluminescence imaging of wild-type OPM2 cells (left panel) and BCMA knockout OPM2 cells (right panel), following treatment with 5 x 10° cells expressing the indicated CAR(s).

[0260] FIG. 39 shows the survival of mice injected with a mixed composition of wild-type and 5- 10% BCMA knockout OPM2 cells, following treatment with 2.5 x 10° cells expressing the indicated CAR(S).

[0261] FIGS. 40A-C depict tumor burden in mice, as assessed via bioluminescence imaging, injected with a mixed composition of wild-type and 5-10% BCMA knockout OPM2 cells, 0 days (FIG. 40A), 22 days (Fig. 40B), or 34 days (FIG. 40C) following treatment with 5 x 10° cells expressing the indicated CAR(s).

[0262] FIGS. 41A and 41B show loss of expression of the trailing CAR (BCMA and GPRC5D, respectively) in non-codon diverged bicistronic constructs.

[0263] FIGS. 42A and 42B show the codon divergence of the bicistronic constructs rescues expression of the trailing CAR (BCMA and GPRCS5D, respectively).

[0264] FIG. 43 shows stimulation of Jurkat Nur77-RFP reporter cells expressing the indicated CAR(s) following co-culture with target cells.

[0265] FIGS. 44A-C show the expression of IFN-gamma, IL-2, and TNF-alpha (respectively) by primary human T cells expressing the indicated CAR(S), upon co-culture with target cells.

[0266] FIG. 45 shows antigen-specific activation of Jurkat Nur77-RFP reporter cells transduced with the indicated CAR(s), upon co-culture with OPM2 WT cells, OPM2 BCMA KO cells, or OPM2 GPRCS5D KO cells.

[0267] FIGS. 46A-C show the expression of IFN-gamma, IL-2, and TNF-alpha (respectively) by primary human T cells expressing the indicated CAR(s), when cultured with OPM2 WT cells, OPM2 BCMA KO cells, or OPM2 GPRC5D KO cells.

[0268] FIG. 47A shows tumor burden (as assessed by BLI) in mice injected with OPM2 WT cells and treated with cells expressing the indicated CAR(s). FIGS. 47B and 47C show tumor burden (as assessed by BLI) in mice injected with a combination of OPM2 WT and BCMA KO cells (FIG. 47B) or a combination of OPM2 WT and GPRC5D KO cells (FIG. 47C) and treated with cells expressing the indicated CAR(s).

[0269] FIG. 48 shows the percent survival of mice from FIGS. 47A-C. Detailed Description

[0270] Provided herein are chimeric antigen receptors (CARs) targeting or directed to G Protein- Coupled Receptor Class C Group 5 Member D (GPRCS5D) and GPRCS5D-expressing cells and disease. Also provided are cells, such as T cells, engineered to express a provided anti-GPRC5D CAR and compositions containing such cells. It is observed that GPRCS5D is expressed, e.g., heterogeneously expressed, in certain diseases and conditions such as malignancies, or on tissues or cells thereof, e.g., on malignant plasma cells such as from relapsed or newly diagnosed myeloma patients, for example, with little expression on normal tissues. Among the provided embodiments are approaches useful in the treatment of diseases and conditions and / or for targeting such cell types, including nucleic acid molecules that encode GPRC5D-binding receptors, including chimeric antigen receptors (CARs), and the encoded receptors such as the encoded CARs, and compositions and articles of manufacture comprising the same. The receptors generally can contain antibodies (including antigen-binding antibody fragments, such as heavy chain variable (Vy) regions, single domain antibody fragments and single chain fragments, including scFvs) specific for GPRCSD. Also provided are cells, such as engineered or recombinant cells expressing such GPRC5D-binding receptors, e.g., anti-GPRCSD CARs and / or containing nucleic acids encoding such receptors, and compositions and articles of manufacture and therapeutic doses containing such cells.

[0271] Adoptive T cell therapies, such as CAR-T cell therapies, have shown promise for treating multiple myeloma, with clinical efforts primarily focused on targeting theB cell maturation antigen (BCMA). However, although BCMA is expressed on many malignant plasma cells, expression levels, in some cases, can be heterogeneous. In some aspects, heterogeneity in target antigen expression can lead to variable or inconsistent response. In some aspects, it also has been observed that expression of BCMA on the cell surface varies over time due to gamma secretase-mediated shedding of the extracellular domain. Similar to observations with CD19 and CD22 CAR antigens, it has been reported that BCMA antigen down-regulation occurs in multiple myeloma (MM) patients who relapsed after BCMA-targeted T cell therapy (Brudno et al. (2018) J. Clin. Oncol., JCO2018778084,; Cohen et al. (2017) Blood 130:505). Also, in some contexts, recombinant receptors can exhibit antigen-independent activity or signaling (also known as “tonic signaling”), which could lead to undesirable effects, such as due to increased differentiation and / or exhaustion of T cells that express the recombinant receptor. In some aspects, such activities may limit the T cell's activity, effect or potency. In some cases, during engineering and ex vivo expansion of the cells for recombinant receptor expression, the cells may exhibit phenotypes indicative of exhaustion, due to tonic signaling through the recombinant receptor. In some cases, alternative or additional MM-targeted T cell therapy approaches are needed.

[0272] The provided embodiments relate to GPRC5SD as a CAR T cell target for multiple myeloma. GPRCSD (Uniprot Acc. No. QONZD], e.g. set forth in SEQ ID NO:49) is a G protein coupled receptor class C, group 5 member D that belongs to the RAIG (retinoic acid-inducible gene-1) family. It is a seven transmembrane helix 39kDa G-protein coupled receptor with two reported isoforms, with the isoform differences occurring in the intracellular C terminus of the protein. Results herein show that GPRC5D is expressed at high levels in multiple myeloma and, overall, it is expressed at low levels in most normal tissues.

[0273] The observations herein demonstrate protein expression of GPRCSD on multiple myeloma cells, supporting it as a feasible CAR T cell target for treating MM, including based on evaluation of potential on target / off tumor toxicity. Furthermore, among provided chimeric antigen receptors are chimeric receptors that display low tonic signaling, thereby minimizing possibility of antigen- independent (tonic) signaling. In particular, anti-GPRC5D CARs provided herein include CARs with high antigen-dependent activation and minimal tonic signaling. In particular, it is found that certain constructs, including those with a particular orientation of the variable heavy (VH) and variable light (VL) chain in the extracellular portion of the antibody fragment of the CAR and / or that contain a spacer of a certain length, exhibit advantageous properties including high antigen-dependent activation and low tonic signaling compared to alternative anti-GPRC5D CAR formats, such as those with shorter spacers.

[0274] In some embodiments, the spacer generally is a sequence of amino acids located between, such that connects, the extracellular antigen-binding domain and the transmembrane domain of the CAR. In particular embodiments of anti-GPRC5D CARs the spacer is a portion of an immunoglobulin, e.g. from IgG4 or IgG2, such as a portion containing, a hinge domain, a CH2 domain and a CH3 domain. Among such spacers are portions of human immunoglobulins or modified forms thereof, including those that have a length of greater than 125 amino acids in lengths, such as greater than 150 amino acids, greater than 180 amino acids, greater than 200 amino acids or greater than 200 amino acids in length. In some embodiments, an immunoglobulin spacer is a hybrid or chimeric spacers and / or is modified, such as to reduce or prevent glycosylation. In some embodiments, a provided anti-GPRC5D CAR includes an 1gG4 / 1gG2 hinge — IgG4 / IgG2 CH2 — IgG4 CH3 immunoglobulin hybrid / modified spacer, such as set forth in SEQ ID NO:17.

[0275] In some embodiments, among CARs provided herein are those encoded by polynucleotides that are optimized, or contain certain features designed for optimization, such as for codon usage, to reduce RNA heterogeneity and / or to modify, e.g., increase or render more consistent among cell product lots, expression, such as surface expression, of the encoded receptor. In some embodiments, polynucleotides, encoding GPRC5D-binding cell surface proteins, are modified as compared to a reference polynucleotide, such as to remove cryptic or hidden splice sites, to reduce RNA heterogeneity. In some embodiments, polynucleotides, encoding GPRC5D-binding cell surface proteins, are codon optimized, such as for expression in a mammalian, e.g., human, cell, such as in a human T cell. In some aspects, the modified polynucleotides result in in improved, e.g., increased or more uniform or more consistent level of, expression, e.g., surface expression, when expressed in a cell. Such polynucleotides can be utilized in constructs for generation of engineered cells that express the encoded GPRC5D- binding cell surface protein. Thus, also provided are cells expressing the recombinant receptors encoded by the polynucleotides provided herein and uses thereof in adoptive cell therapy, such as treatment of diseases and disorders associated with GPRCS5D expression, e.g., multiple myeloma.

[0276] Provided are monotherapy approaches utilizing anti-GPRC5D CAR expressed on autologous primary T cells for use as a therapeutic agent against multiple myeloma plasma cells. In some embodiments, a monotherapy approach may be desirable in subjects known or suspected or selected as having low or no BCMA-expressing MM plasma cells, and / or that have relapsed following remission, are refractory to, have failed treatment with or are intolerant to treatment with an anti-BCMA CAR.

[0277] Also provided herein are multi-targeting strategies that targes a first antigen and a second antigen associated with a particular disease or condition, such as multiple myeloma. In some embodiments, multiple recombinant receptors specifically bind or target different antigens are encoded by the same polynucleotide constructs, or included in the same cells, compositions, and methods provided herein. In some embodiments, the plurality of antigens, e.g., the first antigen and the second antigen, are expressed or suspected of being expressed on the cell, tissue, or disease or condition being targeted, such as on the cancer cell. In some aspects, the cell, tissue, disease or condition is multiple myeloma or a multiple myeloma cell.

[0278] For example, also provided herein is a dual therapy targeting approach of anti-GPRC5D CAR-expressing cells in combination with anti-BMCA CAR-expressing cells for use as a therapeutic agent against MM plasma cells. In some aspects, a dual targeting approach may be advantageous to overcome limitations associated with heterogeneous expression of BCMA and / or GPRC5D on MM plasma cells. It is observed that GPRCS5D and BCMA are expressed, e.g., heterogeneously expressed, in certain diseases and conditions such as malignancies, or on tissues or cells thereof, e.g., on malignant plasma cells such as from relapsed or newly diagnosed myeloma patients, for example, with little expression on normal tissues. Due to the roles of GPRCSD and BCMA in various diseases and conditions, including cancer, both GPRC5D and BCMA are therapeutic targets.

[0279] In some cases, simultaneously targeting both antigens as provided herein may improve the depth and durability of responses across patients, in addition to minimizing relapse due to antigen escape. A mechanism of resistance to CAR T-cell therapies, as evidenced by data from CAR T-cell trials in B- cell malignancies, may be the loss or downregulation (“escape”) of the target antigen. (Robbie G. Majzner and Crystal L. Mackall, Cancer Discov August 22 2018; DOI 10.1158 / 2159-8290.CD-18-0442). Such a combination or dual targeting strategy may achieve synergistic or improved tumor responses based on targeting two antigens compared to monotherapy approaches involving only single antigen targeting. Indeed, studies herein demonstrate that BCMA and GPRCS5D expression are independent of each other. A dual targeting approach may be advantageous to overcome problems due to potential for antigen loss and / or to maximize antigen targeting in MM. The observations herein demonstrate protein expression of GPRC5D, BCMA, or both, on multiple myeloma cells, supporting both antigens as feasible CAR T cell targets for treating MM, including based on evaluation of potential on target / off tumor toxicity.

[0280] Among the provided embodiments are approaches useful in the treatment of diseases and conditions and / or for targeting such cell types, including nucleic acid molecules that encode GPRC5D- binding receptors and BCMA -binding receptors, including chimeric antigen receptors (CARs), and the encoded receptors such as the encoded CARs, and compositions and articles of manufacture comprising the same. The receptors generally can contain antibodies (including antigen-binding antibody fragments, such as heavy chain variable (Vx) regions, single domain antibody fragments and single chain fragments, including single chain variable fragments (scFvs)) specific for GPRC5D or BCMA. Also provided are cells, such as engineered or recombinant cells expressing such GPRC5D-binding receptors, e.g., anti- GPRC5D CARs, and BCMA-binding receptors, e.g. anti-BCMA CARs, and / or containing nucleic acids encoding such receptors, and compositions and articles of manufacture and therapeutic doses containing such cells. Among provided embodiments are polynucleotides that are bicistronic for expression of multiple CARs, such as an anti-GPRCD CAR and an anti-BCMA CAR. The observations herein demonstrate that expression of multiple CARs, e.g. an anti-GPRC5D CAR and an anti-BCMA CAR, in a cell can be improved by codon diverging a polynucleotide sequence encoding one or more of the CARs. It is found that codon divergence of a polynucleotide construct encoding two CARs improves expression of a nucleotide sequence encoding a CAR that is 3’ prime (or C-terminal) relative to nucleotide sequence encoding the other CAR.

[0281] Additionally, it is found that provided CARs containing a spacer of a certain length, exhibit advantageous properties including high antigen-dependent activation and low tonic signaling compared to alternative anti-GPRC5D or anti-BCMA CAR formats, such as those with shorter spacers. In some embodiments, the spacer component of a CAR generally is a sequence of amino acids located between, such that connects, the extracellular antigen-binding domain and the transmembrane domain of the CAR. In particular embodiments of an anti-GPRCS5D or an anti-BCMA CAR, the spacer is a portion of an immunoglobulin, e.g. from IgG4 or IgG2, such as a portion containing, a hinge domain, a CH2 domain and a CH3 domain. Among such spacers are portions of human immunoglobulins or modified forms thereof, including those that have a length of greater than 125 amino acids in lengths, such as greater than 150 amino acids, greater than 180 amino acids, greater than 200 amino acids or greater than 200 amino acids in length. In some embodiments, an immunoglobulin spacer is a hybrid or chimeric spacers and / or is modified, such as to reduce or prevent glycosylation. In some embodiments, a provided anti-GPRC5D or anti-BCMA CAR includes an IgG4 / IgG2 hinge — IgG4 / IgG2 CH2 — IgG4 CH3 immunoglobulin hybrid / modified spacer, such as set forth in SEQ ID NO:17. In particular embodiments, the polynucleotide encoding the CAR contains a spacer region that has been modified to eliminate splice sites, such as cryptic splice and / or acceptor sites. Exemplary nucleotides encoding the spacer are described. In some embodiments, the coding sequence for the spacer comprises the nucleic acid sequence set forth in SEQ ID NO: 48 (also set forth in SEQ ID NO: 74). In some embodiments, the provided CARs exhibit reduced RNA heterogeneity when expressed in cells (e.g. T cells). In some embodiments, the provided polynucleotides encoding the CARs also can be codon optimized to further improve expression.

[0282] All publications, including patent documents, scientific articles and databases, referred to in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference. If a definition set forth herein is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications and other publications that are herein incorporated by reference, the definition set forth herein prevails over the definition that is incorporated herein by reference.

[0283] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. IL GPRC5D-Binding Receptors and Encoding Polynucleotides

[0284] Provided in some aspects are GPRC5D-binding agents, such as recombinant receptors or chimeric antigen receptors that bind GPRCS5D molecules and polynucleotides encoding GPRC5D binding cell surface proteins, such as recombinant receptors (e.g., CARs), and cells expressing such receptors. The GPRC5D-binding cell surface proteins generally contain antibodies (e.g., antigen-binding antibody fragments), and / or other binding peptides that specifically bind to GPRC5D, such as to GPRCS5D proteins, such as human GPRC5D protein. In some aspects, the agents bind to an extracellular portion of GPRC5D.

[0285] Among the provided polynucleotides are those that encode recombinant receptors, such as antigen receptors, that specifically bind GPRC5D. In some aspects, the encoded receptors, such as those containing GPRC5D-binding polypeptides, and compositions and articles of manufacture and uses of the same, also are provided.

[0286] Among the GPRC5D-binding polypeptides are antibodies, such as single-chain antibodies (e.g., antigen binding antibody fragments), or portions thereof. In some examples, the recombinant receptors are chimeric antigen receptors, such as those containing anti-GPRCS5D antibodies or antigen- binding fragments thereof. The provided polynucleotides can be incorporated into constructs, such as deoxyribonucleic acid (DNA) or RNA constructs, such as those that can be introduced into cells for expression of the encoded recombinant GPRC5D-binding receptors. t Components of Encoded Recombinant GPRC5D-Binding Receptors

[0287] The provided GPRC5D-binding receptors generally contain an extracellular binding molecule and an intracellular signaling domain. Among the provided receptors are polypeptides containing antibodies, such as recombinant cell surface receptors containing anti-GPRCS5D antibodies. Such receptors include chimeric antigen receptors that contain such antibodies.

[0288] Among the provided recombinant receptors are antigen receptors that include a GPRC5D- binding fragment. The recombinant receptors include antigen receptors that specifically bind to GPRCS5D, such as antigen receptors containing the anti-GPRC5D antibodies, e.g., GPRC5D antigen- binding fragments. Among the antigen receptors are functional non-TCR antigen receptors, such as chimeric antigen receptors (CARs). Also provided are cells expressing the recombinant receptors and uses thereof in adoptive cell therapy, such as treatment of diseases and disorders associated with GPRC5D expression, e.g., multiple myeloma. a. Extracellular Antigen-binding domain

[0289] Among the chimeric receptors are chimeric antigen receptors (CARs). The chimeric receptors, such as CARs, generally include an extracellular antigen binding domain that includes, is, or comprises an anti-GPRCS5D antibody. Thus, the chimeric receptors, e.g., CARs, typically include in their extracellular portions one or more GPRCS5D-binding molecules, such as one or more antigen-binding fragment, domain, or portion, or one or more antibody variable regions, and / or antibody molecules, such as those described herein.

[0290] The term “antibody” herein is used in the broadest sense and includes polyclonal and monoclonal antibodies, including intact antibodies and functional (antigen-binding) antibody fragments, including fragment antigen binding (Fab) fragments, F(ab')2 fragments, Fab’ fragments, Fv fragments, recombinant IgG (rIgG) fragments, heavy chain variable (Vu) regions capable of specifically binding the antigen, single chain antibody fragments, including single chain variable fragments (scFv), and single domain antibodies (e.g., sdAb, sdFv, nanobody) fragments. The term encompasses genetically engineered and / or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific, e.g., bispecific or trispecific, antibodies, diabodies, triabodies, and tetrabodies, tandem di- scFv, tandem tri-scFv. Unless otherwise stated, the term “antibody” should be understood to encompass functional antibody fragments thereof also referred to herein as “antigen-binding fragments.” The term also encompasses intact or full-length antibodies, including antibodies of any class or sub-class, including IgG and sub-classes thereof, IgM, IgE, IgA, and IgD.

[0291] The terms “complementarity determining region,” and “CDR,” synonymous with “hypervariable region” or “HVR,” are known in the art to refer to non-contiguous sequences of amino acids within antibody variable regions, which confer antigen specificity and / or binding affinity. In general, there are three CDRs in each heavy chain variable region (CDR-H1, CDR-H2, CDR-H3) and three CDRs in each light chain variable region (CDR-L1, CDR-L2, CDR-L3). “Framework regions” and “FR” are known in the art to refer to the non-CDR portions of the variable regions of the heavy and light chains. In general, there are four FRs in each full-length heavy chain variable region (FR-HI1, FR-H2, FR-H3, and FR-H4), and four FRs in each full-length light chain variable region (FR-L1, FR-L2, FR-L3, and FR-L4).

[0292] The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme); Al-Lazikani et al., (1997) JMB 273,927-948 (“Chothia” numbering scheme); MacCallum er al., J. Mol. Biol. 262:732-745 (1996), “Antibody-antigen interactions: Contact analysis and binding site topography,” J. Mol. Biol. 262, 732- 745.” (“Contact” numbering scheme); Lefranc MP et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Dev Comp Immunol, 2003 Jan;27(1):55-77 (“IMGT” numbering scheme); Honegger A and Pliickthun A, “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool,” J Mol Biol, 2001 Jun 8;309(3):657-70, (“Aho” numbering scheme); and Martin et al., “Modeling antibody hypervariable loops: a combined algorithm,” PNAS, 1989, 86(23):9268-9272, (“AbM” numbering scheme).

[0293] The boundaries of a given CDR or FR may vary depending on the scheme used for identification. For example, the Kabat scheme is based on structural alignments, while the Chothia scheme is based on structural information. Numbering for both the Kabat and Chothia schemes is based upon the most common antibody region sequence lengths, with insertions accommodated by insertion letters, for example, “30a,” and deletions appearing in some antibodies. The two schemes place certain insertions and deletions (“indels™) at different positions, resulting in differential numbering. The Contact scheme is based on analysis of complex crystal structures and is similar in many respects to the Chothia numbering scheme. The AbM scheme is a compromise between Kabat and Chothia definitions based on that used by Oxford Molecular’s AbM antibody modeling software.

[0294] Table 1, below, lists exemplary position boundaries of CDR-L1, CDR-L2, CDR-L3 and CDR-H1, CDR-H2, CDR-H3 as identified by Kabat, Chothia, AbM, and Contact schemes, respectively. For CDR-HI, residue numbering is listed using both the Kabat and Chothia numbering schemes. FRs are located between CDRs, for example, with FR-L1 located before CDR-L1, FR-L2 located between CDR- L1 and CDR-L2, FR-L3 located between CDR-L2 and CDR-L3 and so forth. It is noted that because the shown Kabat numbering scheme places insertions at H35A and H35B, the end of the Chothia CDR-H1 loop when numbered using the shown Kabat numbering convention varies between H32 and H34, depending on the length of the loop. Table 1. Boundaries of CDRs according to various numbering schemes. CDR Kabat Chothia AbM Contact CDR-L1 L24--L.34 L24--L34 124-134 L30--L36 CDR-L2 L50--L56 L50--L56 L50--L56 L46--L55 CDR-L3 L89--L97 189--L.97 189-197 L89--L.96 CDR-H1 (Kabat Numbering") H31--H35B | H26--H32..34 H26--H35B H30--H35B CDR-H1 (Chothia Numbering?) H31--H35 H26--H32 H26--H35 H30--H35 CDR-H2 H52--H56 H50--H58 H47--H58 CDR-H3 H95--H102 H93--H101 1 - Kabat er al. (1991), “Sequences of Proteins of Immunological Interest,” Sth Ed. Public Health Service, National Institutes of Health, Bethesda, MD 2 - Al-Lazikani et al., (1997) IMB 273,927-948

[0295] Thus, unless otherwise specified, a “CDR” or “complementary determining region,” or individual specified CDRs (e.g., CDR-H1, CDR-H2, CDR-H3), of a given antibody or region thereof, such as a variable region thereof, should be understood to encompass a (or the specific) complementary determining region as defined by any of the aforementioned schemes or other known schemes. For example, where it is stated that a particular CDR (e.g., a CDR-H3) contains the amino acid sequence of a corresponding CDR in a given Vg or Vi region amino acid sequence, it is understood that such a CDR has a sequence of the corresponding CDR (e.g., CDR-H3) within the variable region, as defined by any of the aforementioned schemes or other known schemes. In some embodiments, specific CDR sequences are specified. Exemplary CDR sequences of provided antibodies are described using various numbering schemes, although it is understood that a provided antibody can include CDRs as described according to any of the other aforementioned numbering schemes or other numbering schemes known to a skilled artisan.

[0296] Likewise, unless otherwise specified, a FR or individual specified FR(s) (e.g., FR-H1, FR- H2, FR-H3, FR-H4), of a given antibody or region thereof, such as a variable region thereof, should be understood to encompass a (or the specific) framework region as defined by any of the known schemes. In some instances, the scheme for identification of a particular CDR, FR, or FRs or CDRs is specified, such as the CDR as defined by the Kabat, Chothia, AbM or Contact method or other known schemes. In other cases, the particular amino acid sequence of a CDR or FR is given.

[0297] The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable regions of the heavy chain and light chain (Vu and V1, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three CDRs. (See, e.g., Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007). A single Vy or Vi domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a Vy or V1 domain from an antibody that binds the antigen to screen a library of complementary Vy or Vi domains, respectively (see, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991)).

[0298] Among the antibodies included in the provided CARs are antibody fragments. An “antibody fragment” or “antigen-binding fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab’, Fab'-SH, F(ab")2; diabodies; linear antibodies; heavy chain variable (Vy) regions, single-chain antibody molecules such as scFvs and single-domain antibodies comprising only the Vu region; and multispecific antibodies formed from antibody fragments. In some embodiments, the antigen-binding domain in the provided CARs is or comprises an antibody fragment comprising a variable heavy chain (Vy) and a variable light chain (V1) region. In particular embodiments, the antibodies are single-chain antibody fragments comprising a heavy chain variable (Vy) region and / or a light chain variable (Vy) region, such as scFvs.

[0299] Single-domain antibodies (sdAbs) are antibody fragments comprising all or a portion of the heavy chain variable region or all or a portion of the light chain variable region of an antibody. In certain embodiments, a single-domain antibody is a human single-domain antibody.

[0300] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells. In some embodiments, the antibodies are recombinantly-produced fragments, such as fragments comprising arrangements that do not occur naturally, such as those with two or more antibody regions or chains joined by synthetic linkers, e.g., peptide linkers, and / or that are may not be produced by enzyme digestion of a naturally-occurring intact antibody. In some aspects, the antibody fragments are scFvs.

[0301] A “humanized” antibody is an antibody in which all or substantially all CDR amino acid residues are derived from non-human CDRs and all or substantially all FR amino acid residues are derived from human FRs. A humanized antibody optionally may include at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of a non-human antibody, refers to a variant of the non-human antibody that has undergone humanization, typically to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.§., the antibody from which the CDR residues are derived), e.g., to restore or improve antibody specificity or affinity.

[0302] Among the anti-GPRCS5D antibodies included in the provided CARs are human antibodies. A “human antibody” is an antibody with an amino acid sequence corresponding to that of an antibody produced by a human or a human cell, or non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences, including human antibody libraries. The term excludes humanized forms of non-human antibodies comprising non-human antigen-binding regions, such as those in which all or substantially all CDRs are non-human. The term includes antigen-binding fragments of human antibodies.

[0303] Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal's chromosomes. In such transgenic animals, the endogenous immunoglobulin loci have generally been inactivated. Human antibodies also may be derived from human antibody libraries, including phage display and cell-free libraries, containing antibody-encoding sequences derived from a human repertoire.

[0304] Among the antibodies included in the provided CARs are those that are monoclonal antibodies, including monoclonal antibody fragments. The term “monoclonal antibody” as used herein refers to an antibody obtained from or within a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical, except for possible variants containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different epitopes, each monoclonal antibody of a monoclonal antibody preparation is directed against a single epitope on an antigen. The term is not to be construed as requiring production of the antibody by any particular method. A monoclonal antibody may be made by a variety of techniques, including but not limited to generation from a hybridoma, recombinant DNA methods, phage-display and other antibody display methods.

[0305] In some embodiments, the CAR includes a GPRCS5D-binding portion or portions of the antibody molecule, such as a heavy chain variable (Vi) region and / or light chain variable (V1) region of the antibody, e.g., an scFv antibody fragment. In some embodiments, the provided GPRC5D-binding CARs contain an antibody, such as an anti-GPRC5D antibody, or an antigen-binding fragment thereof that confers the GPRC5D-binding properties of the provided CAR. In some embodiments, the antibody or antigen-binding domain can be any anti-GPRCS5D antibody described or derived from any anti- GPRCS5D antibody described (see, e.g., WO 2016 / 090312, WO 2016 / 090329, WO 2018 / 017786). Any of such anti-GPRCS5D antibodies or antigen-binding fragments can be used in the provided CARs. In some embodiments, the anti-GPRC5D CAR contains an antigen-binding domain that is an scFv containing a variable heavy (Va) and / or a variable light (V1) region derived from an antibody described in WO 2016 / 090312, WO 2016 / 090329, or WO 2018 / 017786.

[0306] In some embodiments, the antibody, e.g., the anti-GPRC5D antibody, or antigen-binding fragment, contains a heavy and / or light chain variable (Vy or V1) region sequence as described, or a sufficient antigen-binding portion thereof. In some embodiments, the anti-GPRC5D antibody, e.g., antigen-binding fragment, contains a Vu region sequence or sufficient antigen-binding portion thereof that contains a CDR-H1, CDR-H2 and / or CDR-H3 as described. In some embodiments, the anti- GPRCSD antibody, e.g., antigen-binding fragment, contains a Vy. region sequence or sufficient antigen- binding portion that contains a CDR-L1, CDR-L2 and / or CDR-L3 as described. In some embodiments, the anti-GPRC5D antibody, e.g., antigen-binding fragment, contains a Vu region sequence that contains a CDR-HI, CDR-H2 and / or CDR-H3 as described and contains a Vy region sequence that contains a CDR- L1, CDR-L2 and / or CDR-L3 as described. Also among the antibodies are those having sequences at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identical to such a sequence.

[0307] In some embodiments, the antibody or antibody fragment, in the provided CAR, has a Vu region of any of the antibodies or antibody binding fragments described in any of WO 2016 / 090312, WO 2016 / 090329, and WO 2018 / 017786.

[0308] In some embodiments, the CAR contains an antibody or antigen-binding fragment thereof, that has a heavy chain variable (Vg) region having the amino acid sequence selected from any one of SEQ ID NOs: 21, 23, 25, 27, 29, 31, or 33, or an amino acid sequence that has at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the Vy region amino acid selected from any one of SEQ ID NOs: 21, 23, 25, 27, 29, 31, or 33, or contains a CDR-H1, CDR-H2, and / or CDR-H3 present in such a Vg sequence.

[0309] In some embodiments, the Vu region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, CDR-H2, and / or CDR-H3 according to Kabat numbering. In some embodiments, the Vy region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, CDR-H2, and / or CDR-H3 according to Chothia numbering. In some embodiments, the Vy region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, CDR-H2, and / or CDR-H3 according to AbM numbering.

[0310] In some embodiments, the CAR contains an antibody or antigen-binding fragment thereof, that has a variable heavy chain (Vg) region comprising a CDR-H1 comprising the amino acid sequence selected from SEQ ID NOs: 75, 78, 80, 82, 90, 93, 95, 97, 105, 108, 110, 112, 120, 123, 125, 127, 135, 138, 140, 142, 152, 162, 165, 167, and 169; (b) a CDR-H2 comprising the amino acid sequence selected from SEQ ID NOs: 76, 79, 81, 83, 91, 94, 96, 98, 106, 109, 111, 113, 121, 124, 126, 128, 136, 139, 141, 143, 150, 153, 154, 155, 163, 166, 168, and 170; and (c) a CDR-H3 comprising the amino acid sequence selected from SEQ ID NOs: 77, 84, 92, 99, 107, 114, 122, 129, 137, 144, 151, 156, 164, and 171.

[0311] In some embodiments, the antibody or antigen-binding fragment thereof comprises a Vu region comprising a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOs:75, 76 and 77, respectively; SEQ ID NOs:78, 79 and 77, respectively; SEQ ID NOs:80, 81 and 77, respectively; SEQ ID NOs:82, 83 and 84, respectively; SEQ ID NOs:90, 91 and 92, respectively; SEQ ID NOs:93, 94 and 92, respectively; SEQ ID NOs:95, 96 and 92, respectively; SEQ ID NOs:97, 98 and 99, respectively; SEQ ID NOs:105, 106 and 107, respectively; SEQ ID NOs:108, 109 and 107, respectively; SEQ ID NOs:110, 111 and 107, respectively; SEQ ID NOs:112, 113 and 114, respectively; SEQ ID NOs:120, 121 and 122, respectively; SEQ ID NOs:123, 124 and 122, respectively; SEQ ID NOs:125, 126 and 122, respectively; SEQ ID NOs:127, 128 and 129, respectively; SEQ ID NOs:135, 136 and 137, respectively; SEQ ID NOs:138, 139 and 137, respectively; SEQ ID NOs:140, 141 and 137, respectively; SEQ ID NOs:142, 143 and 144, respectively; SEQ ID NOs:135, 150 and 151, respectively; SEQ ID NOs:152, 153 and 151, respectively; SEQ ID NOs:140, 154 and 151, respectively; SEQ ID NOs:142, 155 and 156, respectively; SEQ ID NOs:162, 163 and 164, respectively; SEQ ID NOs:165, 166 and 164, respectively; SEQ ID NOs: 167, 168 and 164, respectively; SEQ ID NOs: 169, 170 and 171, respectively.

[0312] In some embodiments, the antibody or antigen-binding fragment thereof comprises a Vu region comprising the amino acid sequence of SEQ ID NOs:75, 76 and 77, respectively; SEQ ID NOs:78, 79 and 77, respectively; SEQ ID NOs:80, 81 and 77, respectively; SEQ ID NOs:82, 83 and 84, respectively; SEQ ID NOs:90, 91 and 92, respectively; SEQ ID NOs:93, 94 and 92, respectively; SEQ ID NOs:95, 96 and 92, respectively; SEQ ID NOs:97, 98 and 99, respectively; SEQ ID NOs:105, 106 and 107, respectively; SEQ ID NOs:108, 109 and 107, respectively; SEQ ID NOs:110, 111 and 107, respectively; SEQ ID NOs:112, 113 and 114, respectively; SEQ ID NOs:120, 121 and 122, respectively; SEQ ID NOs:123, 124 and 122, respectively; SEQ ID NOs:125, 126 and 122, respectively; SEQ ID NOs:127, 128 and 129, respectively; SEQ ID NOs:135, 136 and 137, respectively; SEQ ID NOs:138, 139 and 137, respectively; SEQ ID NOs:140, 141 and 137, respectively; SEQ ID NOs:142, 143 and 144, respectively; SEQ ID NOs:135, 150 and 151, respectively; SEQ ID NOs:152, 153 and 151, respectively; SEQ ID NOs:140, 154 and 151, respectively; SEQ ID NOs:142, 155 and 156, respectively; SEQ ID NOs:162, 163 and 164, respectively; SEQ ID NOs:165, 166 and 164, respectively; SEQ ID NOs:167, 168 and 164, respectively; SEQ ID NOs:169, 170 and 171, respectively.

[0313] In some embodiments, the antibody or antigen-binding fragment thereof comprises a CDR- HI, CDR-H2 and CDR-H3, respectively, comprising the amino acid sequence of a CDR-H1, a CDR-H2, and a CDR-H3 contained within the Vu region amino acid sequence set forth in any one of SEQ ID NOs: 21, 23, 25,27, 29, 31, or 33.

[0314] In some embodiments of the antibody or antigen-binding fragment thereof provided herein, the Vu region comprises any of the CDR-H1, CDR-H2 and CDR-H3 as described and comprises a framework region 1 (FR1), a FR2, a FR3 and / or a FR4 having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity, respectively, to a FR1, a FR2, a FR3 and / or a FR4 contained within the Vy region amino acid sequence set forth in any one of SEQ ID NOs: 21, 23, 25, 27, 29, 31, or 33.

[0315] In some embodiments, the antibody or antigen-binding fragment thereof comprises a Vu region comprising the amino acid sequence set forth in any one of SEQ ID NOs: 21, 23, 25, 27, 29, 31, or 33.

[0316] In some embodiments, the antibody or antibody fragment, in the provided CAR (e.g. an anti- GPRC5D CAR), comprising a Vg region further comprises a light chain or a sufficient antigen binding portion thereof. For example, in some embodiments, the antibody or antigen-binding fragment thereof contains a Vy region and a Vi region, or a sufficient antigen-binding portion of a Vy and Vi region. In such embodiments, a Vg region sequence can be any of the above described Vi sequence. In some such embodiments, the antibody is an antigen-binding fragment, such as a Fab or an scFv. In some such embodiments, the antibody is a full-length antibody that also contains a constant region.

[0317] In some embodiments, a CAR provided herein, contains an antibody such as an anti- GPRCS5D antibody, or antigen-binding fragment thereof that contains any of the above Vg region and contains a variable light chain region or a sufficient antigen binding portion thereof. For example, in some embodiments, the CAR contains an antibody or antigen-binding fragment thereof that contains a Vuregion and a variable light chain (V1) region, or a sufficient antigen-binding portion of a Vy and Vi region. In such embodiments, a Vi region sequence can be any of the above described Vu sequence. In some such embodiments, the antibody is an antigen-binding fragment, such as a Fab or an scFv. In some such embodiments, the antibody is a full-length antibody that also contains a constant region.

[0318] In some embodiments, the antibody or antigen-binding fragment has a V1. region described in any of WO 2016 / 090312, WO 2016 / 090329, and WO 2018 / 017786.

[0319] In some embodiments, the CAR contains an antibody or antigen-binding fragment thereof, that has a light chain variable (V1) region having the amino acid sequence selected from any one of SEQ ID NOs: 22, 24, 26, 28, 30, 32, 34, 63, 64, 65, 66, 67, 68, or 69, or an amino acid sequence that has at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the Vi. region amino acid selected from any one of SEQ ID NOs: 22, 24, 26, 28, 30, 32, 34, 63, 64, 65, 66, 67, 68, or 69, or contains a CDR-L1, CDR-L2, and / or CDR-L3 present in such a Vi. sequence. In some embodiments, the CAR contains an antibody or antigen-binding fragment thereof, that has a light chain variable (V1) region having the amino acid sequence selected from any one of SEQ ID NOs: 22, 24, 26, 28, 30, 32, or 34, or an amino acid sequence that has at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the Vy region amino acid selected from any one of SEQ ID NOs: 22, 24, 26, 28, 30, 32, or 34, or contains a CDR-L1, CDR-L2, and / or CDR-L3 present in such a Vi, sequence. In some embodiments, the CAR contains an antibody or antigen-binding fragment thereof, that has a light chain variable (V1) region having the amino acid sequence selected from any one of SEQ ID NOs: 63, 64, 65, 66, 67, 68 or 69, or an amino acid sequence that has at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the Vi region amino acid selected from any one of SEQ ID NOs: 63, 64, 65, 66, 67, 68, or 69, or contains a CDR-L1, CDR-L2, and / or CDR-L3 present in such a Vi sequence.

[0320] In some embodiments, the Vy region of an antibody or antigen-binding fragment thereof comprises a CDR-L1, CDR-L2, and / or CDR-L3 according to Kabat numbering. In some embodiments, the V1 region of an antibody or antigen-binding fragment thereof comprises a CDR-L1, CDR-L2, and / or CDR-L3 according to Chothia numbering. In some embodiments, the Vy. region of an antibody or antigen-binding fragment thereof comprises a CDR-L1, CDR-L2, and / or CDR-L3 according to AbM numbering.

[0321] In some embodiments, the CAR contains an antibody or antigen-binding fragment thereof, that has a variable light chain (V1) region comprising a CDR-L1 comprising the amino acid sequence selected from SEQ ID NOs: 85, 88, 100, 103, 115, 118, 130, 133, 145, 148, 157, 160, 172, and 174; (b) a CDR-L2 comprising the amino acid sequence selected from SEQ ID NOs: 86, 89, 101, 104, 116, 119, 131, 134, 146, 149, 158, and 161; and (c) a CDR-L3 comprising the amino acid sequence selected from SEQ ID NOs: 87, 102, 117, 132, 147, 159, 173, and 175.

[0322] In some embodiments, the antibody or antigen-binding fragment thereof comprises a VL region comprising a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:85, 86 and 87, respectively; SEQ ID NOs:88, 89 and 87, respectively; SEQ ID NOs:100, 101 and 102, respectively; SEQ ID NOs:103, 104 and 102, respectively; SEQ ID NOs:115, 116 and 117, respectively; SEQ ID NOs:118, 119 and 117, respectively; SEQ ID NOs:130, 131 and 132, respectively; SEQ ID NOs:133, 134 and 132, respectively; SEQ ID NOs:145, 146 and 147, respectively; SEQ ID NOs:148, 149 and 147, respectively; SEQ ID NOs:157, 158 and 159, respectively; SEQ ID NOs:160, 161 and 159, respectively; SEQ ID NOs:172, 86 and 173, respectively; SEQ ID NOs:174, 89 and 175, respectively; SEQ ID NOs:174, 89 and 297, respectively.

[0323] In some embodiments, the antibody or antigen-binding fragment thereof comprises a VL region comprising the amino acid sequence of SEQ ID NOs:85, 86 and 87, respectively; SEQ ID NOs:88, 89 and 87, respectively; SEQ ID NOs:100, 101 and 102, respectively; SEQ ID NOs:103, 104 and 102, respectively; SEQ ID NOs:115, 116 and 117, respectively; SEQ ID NOs:118, 119 and 117, respectively; SEQ ID NOs:130, 131 and 132, respectively; SEQ ID NOs:133, 134 and 132, respectively; SEQ ID NOs: 145, 146 and 147, respectively; SEQ ID NOs:148, 149 and 147, respectively; SEQ ID NOs:157, 158 and 159, respectively; SEQ ID NOs:160, 161 and 159, respectively; SEQ ID NOs:172, 86 and 173, respectively; SEQ ID NOs:174, 89 and 175, respectively; SEQ ID NOs:174, 89 and 297, respectively.

[0324] In some embodiments, the antibody or antigen-binding fragment thereof contains a CDR-L1, CDR-L2, and CDR-L3, respectively, contained within the Vi region amino acid sequence selected from any one of SEQ ID NOs: 22, 24, 26, 28, 30, 32, 34, 63, 64, 65, 66, 67, 68, or 69. In some embodiments, the antibody or antigen-binding fragment thereof contains a CDR-L1, CDR-L2, and CDR-L3, respectively, contained within the Vy region amino acid sequence selected from any one of SEQ ID NOs: 22,24, 26,28, 30, 32, or 34. In some embodiments, the antibody or antigen-binding fragment thereof contains a CDR-L1, CDR-L2, and CDR-L3, respectively, contained within the Vy region amino acid sequence selected from any one of SEQ ID NOs: 63, 64, 65, 66, 67, 68, or 69.

[0325] Among the CARs provided herein is a CAR in which the antibody, such as an anti-GPRC5D antibody, or antibody fragment, in the provided CAR, comprises a Vy region amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in any of SEQ ID NOs: 21, 23, 25, 27, 29, 31, or 33 and a Vi region comprising an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 22, 24, 26, 28, 30. 32, 34, 63, 64, 65, 66, 67, 68, or 69.

[0326] In some embodiments, the Vu region of the antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2, a CDR-H3, respectively, comprising the amino acid sequences of CDR-HI, CDR-H2, and CDR-H3 contained within the Vy region amino acid sequence selected from any one of SEQ ID NOs: 21, 23, 25, 27, 29, 31, or 33; and comprises a CDR-L1, a CDR-L2, a CDR-L3, respectively, comprising the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3, respectively contained within the Vy region amino acid sequence selected from any one of SEQ ID NOs: 22, 24, 26, 28, 30, 32, 34, 63, 64, 65, 66, 67, 68, or 69.

[0327] In some embodiments, the Vx region of the antibody or antigen-binding fragment thereof comprise the amino acid sequence of SEQ ID NOs: 21, 23, 25, 27, 29, 31, or 33 and the and Vy regions of the antibody or antigen-binding fragment comprises the amino acid sequence 22, 24, 26, 28, 30, 32, or 34. In some embodiments, the Vi and V1 regions of the antibody or antigen-binding fragment thereof comprise the amino acid sequences of SEQ ID NOs: 21 and 22, respectively; SEQ ID NOs: 23 and 24, respectively; SEQ ID NOs: 25 and 26, respectively; SEQ ID NOs: 27 and 28, respectively; SEQ ID NOs: 29 and 30, respectively; SEQ ID NOs: 31 and 32, respectively; or SEQ ID NOs: 33 and 34, respectively, or any antibody or antigen-binding fragment thereof that has at least 90% sequence identity to any of the above Vg and Vi, such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0328] For example, the Vy and Vy regions of the antibody or antigen-binding fragment thereof provided therein comprise the amino acid sequences selected from: SEQ ID NOs: 21 and 22; SEQ ID NOs: 23 and 24; SEQ ID NOs: 25 and 26; SEQ ID NOs: 27 and 28; SEQ ID NOs: 29 and 30; SEQ ID NOs: 31 and 32; SEQ ID NOs: 33 and 34, respectively. In other examples, the Vu and Vy regions of the antibody or antigen-binding fragment thereof provided therein comprise the amino acid sequences selected from: SEQ ID NOs: 21 and 63; SEQ ID NOs: 23 and 64; SEQ ID NOs: 25 and 65; SEQ ID NOs: 27 and 66; SEQ ID NOs: 29 and 67; SEQ ID NOs: 31 and 68; SEQ ID NOs: 33 and 69, respectively.

[0329] In some embodiments, the antibody or antigen-binding fragment thereof, in the provided CAR, is a single-chain antibody fragment, such as a single chain variable fragment (scFv) or a diabody or a single domain antibody (sdAb). In some embodiments, the antibody or antigen-binding fragment is a single domain antibody comprising only the Vy region. In some embodiments, the antibody or antigen binding fragment is an scFv comprising a heavy chain variable (Vg) region and a light chain variable (V1) region. In some embodiments, the single-chain antibody fragment (e.g., scFv) includes one or more linkers joining two antibody domains or regions, such as a heavy chain variable (Vg) region and a light chain variable (V1) region. The linker typically is a peptide linker, e.g., a flexible and / or soluble peptide linker. Among the linkers are those rich in glycine and serine and / or in some cases threonine. In some embodiments, the linkers further include charged residues such as lysine and / or glutamate, which can improve solubility. In some embodiments, the linkers further include one or more proline.

[0330] Accordingly, the provided CARs contain anti-GPRC5D antibodies that include single-chain antibody fragments, such as scFvs and diabodies, particularly human single-chain antibody fragments, typically comprising linker(s) joining two antibody domains or regions, such Vg and Vi regions. The linker typically is a peptide linker, e.g., a flexible and / or soluble peptide linker, such as one rich in glycine and serine.

[0331] In some aspects, the linkers rich in glycine and serine (and / or threonine) include at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% such amino acid(s). In some embodiments, they include at least at or about 50%, 55%, 60%, 70%, or 75%, glycine, serine, and / or threonine. In some embodiments, the linker is comprised substantially entirely of glycine, serine, and / or threonine. The linkers generally are between about 5 and about 50 amino acids in length, typically between at or about 10 and at or about 30, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, and in some examples between 10 and 25 amino acids in length. Exemplary linkers include linkers having various numbers of repeats of the sequence GGGGS (4GS; SEQ ID NO: 50) or GGGS (3GS; SEQ ID NO: 51), such as between 2, 3, 4, and 5 repeats of such a sequence. Exemplary linkers include those having or consisting of a sequence set forth in SEQ ID NO: 52 (GGGGSGGGGSGGGGS). Exemplary linkers further include those having or consisting of the sequence set forth in SEQ ID NO: 53 (GSTSGSGKPGSGEGSTKG). Exemplary linkers further include those having or consisting of the sequence set forth in SEQ ID NO: 54 (SRGGGGSGGGGSGGGGSLEMA). An exemplary linker includes those having or consisting of the sequence set forth in SEQ ID NO: 47 (GSRGGGGSGGGGSGGGGSLEMA).

[0332] Accordingly, in some embodiments, the provided embodiments include single-chain antibody fragments, e.g., scFvs, comprising one or more of the aforementioned linkers, such as glycine / serine rich linkers, including linkers having repeats of GGGS (SEQ ID NO: 51) or GGGGS (SEQ ID NO: 50), such as the linker set forth in SEQ ID NO: 47, 52 or 54.

[0333] In some embodiments, the Vi region may be amino terminal to the Vy region. In some embodiments, the Vg region may be carboxy terminal to the Vi region. In particular embodments, the fragment, e.g., scFv, may include a Vg region or portion thereof, followed by the linker, followed by a Vi. region or portion thereof. In other embodiments, the fragment, e.g., the scFv, may include the Vi region or portion thereof, followed by the linker, followed by the Vy region or portion thereof.

[0334] In some aspects, an scFv provided herein comprises the amino acid sequence selected from any one of SEQ ID NOs: 1-14, or has an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence selected from any one of SEQ ID NOs: 1-14.

[0335] Among a provided anti-GPRC5D CAR is a CAR in which the antibody or antigen-binding fragment contains a Vg region comprising the sequence set forth in SEQ ID NO:21 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:21; and contains a Vy region comprising the sequence set forth in SEQ ID NO:22 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:22. In some embodiments, the provided CAR is a CAR in which the antibody or antigen-binding fragment contains a Vy region comprising the sequence set forth in SEQ ID NO:21 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:21; and contains a Vy, region comprising the sequence set forth in SEQ ID NO:63 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:63. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vy region that has a CDRHI1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 75, 76 and 77, respectively and a Vy region that has a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 85, 86, and 87, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vy region that has a CDRH1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 78, 79 and 77, respectively and a Vy region that contains a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 85, 86, and 87, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vg region that has a CDRHI1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 80, 81 and 77, respectively and a Vi. region that contains a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 85, 86, and 87, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vy region that has a CDRHI1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 82, 83 and 84, respectively and a V1 region that contains a CDRLI, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 88, 89 and 87, respectively. In some embodiments, the Vy region comprises the sequence set forth in SEQ ID NO:21 and the Vy region comprises the sequence set forth in SEQ ID NO:22. In some embodiments, the Vy region comprises the sequence set forth in SEQ ID NO:21 and the Vy region comprises the sequence set forth in SEQ ID NO:63. In some embodiments, the antibody or antigen-binding fragment is a single- chain antibody fragment, such as an scFv. In some embodiments, the scFv comprises the sequence of amino acids set forth in SEQ ID NO:1 or a sequence of amino acids at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:1. In some embodiments, the scFv is encoded by a nucleotide sequence set forth in SEQ ID NO:257 or a sequence of nucleotides at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:257. In some embodiments, the scFv comprises the sequence of amino acids set forth in SEQ ID NO:2 or a sequence of amino acids at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:2. n some embodiments, the scFv is encoded by a nucleotide sequence set forth in SEQ ID NO:258 or a sequence of nucleotides at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%; at or about 98%, or at or about 99% identity to SEQ ID NO:258.

[0336] Among a provided anti-GPRC5D CAR is a CAR in which the antibody or antigen-binding fragment contains a Vy region comprising the sequence set forth in SEQ ID NO:23 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:23; and contains a Vy. region comprising the sequence set forth in SEQ ID NO:24 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:24. In some embodiments, the provided CAR is a CAR in which the antibody or antigen-binding fragment contains a Vg region comprising the sequence set forth in SEQ ID NO:23 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:23; and contains a Vy, region comprising the sequence set forth in SEQ ID NO:64 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:64. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vg region that has a CDRH, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 90, 91, 92, respectively and a Vy region that has a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS:100, 101 and 102, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vy region that has a CDRH1, a CDRH? and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 93, 94 and 92, respectively and a Vy region that contains a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 100, 101 and 102, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vg region that has a CDRH1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 95, 96 and 92, respectively and a Vi region that contains a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 100, 101 and 102, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vg region that has a CDRHI1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 97, 98 and 99, respectively and a Vi region that contains a CDRLI, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 103, 104 and 102, respectively. In some embodiments, the Vr region comprises the sequence set forth in SEQ ID NO:23 and the Vy region comprises the sequence set forth in SEQ ID NO:24. In some embodiments, the Vu region comprises the sequence set forth in SEQ ID NO:23 and the V1 region comprises the sequence set forth in SEQ ID NO:64. In some embodiments, the antibody or antigen-binding fragment is a single- chain antibody fragment, such as an scFv. In some embodiments, the scFv comprises the sequence of amino acids set forth in SEQ ID NO:3 or a sequence of amino acids at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:3. In some embodiments, the scFv is encoded by a nucleotide sequence set forth in SEQ ID NO:259 or a sequence of nucleotides at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:259. In some embodiments, the scFv comprises the sequence of amino acids set forth in SEQ ID NO:4 or a sequence of amino acids at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:4. In some embodiments, the scFv is encoded by a nucleotide sequence set forth in SEQ ID NO:260 or a sequence of nucleotides at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:260.

[0337] Among a provided anti-GPRC5D CAR is a CAR in which the antibody or antigen-binding fragment contains a Vg region comprising the sequence set forth in SEQ ID NO:25 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:25; and contains a Vy. region comprising the sequence set forth in SEQ ID NO:26 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:26. In some embodiments, the provided CAR is a CAR in which the antibody or antigen-binding fragment contains a Vy region comprising the sequence set forth in SEQ ID NO:25 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:25; and contains a Vy region comprising the sequence set forth in SEQ ID NO:65 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:65. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vg region that has a CDRHI1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 105, 106, 107, respectively and a Vi region that has a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 115, 116 and 117, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vy region that has a CDRH], a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 108, 109 and 107, respectively and a Vi region that contains a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 115, 116 and 117, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vy region that has a CDRHI, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 110, 111 and 107, respectively and a Vi region that contains a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 115, 116 and 117, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vg region that has a CDRH1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 112, 113 and 114, respectively and a VL. region that contains a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 118, 119 and 117, respectively. In some embodiments, the Vy region comprises the sequence set forth in SEQ ID NO:25 and the Vy region comprises the sequence set forth in SEQ ID NO:26. In some embodiments, the Vg region comprises the sequence set forth in SEQ ID NO:25 and the Vy region comprises the sequence set forth in SEQ ID NO:65. In some embodiments, the antibody or antigen- binding fragment is a single-chain antibody fragment, such as an scFv. In some embodiments, the scFv comprises the sequence of amino acids set forth in SEQ ID NO:S or a sequence of amino acids at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%; or at or about 99% identity to SEQ ID NO:5. In some embodiments, the scFv is encoded by a nucleotide sequence set forth in SEQ ID NO:261 or a sequence of nucleotides at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:261. In some embodiments, the scFv comprises the sequence of amino acids set forth in SEQ ID NO:6 or a sequence of amino acids at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:6. In some embodiments, the scFv is encoded by a nucleotide sequence set forth in SEQ ID NO:262 or a sequence of nucleotides at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:262.

[0338] Among a provided anti-GPRC5D CAR is a CAR in which the antibody or antigen-binding fragment contains a Vg region comprising the sequence set forth in SEQ ID NO:27 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:27; and contains a Vy. region comprising the sequence set forth in SEQ ID NO:28 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:28. In some embodiments, the provided CAR is a CAR in which the antibody or antigen-binding fragment contains a Vy region comprising the sequence set forth in SEQ ID NO:27 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:27; and contains a Vy region comprising the sequence set forth in SEQ ID NO:66 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:66. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vg region that has a CDRHI1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 120, 121 and 122, respectively and a V1. region that has a CDRLI, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 130, 131 and 132, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vy region that has a CDRH, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 123, 124 and 122, respectively and a Vy region that contains a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 130, 131 and 132, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vy region that has a CDRH1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 125, 126 and 122, respectively and a Vy region that contains a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 130, 131 and 132, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vy region that has a CDRH1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 127, 128 and 129, respectively and a Vy region that contains a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 133, 134 and 132, respectively. In some embodiments, the Vy region comprises the sequence set forth in SEQ ID NO:27 and the V1 region comprises the sequence set forth in SEQ ID NO:28. In some embodiments, the Vg region comprises the sequence set forth in SEQ ID NO:27 and the V1 region comprises the sequence set forth in SEQ ID NO:66. In some embodiments, the antibody or antigen-binding fragment is a single-chain antibody fragment, such as an scFv. In some embodiments, the scFv comprises the sequence of amino acids set forth in SEQ ID NO:7 or a sequence of amino acids at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:7. In some embodiments, the scFv is encoded by a nucleotide sequence set forth in SEQ ID NO:263 or a sequence of nucleotides at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:263. In some embodiments, the scFv comprises the sequence of amino acids set forth in SEQ ID NO:8 or a sequence of amino acids at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:8. In some embodiments, the scFv is encoded by a nucleotide sequence set forth in SEQ ID NO:264 or a sequence of nucleotides at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:264.

[0339] Among a provided anti-GPRC5D CAR is a CAR in which the antibody or antigen-binding fragment contains a Vy region comprising the sequence set forth in SEQ ID NO:29 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:29; and contains a Vy region comprising the sequence set forth in SEQ ID NO:30 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:30. In some embodiments, the provided CAR is a CAR in which the antibody or antigen-binding fragment contains a Vy region comprising the sequence set forth in SEQ ID NO:29 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:29; and contains a V1 region comprising the sequence set forth in SEQ ID NO:67 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:67. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vg region that has a CDRHI1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 135, 136 and 137, respectively and a Vy. region that has a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 145, 146 and 147, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vy region that has a CDRH, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 138, 139 and 137, respectively and a Vy, region that contains a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 145, 146 and 147, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vy region that has a CDRHI, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 140, 141 and 137, respectively and a Vy region that contains a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 145, 146 and 147, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vy region that has a CDRH1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 142, 143 and 144, respectively and a Vi region that contains a CDRLI, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 148, 149 and 147, respectively. In some embodiments, the Vy region comprises the sequence set forth in SEQ ID NO:29 and the V1 region comprises the sequence set forth in SEQ ID NO:30. In some embodiments, the Vg region comprises the sequence set forth in SEQ ID NO:29 and the V1 region comprises the sequence set forth in SEQ ID NO:67. In some embodiments, the antibody or antigen-binding fragment is a single-chain antibody fragment, such as an scFv. In some embodiments, the scFv comprises the sequence of amino acids set forth in SEQ ID NO:9 or a sequence of amino acids at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:9. In some embodiments, the scFv is encoded by a nucleotide sequence set forth in SEQ ID NO:265 or a sequence of nucleotides at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%; at or about 98%, or at or about 99% identity to SEQ ID NO:265. In some embodiments, the scFv comprises the sequence of amino acids set forth in SEQ ID NO:10 or a sequence of amino acids at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:10. In some embodiments, the scFv is encoded by a nucleotide sequence set forth in SEQ ID NO:266 or a sequence of nucleotides at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:266.

[0340] Among a provided anti-GPRC5D CAR is a CAR in which the antibody or antigen-binding fragment contains a Vg region comprising the sequence set forth in SEQ ID NO:31 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:31; and contains a Vy. region comprising the sequence set forth in SEQ ID NO:32 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:32. In some embodiments, the provided CAR is a CAR in which the antibody or antigen-binding fragment contains a Vy region comprising the sequence set forth in SEQ ID NO:31 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:31; and contains a Vy region comprising the sequence set forth in SEQ ID NO:68 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:68. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vg region that has a CDRHI1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 135, 150 and 151, respectively and a Vy. region that has a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 157, 158 and 159, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vy region that has a CDRHI, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 152, 153 and 151, respectively and a Vy region that contains a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 157, 158 and 159, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vy region that has a CDRH1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 140, 154 and 151, respectively and a Vy region that contains a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 157, 158 and 159, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vy region that has a CDRH1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 142, 155 and 156, respectively and a Vy region that contains a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 160, 161 and 159, respectively. In some embodiments, the Vy region comprises the sequence set forth in SEQ ID NO:31 and the V1 region comprises the sequence set forth in SEQ ID NO:32. In some embodiments, the Vg region comprises the sequence set forth in SEQ ID NO:31 and the Vy region comprises the sequence set forth in SEQ ID NO:68. In some embodiments, the antibody or antigen-binding fragment is a single-chain antibody fragment, such as an scFv. In some embodiments, the scFv comprises the sequence of amino acids set forth in SEQ ID NO:11 or a sequence of amino acids at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:11. In some embodiments, the scFv is encoded by a nucleotide sequence set forth in SEQ ID NO:267 or a sequence of nucleotides at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:267. In some embodiments, the scFv comprises the sequence of amino acids set forth in SEQ ID NO:12 or a sequence of amino acids at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:12. In some embodiments, the scFv is encoded by a nucleotide sequence set forth in SEQ ID NO:268 or a sequence of nucleotides at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:268.

[0341] Among a provided anti-GPRC5D CAR is a CAR in which the antibody or antigen-binding fragment contains a Vy region comprising the sequence set forth in SEQ ID NO:33 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:33; and contains a Vy. region comprising the sequence set forth in SEQ ID NO:34 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:34. In some embodiments, the provided CAR is a CAR in which the antibody or antigen-binding fragment contains a Vy region comprising the sequence set forth in SEQ ID NO:33 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:33; and contains a Vy region comprising the sequence set forth in SEQ ID NO:69 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:69. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vg region that has a CDRHI1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 162, 163 and 164, respectively and a V1. region that has a CDRLI, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 172, 86, 173, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vi region that has a CDRH1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 165, 166 and 164, respectively and a Vy, region that contains a CDRLI1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 172, 86 and 173, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vu region that has a CDRH1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 167, 168 and 164, respectively and a Vy region that contains a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 172, 86 and 173, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vy region that has a CDRH1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 169, 170, 171, respectively and a V1 region that contains a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 174, 89 and 175, respectively. In some embodiments, the antibody or antigen-binding fragment of the provided CAR contains a Vy region that has a CDRH1, a CDRH2 and a CDRH3 comprising the amino acid sequence of SEQ ID NOS: 169, 170, 171, respectively and a Vy region that contains a CDRL1, a CDRL2 and a CDRL3 comprising the amino acid sequence of SEQ ID NOS: 174, 89 and 297, respectively. In some embodiments, the Vu region comprises the sequence set forth in SEQ ID NO:33 and the Vy region comprises the sequence set forth in SEQ ID NO:34. In some embodiments, the Vg region comprises the sequence set forth in SEQ ID NO:33 and the Vi. region comprises the sequence set forth in SEQ ID NO:69. In some embodiments, the antibody or antigen-binding fragment is a single-chain antibody fragment, such as an scFv. In some embodiments, the scFv comprises the sequence of amino acids set forth in SEQ ID NO:13 or a sequence of amino acids at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:13. In some embodiments, the scFv is encoded by a nucleotide sequence set forth in SEQ ID NO:269 or a sequence of nucleotides at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:269. In some embodiments, the scFv comprises the sequence of amino acids set forth in SEQ ID NO:14 or a sequence of amino acids at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%; at or about 98%, or at or about 99% identity to SEQ ID NO:14. In some embodiments, the scFv is encoded by a nucleotide sequence set forth in SEQ ID NO:270 or a sequence of nucleotides at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:270.

[0342] Among the antibodies, e.g., antigen-binding fragments, in the provided CARs, are human antibodies. In some embodiments of a provided human anti-GPRCSD antibody, e.g., antigen-binding fragments, the human antibody contains a Vu region that comprises a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain V segment, a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain D segment, and / or a portion having at least 95%, 96%, 97%, 98%, 99%. or 100% sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain J segment; and / or contains a Vy region that comprises a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence encoded by a germline nucleotide human kappa or lambda chain V segment, and / or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence encoded by a germline nucleotide human kappa or lambda chain J segment. In some embodiments, the portion of the Vu region corresponds to the CDR-H1, CDR-H2 and / or CDR-H3. In some embodiments, the portion of the Vu region corresponds to the framework region 1 (FR1), FR2, FR2 and / or FR4. In some embodiments, the portion of the Vy. region corresponds to the CDR-L1, CDR-L2 and / or CDR-L3. In some embodiments, the portion of the Vy region corresponds to the FR1, FR2, FR2 and / or FR4.

[0343] In some embodiments, the human antibody, e.g., antigen-binding fragment, contains a CDR- H1 having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of the corresponding CDR-HI region within a sequence encoded by a germline nucleotide human heavy chain V segment. For example, the human antibody in some embodiments contains a CDR-HI having a sequence that is 100% identical or with no more than one, two or three amino acid differences as compared to the corresponding CDR-H1 region within a sequence encoded by a germline nucleotide human heavy chain V segment.

[0344] In some embodiments, the human antibody, e.g., antigen-binding fragment, contains a CDR- H2 having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of the corresponding CDR-H2 region within a sequence encoded by a germline nucleotide human heavy chain V segment. For example, the human antibody in some embodiments contains a CDR-H2 having a sequence that is 100% identical or with no more than one, two or three amino acid difference as compared to the corresponding CDR-H2 region within a sequence encoded by a germline nucleotide human heavy chain V segment.

[0345] In some embodiments, the human antibody, e.g., antigen-binding fragment, contains a CDR- H3 having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of the corresponding CDR-H3 region within a sequence encoded by a germline nucleotide human heavy chain V segment, D segment and J segment. For example, the human antibody in some embodiments contains a CDR-H3 having a sequence that is 100% identical or with no more than one, two or three amino acid differences as compared to the corresponding CDR-H3 region within a sequence encoded by a germline nucleotide human heavy chain V segment, D segment and J segment.

[0346] In some embodiments, the human antibody, e.g., antigen-binding fragment, contains a CDR- L1 having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of the corresponding CDR-L1 region within a sequence encoded by a germline nucleotide human light chain V segment. For example, the human antibody in some embodiments contains a CDR-L1 having a sequence that is 100% identical or with no more than one, two or three amino acid differences as compared to the corresponding CDR-L1 region within a sequence encoded by a germline nucleotide human light chain V segment.

[0347] In some embodiments, the human antibody, e.g., antigen-binding fragment, contains a CDR- L2 having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of the corresponding CDR-L2 region within a sequence encoded by a germline nucleotide human light chain V segment. For example, the human antibody in some embodiments contains a CDR-L2 having a sequence that is 100% identical or with no more than one, two or three amino acid difference as compared to the corresponding CDR-L2 region within a sequence encoded by a germline nucleotide human light chain V segment.

[0348] In some embodiments, the human antibody, e.g., antigen-binding fragment, contains a CDR- L3 having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence of the corresponding CDR-L3 region within a sequence encoded by a germline nucleotide human light chain V segment and J segment. For example, the human antibody in some embodiments contains a CDR-L3 having a sequence that is 100% identical or with no more than one, two or three amino acid differences as compared to the corresponding CDR-L3 region within a sequence encoded by a germline nucleotide human light chain V segment and J segment.

[0349] In some embodiments, the human antibody, e.g., antigen-binding fragment, contains a framework region that contains human germline gene segment sequences. For example, in some embodiments, the human antibody contains a Vg region in which the framework region, e.g.FR1, FR2, FR3 and FR4, has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a framework region encoded by a human germline antibody segment, such as a V segment and / or J segment. In some embodiments, the human antibody contains a Vy, region in which the framework region e.g. FR1, FR2, FR3 and FR4, has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a framework region encoded by a human germline antibody segment, such as a V segment and / or J segment. For example, in some such embodiments, the framework region sequence contained within the Vg region and / or Vi region differs by no more than 10 amino acids, such as no more than 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid, compared to the framework region sequence encoded by a human germline antibody segment. b. Spacer

[0350] In some embodiments, the recombinant receptor such as a CAR comprising an antibody (e.g., antigen-binding fragment) provided herein, further includes a spacer, which may be or include at least a portion of an immunoglobulin constant region or variant or modified version thereof. In some embodiments, the portion of the immunoglobulin constant regon includes a hinge region, e.g., an IgG4 hinge region, and / or a Cul, Cu2 or Cu3 and / or Fc region. In some embodiments, the constant region or portion is of a human IgG, such as IgG4 or IgG1. In some aspects, the portion of the constant region serves as a spacer region between the antigen-recognition component, such as antigen-binding domain (e.g., scFv) and transmembrane domain. In some embodiments, the length of the spacer is adjusted to optimize the biophysical synapse distance between the CAR-expressing cell, such as a CAR-expressing cell, and the target of the CAR, such as a GPRC5D-expressing tumor cell. In some embodiments, the CAR is expressed by a T-cell, and the length of the spacer is adjusted to a length that is compatible for T- cell activation or to optimize CAR T-cell performance.

[0351] In some embodiments, the spacer can be of a length that provides for increased responsiveness of the cell following antigen binding, as compared to in the absence of the spacer or as compared to an alternative spacer of a different length (e.g. shorter in length). In some examples, the spacer is at or about 12 amino acids in length or is no more than 12 amino acids in length. In some embodiments, the spacer is at least 100 amino acids in length, such as at least 110, 125, 130, 135, 140, 145, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, or 250 amino acids in length. Exemplary spacers include those having at least about 10 to 300 amino acids, about 10 to 200 amino acids, about 50 to 175 amino acids, about 50 to 150 amino acids, about 10 to 125 amino acids, about 50 to 100 amino acids, about 100 to 300 amino acids, about 100 to 250 amino acids, about 125 to 250 amino acids, or about 200 to 250 amino acids, and including any integer between the endpoints of any of the listed ranges. In some embodiments, a spacer region is at least about 12 amino acids, at least about 119 amino acids or less, at least about 125 amino acids, at least about 200 amino acids, or at least about 220 amino acids, or at least about 225 amino acids in length.

[0352] In some embodiments, the spacer has a length of 125 to 300 amino acids in length, 125 to 250 amino acids in length, 125 to 230 amino acids in length, 125 to 200 amino acids in length, 125 to 180 amino acids in length, 125 to 150 amino acids in length, 150 to 300 amino acids in length, 150 to 250 amino acids in length, 150 to 230 amino acids in length, 150 to 200 amino acids in length, 150 to 180 amino acids in length, 180 to 300 amino acids in length, 180 to 250 amino acids in length, 180 to 230 amino acids in length, 180 to 200 amino acids in length, 200 to 300 amino acids in length, 200 to 250 amino acids in length, 200 to 230 amino acids in length, 230 to 300 amino acids in length, 230 to 250 amino acids in length or 250 to 300 amino acids in length. In some embodiments, the spacer is at least or at least about or is or is about 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 221, 222, 223, 224, 225, 226, 227, 228 or 229 amino acids in length, or a length between any of the foregoing.

[0353] Exemplary spacers include an IgG hinge alone, an IgG hinge linked to one or more of a C2 and Cy3 domain, or IgG hinge linked to the Cs3 domain. In some embodiments, the IgG hinge, Cu2 and / or Cu3 can be derived all or in part from IgG4 or IgG2, such as all or in part from humam IgG4 or human IgG2. In some embodiments, the spacer can be a chimeric polypeptide containing one or more of a hinge, Cu2 and / or Cu3 sequence(s) derived from IgG4, IgG2, and / or IgG2 and IgG4. In some embodiments, the hinge region comprises all or a portion of an IgG4 hinge region and / or of an IgG2 hinge region, wherein the IgG4 hinge region is optionally a human IgG4 hinge region and the IgG2 hinge region is optionally a human IgG2 hinge region; the Cy2 region comprises all or a portion of an IgG4 Cr2 region and / or of an IgG2 Cu2 region, wherein the IgG4 C2 region is optionally a human IgG4 C2 region and the IgG2 Cy2 region is optionally a human IgG2 Cu2 region; and / or the C3 region comprises all or a portion of an IgG4 Cx3 region and / or of an IgG2 Cu3 region, wherein the IgG4 Cu3 region is optionally a human IgG4 Cu3 region and the IgG2 Cr3 region is optionally a human IgG2 Cs3 region. In some embodiments, the hinge, Cu2 and Cx3 comprises all or a portion of each of a hinge region, Ca2 and Cu3 from IgG4. In some embodiments, the hinge region is chimeric and comprises a hinge region from human IgG4 and human IgG2; the Cy2 region is chimeric and comprises a C2 region from human IgG4 and human IgG2; and / or the C3 region is chimeric and comprises a Cy3 region from human IgG4 and human IgG2. In some embodiments, the spacer comprises an IgG4 / 2 chimeric hinge or a modified IgG4 hinge comprising at least one amino acid replacement compared to human IgG4 hinge region; an human IgG2 / 4 chimeric Cy2 region; and a human IgG4 Cg3 region.

[0354] In some embodiments, the spacer can be derived all or in part from IgG4 and / or IgG2 and can contain mutations, such as one or more single amino acid mutations in one or more domains. In some examples, the amino acid modification is a substitution of a proline (P) for a serine (S) in the hinge region of an IgG4. In some embodiments, the amino acid modification is a substitution of a glutamine (Q) for an asparagine (N) to reduce glycosylation heterogeneity, such as an N177Q mutation at position 177, in the Cu2 region, of the full-length IgG4 Fe sequence set forth in SEQ ID NO: 281 or an N176Q at position 176, in the Cg2 region, of the full-length IgG2 Fc sequence set forth in SEQ ID NO: 282. In some embodiments, the spacer is or comprises an IgG4 / 2 chimeric hinge or a modified IgG4 hinge; an 1gG2 / 4 chimeric Cu2 region; and an IgG4 Cu3 region. In some embodiments, the spaceris about 228 amino acids in length. In some embodiments, the spacer is set forth in SEQ ID NO: 17. In some embodiments, the spacer comprises the amino acid sequence ESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHN AKTKPREEQFQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQID NO: 17)

[0355] In some embodiments, the spacer is encoded by a polynucleotide that has been optimized for codon expression and / or to eliminate splice sites such as cryptic splice sites. In some embodiments, the coding sequence for the spacer comprises the nucleic acid sequence set forth in SEQ ID NO: 74. In some embodiments, the coding sequence for the spacer comprises the nucleic acid sequence set forth in SEQ ID NO: 73. In some embodiments, the coding sequence for the spacer comprises the nucleic acid sequence set forth in SEQ ID NO: 283. In some embodiments, the coding sequence for the spacer comprises the nucleic acid sequence set forth in SEQ ID NO: 284.

[0356] Additional exemplary spacers include, but are not limited to, those described in Hudecek er al. (2013) Clin. Cancer Res., 19:3153, Hudecek er al. (2015) Cancer Immunol. Res., 3(2):125-135, or international patent application publication number W02014031687. In some embodiments, the nucleotide sequence of the spacer is optimized to reduce RNA heterogeneity upon expression. In some embodiments, the nucleotide sequence of the spacer is optimized to reduce cryptic splice sites or reduce the likelihood of a splice event at a splice site.

[0357] In some embodiments, the spacer has the amino acid sequence set forth in SEQ ID NO:15, and is encoded by the polynucleotide sequence set forth in SEQ ID NO:285. In some embodiments, the spacer has the amino acid sequence set forth in SEQ ID NO:16. In some embodiments, the spacer has the amino acid sequence set forth in SEQ ID NO:286. In some embodiments, the spacer has the amino acid sequence set forth in SEQ ID NO: 288, and is encoded by the polynucleotide sequence set forth in SEQ ID NO: 287. In some embodiments, the spacer has an amino acid sequence set forth in SEQ ID NO: 17, encoded by the polynucleotide sequence set forth in SEQ ID NO: 73, 74, 283 or 284 or a polynucleotide that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%. 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 73, 74, 283 or 284.

[0358] In some embodiments, the spacer has an amino acid sequence that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 17, encoded by a polynucleotide that has been optionally optimized for codon usage and / or to reduce RNA heterogeneity. Methods to reduce RNA heterogeneity, such as by removing cryptic splice donor and / or acceptor sites, are described below, such as in Section L.B.2.b. Observations have shown that cryptic splice donor and / or acceptor sites are present in the spacer region of certain immunoglobulin spacers when present in a CAR. In some embodiments, the spacer in a provided CAR is encoded by a polynucleotide in which one or more cryptic splice donor and / or acceptor sites are eliminated and / or are modified to reduce heterogeneity of the RNA transcribed from the construct, such as mRNA, following expression in a cell. In some embodiments, the spacer is encoded by the nucleotide sequence set forth in SEQ ID NO:74 (also set forth in SEQ ID NO:48). In some embodiments, the spacer is encoded by the nucleotide sequence set forth in SEQ ID NO:283. In some embodiments, the spacer is encoded by the nucleotide sequence set forth in SEQ ID NO:284. In some embodiments, the spacer is encoded by the nucleotide sequence set forth in SEQ ID NO:305. G Transmembrane domain and intracellular signaling components

[0359] The antigen-recognition component generally is linked to one or more intracellular signaling components, such as signaling components that mimic activation through an antigen receptor comp...

Claims

Claims 1. A chimeric antigen receptor comprising: (1) an extracellular antigen-binding domain that specifically binds human G-protein coupled receptor class C group 5 member D (GPRCS5D), wherein the extracellular antigen-binding domain comprises: (1) a variable heavy chain (Vy) region comprising an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:21, 23, 25, 27, 29, 31 or 33; and (ii) a variable light chain (V1) region comprising an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:22, 24, 26, 28, 30, 32, 34, 63, 64, 65, 66, 67, 68 or 69; (2) a spacer of at least 125 amino acids in length; (3) a transmembrane domain; and (4) an intracellular signaling region.

2. A chimeric antigen receptor comprising: (1) an extracellular antigen-binding domain that specifically binds human G-protein coupled receptor class C group 5 member D (GPRCSD), wherein the extracellular antigen-binding domain comprises: (i) a variable heavy chain (Vy) region comprising a heavy chain complementarity determining region 1 (CDR-H1), heavy chain complementarity determining region 2 (CDR-H2) and heavy chain complementarity determining region 3 (CDR-H3) contained within the Vi region amino acid sequence selected from SEQ ID NOs: 21, 23, 25, 27, 29, 31, and 33; and (ii) a variable light chain (V1) region comprising a light chain complementarity determining region 1 (CDR-L1), light chain complementarity determining region 2 (CDR-L2) and light chain complementarity determining region 3 (CDR-L3) contained within the Vi region amino acid sequence selected from SEQ ID NOs: 22, 24, 26, 28, 30, 32, 34, 63, 64, 65, 66, 67, 68, and 69; (2) a spacer of at least 125 amino acids in length; (3) a transmembrane domain; and (4) an intracellular signaling region.

3. A chimeric antigen receptor comprising: (1) an extracellular antigen-binding domain that specifically binds human G-protein coupled receptor class C group 5 member D (GPRC5D), wherein the extracellular antigen-binding domain comprises: (1) a variable heavy chain (Vy) region comprising a CDR-HI comprising the amino acid sequence selected from SEQ ID NOs: 75, 78, 80, 90,93, 95, 105, 108, 110, 120, 123, 125, 135, 138, 140, 152, 162, 165, and 167; (b) a CDR-H2 comprising the amino acid sequence selected from SEQ ID NOs: 76,79, 81, 91, 94, 96, 106, 109, 111, 121, 124, 126, 136, 139, 141, 150, 153, 154, 163, 166, and 168; and (c) a CDR-H3 comprising the amino acid sequence selected from SEQ ID NOs: 77, 92, 107, 122, 137. 151, and 164; and (ii) a variable light chain (V1) region comprising a CDR-L1 comprising the amino acid sequence selected from SEQ ID NOs: 85, 100, 115, , 130, 145, 157, and 172; (b) a CDR-L2 comprising the amino acid sequence selected from SEQ ID NOs: 86, 101, 116, 131, 146, and 158; and (c) a CDR-L3 comprising the amino acid sequence selected from SEQ ID NOs: 87, 102, 117, 132, 147, 159, 173, and 297; (2) a spacer of at least 125 amino acids in length; (3) a transmembrane domain; and (4) an intracellular signaling region.

4. The chimeric antigen receptor of claim 2 or claim 3, wherein the extracellular antigen- binding domain comprises: (1) a variable heavy chain (Vu) region comprising: an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:21, 23, 25, 27, 29, 31 or 33; and (ii) a variable light chain (V1) region comprising an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:22, 24, 26, 28, 30, 32, 34, 63, 64, 65, 66, 67, 68 or 69. 5 The chimeric antigen receptor of any of claims 1-4, wherein the spacer has a length of between 125 and 300 or of between about 125 and about 300, of between 125 and 250 or of between about 125 and about 250, of between 125 and 230 or of between about 125 and about 230, of between 125 and 200 or of between about 125 and about 200, of between 125 and 180 or of between about 125 and about 180, of between 125 and 150 or of between about 125 and about 150, of between 150 and 300 or of between about 150 and about 300, of between 150 and 250 or of between about 150 and about 250, of between 150 and 230 or of between about 150 and about 230, of between 150 and 200 or of between about 150 and about 200, of between 150 and 180 or of between about 150 and about 180, of between 180 and 300 or of between about 180 and about 300, of between 180 and 250 or of between about 180 and about 250, of between 125 and 300 or of between about 125 and about 300, of between 180 and 230 or of between about 180 and about 230, of between 180 and 200 or of between about 180 and about 200, of between 200 and 300 or of between about 200 and about 300, of between 200 and 250 or of between about 200 and about 250, of between 200 and 230 or of between about 200 and about 230, of between 230 and 300 or of between about 230 and about 300, of between 230 and 250 or of between about 230 and about 250 or of between 250 and 300 or of between about 250 and about 300.

6. The chimeric antigen receptor of any of claims 1-5, wherein: the spacer is, or is at least about, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 221, 222, 223,224, 225, 226, 227, 228 or 229 amino acids in length, or has a length between any of the foregoing; or the spacer is about, or is at least about, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 221, 222,223, 224,225,226, 227, 228 or 229 amino acids in length, or has a length between any of the foregoing.

7. The chimeric antigen receptor of any of claims 1-6, wherein the spacer comprises a portion of an immunoglobulin.

8. The chimeric antigen receptor of any of claims 1-7, wherein the spacer comprises a sequence of a hinge region, a CH2 and CH3 region.

9. The chimeric antigen receptor of claim 8, wherein: the hinge region comprises all or a portion of an IgG4 hinge region and / or an IgG2 hinge region, wherein the IgG4 hinge region is optionally a human IgG4 hinge region and the IgG2 hinge region is optionally a human IgG2 hinge region; the Cu2 region comprises all or a portion of an IgG4 Cy2 and / or an IgG2 Cu2, wherein the IgG4 Cu2 is optionally a human IgG4 Cu2 and the IgG2 Cg2 is optionally a human IgG2 Cy2; and / or the Cy3 region comprises all or a portion of an IgG4 Cy3 and / or an IgG2 Cu3, wherein the IgG4 Cw3 is optionally a human IgG4 Cyu3 and the IgG2 Cg3 is optionally a human IgG2 Cg3.

10. The chimeric antigen receptor of claim 8 or claim 9, wherein the hinge region, CH2 and CH3 comprises all or a portion of a hinge, all or a portion of a Cs2 and all or a portion of a Cx3 from human IgG4.

11. The chimeric antigen receptor of claim 8 or claim 9, wherein one or more of the hinge region, the C2 and the Cy3 is chimeric and comprises a hinge, Cx2 and Cu3 from human IgG4 and human IgG2.

12. The chimeric antigen receptor of any of claims 1-11, wherein the spacer comprises an 1gG4 / 2 chimeric hinge region or a modified IgG4 hinge region comprising at least one amino acid replacement compared to a human IgG4 hinge; an IgG2 / 4 chimeric Cy2 region; and an IgG4 Cy3 region.

13. The chimeric antigen receptor of any of claims 1-12, wherein the spacer is or comprises (i) the sequence set forth in SEQ ID NO: 17; (ii) a functional variant of SEQ ID NO:17 that has at least at or about 95%, at or about 96%, at or about 97%, at or about 98% or at or about 99% sequence identity to SEQ ID NO:17; or (iii) a contiguous portion of (i) or (ii) that is at least 125 amino acids in length.

14. The chimeric antigen receptor of any of claims 1-13, wherein the spacer is or comprises the sequence set forth in SEQ ID NO:

17. 1s. The chimeric antigen receptor of any of claims 1-14, wherein the spacer is or comprises the amino acid sequence encoded by the nucleotide sequence set forth in SEQ ID NO:

74.

16. The chimeric antigen receptor of any of claims 1-15, wherein: the Vy region comprises the amino acid sequence set forth in SEQ ID NO:21 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:21; and the Vy region comprises the amino acid sequence set forth in SEQ ID NO:22 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:22; the Vy region comprises the amino acid sequence set forth in SEQ ID NO:21 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:21; and the Vy region comprises the amino acid sequence set forth in SEQ ID NO:63 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%; at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:63; the Vy region comprises the amino acid sequence set forth in SEQ ID NO:23 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:23; and the Vy. region comprises the amino acid sequence set forth in SEQ ID NO:24 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:24; the Vi region comprises the amino acid sequence set forth in SEQ ID NO:23 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:23; and the Vy. region comprises the amino acid sequence set forth in SEQ ID NO:64 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:64; the Vy region comprises the amino acid sequence set forth in SEQ ID NO:25 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:25; and the Vy. region comprises the amino acid sequence set forth in SEQ ID NO:26 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%; at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:26; the Vy region comprises the amino acid sequence set forth in SEQ ID NO:25 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:25; and the Vy region comprises the amino acid sequence set forth in SEQ ID NO:65 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:65; the Vi region comprises the amino acid sequence set forth in SEQ ID NO:27 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:27; and the Vy. region comprises the amino acid sequence set forth in SEQ ID NO:28 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%; at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:28; the Vi region comprises the amino acid sequence set forth in SEQ ID NO:27 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:27; and the Vy. region comprises the amino acid sequence set forth in SEQ ID NO:66 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:66; the Vi region comprises the amino acid sequence set forth in SEQ ID NO:29 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:29; and the Vy region comprises the amino acid sequence set forth in SEQ ID NO:30 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:30; the Vi region comprises the amino acid sequence set forth in SEQ ID NO:29 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:29; and the Vy region comprises the amino acid sequence set forth in SEQ ID NO:67 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:67; the Vu region comprises the amino acid sequence set forth in SEQ ID NO:31 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:31; and the Vy. region comprises the amino acid sequence set forth in SEQ ID NO:32 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%; at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:32; the Vy region comprises the amino acid sequence set forth in SEQ ID NO:31 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:31; and the Vy region comprises the amino acid sequence set forth in SEQ ID NO:68 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:68; the Vy region comprises the amino acid sequence set forth in SEQ ID NO:33 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:33; and the Vy region comprises the amino acid sequence set forth in SEQ ID NO:34 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:34; or the Vi region comprises the amino acid sequence set forth in SEQ ID NO:33 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:33; and the Vy. region comprises the amino acid sequence set forth in SEQ ID NO:69 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%; at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:

69.

17. The chimeric antigen receptor of any of claims 1-16, wherein: the Vy region comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:80, 81 and 77, respectively, and the V1 region comprises the amino acid sequences of SEQ ID NOS:85, 86 and 87, respectively; the Vy region comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:95, 96, 92, respectively, and the Vi region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:100, 101 and 102, respectively; the Vy region comprises a CDR-HI, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:110, 111 and 107, respectively, and the Vi region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequencse of SEQ ID NOS:115, 116 and 117, respectively; the Vy region comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:125, 126 and 122, respectively, and the Vi region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:130, 131 and 132, respectively; the Vy region comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:140, 141 and 137, respectively, and the Vi region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:145, 146 and 147, respectively; the Vy region comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:140, 154 and 151, respectively, and the Vi region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:157, 158 and 159, respectively; the Vy region comprisesa CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:167, 168 and 164, respectively, and the Vy region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:172, 86, 173, respectively; or the Vi region comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:169, 170 and 171, respectively, and the Vi region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:174, 89 and 297, respectively.

18. The chimeric antigen receptor of any of claims 1-17, wherein: the Vy region and the Vi region comprise the amino acid sequence set forth in SEQ ID NOs:21 and 22, respectively or the amino acid sequence set forth in SEQ ID NOs: 21 and 63, respectively; the Vg region and the Vi region comprise the amino acid sequence set forth in SEQ ID NOs:23 and 24, respectively or the amino acid sequence set forth in SEQ ID NOs:23 and 64, respectively; the Vg region and the Vi region comprise the amino acid sequence set forth in SEQ ID NOs:25 and 26, respectively or the amino acid sequence set forth in SEQ ID NOs: 25 and 65, respectively; the Vy region and the Vi region comprise the amino acid sequence set forth in SEQ ID NOs:27 and 28, respectively or the amino acid sequence set forth in SEQ ID NOs: 27 and 66, respectively; the Vy region and the Vy region comprise the amino acid sequence set forth in SEQ ID NOs:29 and 30, respectively or the amino acid sequence set forth in SEQ ID NOs:29 and 67, respective; the Vy region and the Vi region comprise the amino acid sequence set forth in SEQ ID NOs:31 and 32, respectively or the amino acid sequence set forth in SEQ ID Nos: 31 and 68, respectively; or the Vg region and the Vp region comprise the amino acid sequence set forth in SEQ ID NOs:33 and 34 or the amino acid sequence set forth in SEQ ID Nos: 33 and 69, respectively, respectively.

19. The chimeric antigen receptor of any of claims 1-18, wherein: the Vy region comprises the amino acid sequence set forth in SEQ ID NO:21 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:21; and the Vy region comprises the amino acid sequence set forth in SEQ ID NO:22 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:22; the Vy region comprises the amino acid sequence set forth in SEQ ID NO:21 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:21; and the Vy. region comprises the amino acid sequence set forth in SEQ ID NO:63 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:63; the Vi region comprises the amino acid sequence set forth in SEQ ID NO:23 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:23; and the Vy region comprises the amino acid sequence set forth in SEQ ID NO:24 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:24; the Vi region comprises the amino acid sequence set forth in SEQ ID NO:23 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:23; and the Vy. region comprises the amino acid sequence set forth in SEQ ID NO:64 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:64; the Vu region comprises the amino acid sequence set forth in SEQ ID NO:27 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:27; and the Vy. region comprises the amino acid sequence set forth in SEQ ID NO:28 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%; at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:28; the Vy region comprises the amino acid sequence set forth in SEQ ID NO:27 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:27; and the Vy region comprises the amino acid sequence set forth in SEQ ID NO:66 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:66; the Vi region comprises the amino acid sequence set forth in SEQ ID NO:31 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:31; and the Vy region comprises the amino acid sequence set forth in SEQ ID NO:32 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:32; or the Vi region comprises the amino acid sequence set forth in SEQ ID NO:31 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:31; and the Vy region comprises the amino acid sequence set forth in SEQ ID NO:68 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:

68.

20. The chimeric antigen receptor of any of claims 1-19, wherein: the Vy region comprises a CDR-HI, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:80, 81 and 77, respectively, and the Vi region comprises a CDR-L1, CDR- L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:85, 86 and 87, respectively; the Vy region comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:95, 96, 92, respectively, and the Vp region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:100, 101 and 102, respectively; the Vy region comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:125, 126 and 122, respectively, and the Vi region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:130, 131 and 132, respectively; or the Vy region comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:140, 154 and 151, respectively, and the Vi region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:157, 158 and 159, respectively.

21. The chimeric antigen receptor of any of claims 1-20, wherein: the Vy region and the Vi region comprise the amino acid sequence set forth in SEQ ID NOs:21 and 22, respectively or the amino acid sequence set forth in SEQ ID Nos: 21 and 63, respectively; the Vy region and the Vy region comprise the amino acid sequence set forth in SEQ ID NOs:23 and 24, respectively or the amino acid sequence set forth in SEQ ID Nos: 23 and 64, respectively; the Vy region and the Vy region comprise the amino acid sequence set forth in SEQ ID NOs:27 and 28, respectively or the amino acid sequence set forth in SEQ ID Nos: 27 and 66, respectively; or the Vy region and the Vy region comprise the amino acid sequence set forth in SEQ ID NOs:31 and 32, respectively or the amino acid sequence set forth in SEQ ID Nos: 31 and 68, respectively.

22. The chimeric antigen receptor of any of claims 1-21, wherein: the Vy region comprises the amino acid sequence set forth in SEQ ID NO:27 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:27; and the Vy region comprises the amino acid sequence set forth in SEQ ID NO:28 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:28; or the Vy region comprises the amino acid sequence set forth in SEQ ID NO:27 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:27; and the Vy region comprises the amino acid sequence set forth in SEQ ID NO:66 or or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identity to SEQ ID NO:

66.

23. The chimeric antigen receptor of any of claims 1-22, comprising a variable heavy chain (Vg) region comprising a CDR-H1, CDR-H2 and CDR-H3 contained within the Vy region amino acid sequence set forth in SEQ ID NO: 27; and a variable light chain (V1) region comprising a CDR-L1, CDR-L2 and CDR-L3 contained within the V1 region amino acid sequence set forth in SEQ ID NO: 28 or 66.

24. The chimeric antigen receptor of any of claims 1-23, wherein the Vu region comprises the amino acid sequence of SEQ ID NOS:125, 126 and 122, respectively, and the Vi region comprises the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively.

25. The chimeric antigen receptor of any of claims 1-23, wherein the Vu region comprises the amino acid sequence of SEQ ID NOS:127, 128 and 129, respectively, and the Vi region comprises the amino acid sequence of SEQ ID NOS:133, 134 and 132, respectively.

26. The chimeric antigen receptor of any of claims 1-23, wherein the Vu region comprises the amino acid sequence of SEQ ID NOS:120, 121 and 122, respectively, and the Vi region comprises the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively.

27. The chimeric antigen receptor of any of claims 1-23, wherein the Vy region comprises the amino acid sequence of SEQ ID NOS:123, 124 and 122, respectively, and the Vi region comprises the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively.

28. The chimeric antigen receptor of any of claims 1-23, wherein the Vy region and the Vp. regions comprise the amino acid sequence set forth in SEQ ID NOs:27 and 28, respectively or the amino acid sequence set forth in SEQ ID Nos: 27 and 66, respectively.

29. The chimeric antigen receptor of any of claims 1-28, wherein the extracellular antigen- binding domain is a single chain antibody fragment.

30. The chimeric antigen receptor of any of claims 1-29, wherein the single chain antibody fragment is or comprises a single chain variable fragment (scFv).

31. The chimeric antigen receptor of any of claims 1-30, when the Vy region and the Vi region are joined by a flexible linker.

32. The chimeric antigen receptor of claim 31, wherein the linker comprises the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO:52).

33. The chimeric antigen receptor of any of claims 1-32, wherein the Vy region is amino- terminal to the Vy region. 34, The chimeric antigen receptor of any of claims 1-33, wherein: the extracellular antigen-binding domain comprises an amino acid sequence selected from SEQ ID NOs: 1, 3,5,7,9, 11, and 13 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence selected from SEQIDNOs: 1,3,5,7,9, 11, and 13; and / or the extracellular antigen-binding domain is encoded by the nucleotide sequence selected from SEQ ID Nos: 257, 259, 261, 263, 265, 267, and 269 or a nucleotide sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the nucleotide sequence selected from SEQ ID Nos: 257, 259, 261, 263, 265, 267, and 269. 3s. The chimeric antigen receptor of any of claims 1-34, wherein the extracellular antigen- binding domain comprises the amino acid sequence selected from SEQ ID NOs: 1, 3,5, 7,9, 11, and 13.

36. The chimeric antigen receptor of any of claims 1-34, wherein the extracellular antigen- binding domain comprises the amino acid sequence selected from SEQ ID NOs: 1, 3, 7, and 11 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence selected from SEQ ID NOs: 1, 3, 7, and 11.

37. The chimeric antigen receptor of any of claims 1-36, wherein the antigen-binding domain comprises the amino acid sequence selected from SEQ ID NOs: 1, 3, 7, and 11.

38. The chimeric antigen receptor of any of claims 1-34 or 37, wherein the antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO: 7 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

7.

39. The chimeric antigen receptor of any of claims 1-38, wherein the antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO:

7.

40. The chimeric antigen receptor of any of claims 1-32, wherein the Vy region is carboxy- terminal to the Vi region.

41. The chimeric antigen receptor of any of claims 1-32 and 40, wherein: the extracellular antigen-binding domain comprises the amino acid sequence selected from SEQ ID NOs: 2, 4, 6, 8, 10, 12, and 14 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence selected from SEQ ID NOs: 2, 4, 6, 8, 10, 12, and 14; and / or the extracellular antigen-binding domain is encoded by the nucleotide sequence selected from SEQ ID Nos: 258, 260, 262, 264, 266, 268, and 270 or a nucleotide sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the nucleotide sequence selected from SEQ ID Nos: 258, 260, 262, 264, 266, 268, and 270.

42. The chimeric antigen receptor of any of claims 1-32, 40 and 41, wherein the extracellular antigen-binding domain comprises the amino acid sequence selected from SEQ ID NOs: 2, 4, 6, 8, 10, 12, and 14.

43. The chimeric antigen receptor of any of claims 1-32, 40 and 41, wherein the extracellular antigen-binding domain comprises the amino acid sequence selected from SEQ ID NOs: 2, 4, 8, and 12 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence selected from SEQ ID NOs: 2, 4, 8, and 12.

44. The chimeric antigen receptor of any of claims 1-32 or 40-43, wherein the extracellular antigen-binding domain comprises the amino acid sequence selected from SEQ ID NOs: 2, 4, 8, and 12.

45. The chimeric antigen receptor of any of claims 1-32, 40, 41 and 43, wherein the antigen- binding domain comprises the amino acid sequence set forth in SEQ ID NO: 8 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

8.

46. The chimeric antigen receptor of any of claims 1-32 or 40- 45, wherein the extracellular antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO:

8.

47. The chimeric antigen receptor of any of claims 1-46, wherein the intracellular signaling region comprises an intracellular cytoplasmic signaling domain.

48. The chimeric antigen receptor of claim 47, wherein the intracellular signaling domain is or comprises a cytoplasmic signaling domain of a CD3-zeta (CD3() chain or a functional variant or signaling portion thereof.

49. The chimeric antigen receptor of any of claims 47 or 48, wherein the intracellular signaling domain is or comprises the amino acid sequence set forth in SEQ ID NO:20 or an amino acid that has at least at or about 90%, at or about 91%; at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:

20.

50. The chimeric antigen receptor of any of claims 47-49, wherein the intracellular signaling region further comprises a costimulatory signaling region.

51. The chimeric antigen receptor of claim 50, wherein the costimulatory signaling region comprises an intracellular signaling domain of CD28, 4-1BB, or ICOS, or a signaling portion thereof. s2. The chimeric antigen receptor of any of claims 50 or 51, wherein the costimulatory signaling region comprises an intracellular signaling domain of CD28.

53. The chimeric antigen receptor of any of claims 50-52, wherein the costimulatory signaling region is or comprises the amino acid sequence set forth in SEQ ID NO:46 or an amino acid sequence that has at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequence set forth in SEQ ID NO:

46.

54. The chimeric antigen receptor of any of claims 50 or 51, wherein the costimulatory signaling region comprises an intracellular signaling domain of 4-1BB.

5. The chimeric antigen receptor of any of claims 50, 51, and 54, wherein the costimulatory signaling region is or comprises the amino acid sequence set forth in SEQ ID NO:19 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequence set forth in SEQ ID NO:

19.

56. The chimeric antigen receptor of any of claims 50-55, wherein the costimulatory signaling region is between the transmembrane domain and the intracellular signaling region.

57. The chimeric antigen receptor of any of claims 1-56, wherein the transmembrane domain is or comprises a transmembrane domain from CD4, CD28, or CD8.

58. The chimeric antigen receptor of any of claims 1-57, wherein the transmembrane domain is or comprises a transmembrane domain derived from CD28.

59. The chimeric antigen receptor of any of claims 1-58, wherein the transmembrane domain is or comprises the amino acid sequence set forth in SEQ ID NO:18 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequence set forth in SEQ ID NO:

18.

60. A chimeric antigen receptor comprising: (1) an extracellular antigen-binding domain that specifically binds human G-protein coupled receptor class C group 5 member D (GPRCS5D), wherein the extracellular antigen-binding domain comprises: (1) a variable heavy chain (Vu) region comprising an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 27; and (ii) a variable light chain (V1) region comprising an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 28 or 66; (2) a spacer comprising an IgG4 / 2 chimeric hinge or a modified IgG4 hinge; an IgG2 / 4 chimeric Cn2 region; and an IgG4 Cu3 region, optionally that is about 228 amino acids in length or a spacer set forth in SEQ ID NO:17; (3) a transmembrane domain from human CD28; and (4) an intracellular signaling region comprising a cytoplasmic signaling domain of a CD3-zeta (CD3{) chain and an intracellular signaling domain of a T cell costimulatory molecule.

61. The chimeric antigen receptor of claim 60, wherein: the Vy region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the Vg region amino acid sequence set forth in SEQ ID NO: 27; and the Vy region comprises a CDR-L1, CDR-L2 and CDR-L3 contained within the Vy region amino acid sequence set forth in SEQ ID NO: 28 or 66; or the Vu region a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:125, 126 and 122, respectively, and the Vi region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively; the Vy region comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:120, 121 and 122, respectively, and the Vy region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively; or the Vy region comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:123, 124 and 122, respectively, and the Vy region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively.

62. A chimeric antigen receptor comprising: (1) an extracellular antigen-binding domain that specifically binds human G-protein coupled receptor class C group 5 member D (GPRCS5D), wherein the extracellular antigen-binding domain comprises: a Vy region comprising a CDR-H1, CDR-H2 and CDR-H3 contained within the Vg region amino acid sequence set forth in SEQ ID NO: 27; and a variable light (V1) region comprising a CDR-L1, CDR- L2 and CDR-L3 contained within the V1 region amino acid sequence set forth in SEQ ID NO: 28 or 66; or a Vy region comprising a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:125, 126 and 122, respectively, and a Vi region comprising a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively; a Vu region comprising a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:120, 121 and 122, respectively, and a Vp region comprising a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively; or a Vu region comprising a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:123, 124 and 122, respectively, and a Vp region comprising a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:130, 131 and 132, respectively; (2) a spacer comprising an IgG4 / 2 chimeric hinge or a modified IgG4 hinge; an IgG2 / 4 chimeric Cn2 region; and an IgG4 Cu3 region, optionally that is about 228 amino acids in length or a spacer set forth in SEQ ID NO:17; (3) a transmembrane domain from human CD28; and (4) an intracellular signaling region comprising a cytoplasmic signaling domain of a human CD3-zeta (CD3() chain and an intracellular signaling domain of a human CD28 or a human 4-1BB.

63. The chimeric antigen receptor of any of claims 60-62, wherein: the extracellular antigen-binding domain comprises the Vy region amino acid sequence set forth in SEQ ID NO:27 and the Vy region amino acid sequence set forth in SEQ ID NO:28 or 66; and / or the extracellular antigen-binding domain comprises an scFv set forth in SEQ ID NO:7 or SEQ ID NO:

8.

64. The chimeric antigen receptor of any of claims 60-63, wherein the transmembrane domain is or comprises the amino acid sequence set forth in SEQ ID NO:18 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:

18.

65. The chimeric antigen receptor of any of claims 60-64, wherein the intracellular signaling region comprises (a) the amino acid sequence set forth in SEQ ID NO:20 or an amino acid sequence that has at least at or about 90%, at or about 91%, at or about 92%; at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:20 and (b) the amino acid sequence set forth in SEQ ID NO:46 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequence set forth in SEQ ID NO:

46.

66. The chimeric antigen receptor of any of claims 60-65, wherein the intracellular signaling region is or comprises the sequences set forth in SEQ ID NO:20 and SEQ ID NO:

46.

67. The chimeric antigen receptor of any of claims 60-64, wherein the intracellular signaling region comprises (a) the amino acid sequence set forth in SEQ ID NO:20 or an amino acid sequence that has at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:20 and (b) the amino acid sequence set forth in SEQ ID NO:19 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequence set forth in SEQ ID NO:

19.

68. A polynucleotide comprising a nucleotide sequence encoding the chimeric antigen receptor of any of claims 1-67.

69. The polynucleotide of claim 68, wherein the nucleic acid encoding the spacer comprises at least one modified splice donor and / or splice acceptor site, said modified splice donor and / or acceptor site comprising one or more nucleotide modifications corresponding to a reference splice donor site and / or reference splice acceptor site contained in the sequence set forth in SEQ ID NO:

73.

70. The polynucleotide of claim 69, wherein the one or more nucleotide modifications comprise an amino acid substitution.

71. The polynucleotide of any of claim 69 and 70, wherein: the reference splice donor and / or reference splice acceptor site(s) has a splice site prediction score of at least at or about 0.4, at or about 0.5, at or about 0.6, at or about 0.70, at or about 0.75, at or about 0.80, at or about 0.85, at or about 0.90, at or about 0.95, at or about 0.99, or at or about 1.0; and / or the reference splice donor and / or reference splice acceptor site(s) is / are predicted to be involved in a splice event with a probability of at least at or about 40%, at or about 50%, at or about 60%, at or about 70%, at or about 75%, at or about 80%, at or about 85%, at or about 90%, at or about 95%, at or about 99%, or at or about 100%.

72. The polynucleotide of any of claims 69-71, wherein: the reference splice donor site comprises the sequence aatctaagtacggac (SEQ ID NO: 176), tcaactggtacgtgg (SEQ ID NO:177), acaattagtaaggea (SEQ ID NO:178) and / or accacaggtgtatac (SEQ ID NO:179); and / or the reference splice acceptor site comprises the sequence aagtttctttctgtattecaggetgaccgtggataaatcte (SEQ ID NO: 180) and / or gggcaacgtgttctettgeagtgteatgeacgaageectge (SEQ ID NO:181).

73. The polynucleotide of any of claims 69-72, wherein: the reference splice donor site comprises the sequence tcaactggtacgtgg (SEQ ID NO:177); and / or the reference splice acceptor site comprises the sequence aagtttctttctgtattecaggetgaccgtggataaatcte (SEQ ID NO: 180).

74. The polynucleotide of any of claims 69-73, wherein the one or more nucleotide modifications is silent and / or results in a degenerate codon compared to SEQ ID NO:73 and / or does not change the amino acid sequence of the encoded spacer.

745. The polynucleotide of any of claims 69-74, wherein: the modified splice donor site is set forth in agtctaaatacggac (SEQ ID NO:182), tcaactggtatgtgg (SEQ ID NO:183), accatctccaaggee (SEQ ID NO:184) and / or gccecaggtttacac (SEQ ID NO:185); and / or the modified splice acceptor site is set forth in cagtttcttcctgtatagtagactcacegtggataaatcaa (SEQ ID NO:186), gggcaacgtgticagetgeagegtgatgecacgaggecctge (SEQ ID NO: 187) and / or cgecttgtecteettgtcecgeteetectgttgeeggacet (SEQ ID NO: 188).

76. The polynucleotide of any of claims 69-75, wherein the modified splice donor site is set forth in tcaactggtatgtgg (SEQ ID NO:183) and / or the modified acceptor site is set forth in cagtttcttcctgtatagtagactcaccgtggataaatcaa (SEQ ID NO: 186) and / or cgecttgtcctecttgteecgeteetectgttgeeggacet (SEQ ID NO: 188).

77. The polynucleotide of any of claims 69-76, wherein the spacer is encoded by the nucleotide sequence set forth in SEQ ID NO:

74.

78. The polynucleotide of any of claims 68-77, wherein, upon expression in a cell, the transcribed RNA, optionally messenger RNA (mRNA), from the polynucleotide exhibits reduced heterogeneity compared to the heterogeneity of the mRNA transcribed from a reference polynucleotide, said reference polynucleotide encoding the same amino acid sequence as the polynucleotide, wherein the reference polynucleotide differs by the presence of one or more splice donor site and / or one or more splice acceptor site in the nucleic acid encoding the spacer and / or comprises one or more nucleotide modifications compared to the polynucleotide and / or comprises the spacer set forth in SEQ ID NO:

73.

79. The polynucleotide of any of claims 68-78, wherein the polynucleotide is codon- optimized for expression in a human cell.

80. The polynucleotide of any of claims 68-78, wherein the chimeric antigen receptor is a first chimeric antigen receptor and the polynucleotide further comprises a nucleotide sequence encoding a second chimeric antigen receptor.

81. The polynucleotide of claim 80, wherein the first and second chimeric antigen receptors are separated by one or more multicistronic element(s).

82. The polynucleotide of claim 81, wherein the one or more multicistronic element is or comprises a ribosome skip sequence, optionally wherein the ribosome skip sequence is a T2A, a P2A, an E2A., or an F2A element.

83. The polynucleotide of claim 82, wherein the nucleotide sequence encoding the one or ‘more multicistronic element is codon diverged.

84. The polynucleotide of claim 82 or claim 83, wherein the nucleotide sequence encoding the one or more multicistronic element is or comprises the sequence set forth in SEQ ID NO:

319.

85. The polynucleotide of any of claims 80-84, wherein the second chimeric antigen receptor (CAR) comprises an extracellular antigen-binding domain that specifically binds a second antigen expressed on or associated with multiple myeloma.

86. The polynucleotide of 85, wherein the second CAR further comprises a spacer, a transmembrane domain, and an intracellular signaling region.

87. The polynucleotide of claim 85 or claim 86, wherein the second antigen is selected from B cell maturation antigen (BCMA), CD38, CD138, CS-1, BAFF-R, TACI, and FcRHS.

88. The polynucleotide of any of claims 85-87, wherein the second antigen is BCMA.

89. The polynucleotide of any of claims 85-88, wherein the second CAR comprises: (1) an extracellular antigen-binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain comprises: (1) a variable heavy chain (Vu) region comprising an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NOs: 189, 191, 193, 195 or 197; and (ii) a variable light chain (V1) region comprising an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 190, 192, 194, 196 or 198; (2) a spacer, optionally a spacer comprising an IgG4 / 2 chimeric hinge or a modified IgG4 hinge; an IgG2 / 4 chimeric Cu2 region; and an IgG4 Cu3 region, optionally that is about 228 amino acids in length, or a spacer set forth in SEQ ID NO:17; (3) a transmembrane domain; and (4) an intracellular signaling region.

90. The polynucleotide of claim 89, wherein the Vi region of the second CAR comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the Vy region amino acid sequence set forth in SEQ ID NO: 189, 191, 193, 195 or 197; and the Vi region of the second CAR comprises a CDR-L1, CDR-L2 and CDR-L3 contained within the Vy region amino acid sequence set forth in SEQ ID NO: 190, 192, 194, 196 or 198.

91. The polynucleotide of any of claims 85-88, wherein the second CAR comprises: (1) an extracellular antigen-binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain comprises: (i) a variable heavy chain (Vy) region comprising a heavy chain complementarity determining region 1 (CDR-H1) comprising the amino acid sequence selected from SEQ ID NOs: 199, 202, 206, and 209; (b) a heavy chain complementarity determining region 2 (CDR-H2) comprising the amino acid sequence selected from SEQ ID NOs: 200, 203, 207, and 210; and (c) a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence selected from SEQ ID NOs: 201, 204, 205, 208, and 211; and (ii) a variable light chain (V1) region comprising a light chain complementarity determining region 1 (CDR-L1) comprising the amino acid sequence selected from SEQ ID NOs: 218, 221, 224, 227, and 230; (b) a light chain complementarity determining region 2 (CDR-L2) comprising the amino acid sequence selected from any one of SEQ ID NOs: 219, 222, 225, 228, and 231; and (c) a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence selected from SEQ ID NOs: 220, 223, and 226; (2) a spacer, optionally a spacer comprising an IgG4 / 2 chimeric hinge or a modified IgG4 hinge; an IgG2 / 4 chimeric Cu2 region; and an IgG4 Cu3 region, optionally that is at or about 228 amino acids in length, or a spacer set forth in SEQ ID NO:17; (3) a transmembrane domain; and (4) an intracellular signaling region.

92. The polynucleotide of any of claims 89-91, wherein: the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:199, 200 and 201, respectively, and the Vi region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:218, 219 and 220, respectively; the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:202, 203, 204, respectively, and the Vi region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:221, 222 and 223, respectively; the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:199, 200, 205, respectively, and the Vi region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:224, 225, and 226, respectively; the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:206, 207, 208, respectively, and the Vi region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:227, 228 and 229, respectively; or the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Viregion of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively.

93. The polynucleotide of any of claims 89-91, wherein: the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Viregion of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively.

94. The polynucleotide of any of claims 89-93, wherein: the Vy region and Vy, region of the second CAR comprise (a) the amino acid sequences set forth in SEQ ID NO:189 and SEQ ID NO:190, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:189 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%; at or about 98%, or at or about 99% sequence identity to SEQ ID NO:190; the Vy region and Vy, region of the second CAR comprise (a) the amino acid sequences set forth in SEQ ID NO:191 and SEQ ID NO:192, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:191 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:192; the Vy region and Vi region of the second CAR comprise (a) the amino acid sequences set forth in SEQ ID NO:193 and SEQ ID NO:194, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:193 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%; at or about 98%, or at or about 99% sequence identity to SEQ ID NO:194; the Vy region and Vy, region of the second CAR comprise (a) the amino acid sequences set forth in SEQ ID NO:195 and SEQ ID NO:196, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:195 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:196; or the Vy region and Vy region of the second CAR comprises (a) the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:197 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:

198.

95. The polynucleotide of any of claims 89-94, wherein: the Vy region and Vi region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:189 and SEQ ID NO:190, respectively; the Vy region and Vi region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:191 and SEQ ID NO:192; the Vy region and Vy, region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:193 and SEQ ID NO:194; the Vy region and Vy, region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:195 and SEQ ID NO:196; or the Vy region and Vy, region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively.

96. The polynucleotide of any of claims 89-95, wherein the Vu region of the second CAR is amino-terminal to the Vi region.

97. The polynucleotide of any of claims 89-95, wherein the Vy region of second CAR is carboxy-terminal to the Vi region.

98. The polynucleotide of any of claims 89-97, wherein the antigen-binding domain of the second CAR comprises the amino acid sequence selected from SEQ ID NOs: 237, 238, 239, 240, and 241 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%; at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence selected from SEQ ID NOs: 237, 238, 239, 240, and 241.

99. The polynucleotide of any of claims 89-98, wherein the antigen-binding domain of the second CAR comprises the amino acid sequence selected from SEQ ID NOs: 237, 238, 239, 240, and 241.

100. The polynucleotide of any of claims 89-99, wherein: the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Viregion of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively; and / or the Vy region and VL region of the second CAR comprises the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively; and / or the extracellular antigen-binding domain of the second CAR comprises the amino acid sequence set forth in SEQ ID NO: 241 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequence set forth in SEQ ID NO:

241.

101. The polynucleotide of any of claims 86-100, wherein the transmembrane domain of the second CAR is or comprises a transmembrane domain from CD4, CD28, or CDS, optionally from human CD4, human CD28 or human CDS.

102. The polynucleotide of any of claims 86-101, wherein: the transmembrane domain of the second CAR is or comprises a transmembrane domain from human CD28; and / or the transmembrane domain of the second CAR is or comprises the amino acid sequence set forth in SEQ ID NO:18 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:

18.

103. The polynucleotide of any of claims 86-102, wherein the intracellular signaling region of the second CAR comprises an intracellular signaling domain.

104. The polynucleotide of claim 103, wherein the intracellular signaling domain of the second CAR is or comprises a cytoplasmic signaling domain of a CD3-zeta (CD3() chain or a functional variant or signaling portion thereof, optionally a human CD3 zeta chain.

105. The polynucleotide of any of claims 103 or 104, wherein the intracellular signaling region of the second CAR comprises the amino acid sequence set forth in SEQ ID NO:20 or an amino acid sequence that has at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:

20.

106. The polynucleotide of any of claims 103-105, wherein the intracellular signaling region of the second CAR further comprises a costimulatory signaling region.

107. The polynucleotide of claim 106, wherein the costimulatory signaling region of the second CAR comprises an intracellular signaling domain of CD28, 4-1BB, or ICOS, or a signaling portion thereof, optionally of human CD28, human 4-1BB, or human ICOS.

108. The polynucleotide of any of claims 80-107, wherein at least one of the first chimeric antigen receptor and the second chimeric antigen receptor comprises an intracellular signaling region comprising an intracellular signaling domain of 4-1BB or a signaling portion thereof, optionally of human 4-1BB.

109. The polynucleotide of any one of claims 106-108, wherein the costimulatory signaling region of the second CAR comprises an intracellular signaling domain of 4-1BB or a signaling portion thereof, optionally human 4-1BB.

110. The polynucleotide of any of claims 106-108, wherein the costimulatory signaling region of the second CAR comprises: an intracellular signaling domain of human CD28; and / or the amino acid sequence set forth in SEQ ID NO:46 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequence set forth in SEQ ID NO:

46.

111. The polynucleotide of any of claims 106-109, wherein the costimulatory signaling region of the second CAR comprises: an intracellular signaling domain of human 4-1BB; and / or the amino acid sequence set forth in SEQ ID NO:19 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequence set forth in SEQ ID NO:

19.

112. A polynucleotide comprising: (i) a first nucleic acid sequence encoding a first chimeric antigen receptor (CAR) comprising a first antigen binding domain; and (ii) a second nucleic acid sequence encoding a second chimeric antigen receptor (CAR) comprising a second antigen binding domain; wherein the first CAR and second CAR each comprise the following: (a) the first antigen binding domain or the second antigen binding domain, (b) a spacer, (c) a transmembrane domain, and (d) an intracellular signaling region comprising an intracellular signaling domain and a costimulatory signaling region; wherein one or more of (b) through (d) in the first CAR and the same one or more of (b) through (d) in the second CAR comprises the identical amino acid sequence; and wherein the nucleotide sequence(s) encoding the one or more of (b) through (d) in the first CAR differs in sequence from the nucleotide sequence(s) encoding the same one or more of (b) through (d) in the second CAR.

113. A polynucleotide comprising: (i) a first nucleic acid sequence encoding a first chimeric antigen receptor (CAR) comprising a first antigen binding domain capable of binding to one of GPRC5D or BCMA and (ii) a second nucleic acid sequence encoding a second chimeric antigen receptor (CAR) comprising a second antigen binding domain capable of binding to the other of GPRC5D or BCMA; wherein the first CAR and second CAR each comprise the following: (a) the first antigen binding domain or the second antigen binding domain, (b) a spacer, (c) a transmembrane domain, and (d) an intracellular signaling region comprising an intracellular signaling domain and a costimulatory signaling region; wherein one or more of (b) through (d) in the first CAR and the same one or more of (b) through (d) in the second CAR comprises the identical amino acid sequence; and wherein the nucleotide sequence(s) encoding the one or more of (b) through (d) in the first CAR differs in sequence from the nucleotide sequence(s) encoding the same one or more of (b) through (d) in the second CAR.

114. The polynucleotide of any of claims 80-113, wherein at least one of the nucleotide sequence encoding the first chimeric antigen receptor and the nucleotide sequence encoding the second chimeric antigen receptor is codon diverged.

115. A polynucleotide comprising (i) a first nucleic acid sequence encoding a first chimeric antigen receptor (CAR), (ii) a second nucleic acid sequence encoding a second chimeric antigen receptor (CAR) and (iii) a nucleotide sequence encoding a multicistronic element, wherein the first nucleic acid encoding the first CAR and the second nucleic acid encoding the second CAR are separated by the multicistronic element; wherein the first CAR comprises a first antigen binding domain that binds to GPRC5D, optionally wherein the first antigen binding domain is encoded by the nucleotide sequence set forth in SEQ ID NO:311; a spacer encoded by the nucleotide set forth in SEQ ID NO:30S; a transmembrane domain encoded by the nucleotide sequence set forth in SEQ ID NO:307; and an intracellular signaling region comprising an intracellular signaling domain encoded by the nucleotide sequence set forth in SEQ ID NO:309 and a co-stimulatory signaling region encoded by the nucleotide sequence set forth in SEQ ID NO:308:; wherein the second CAR comprises a second antigen binding domain that binds to BCMA optionally wherein the second antigen binding domain is encoded by the nucleotide sequence set forth in SEQ ID NO:310; a spacer encoded by the nucleotide set forth in SEQ ID NO:74; a transmembrane domain encoded by the nucleotide sequence set forth in SEQ ID NO:56; and an intracellular signaling region comprising an intracellular signaling domain encoded by the nucleotide sequence set forth in SEQ ID NO:58 and a co-stimulatory signaling domain region encoded by the nucleotide sequence set forth in SEQ ID NO:60; and wherein the first nucleic acid sequence encoding the first CAR is located toward the 5’ end of the polynucleotide relative to the second nucleic acid sequence encoding the second CAR.

116. A polynucleotide comprising (i) a first nucleic acid sequence encoding a first chimeric antigen receptor (CAR), (ii) a second nucleic acid sequence encoding a second chimeric antigen receptor (CAR), and (iii) a nucleotide sequence encoding a multicistronic element, wherein the first nucleic acid encoding the first CAR and the second nucleic acid encoding the second CAR are separated by the multicistronic element; wherein the first CAR comprises a first antigen binding domain that binds to BCMA, optionally wherein the first antigen binding domain is encoded by the nucleotide sequence set forth in SEQ ID NO:310, a spacer encoded by the nucleotide set forth in SEQ ID NO:74, a transmembrane domain encoded by the nucleotide sequence set forth in SEQ ID NO:56, and an intracellular signaling region comprising an intracellular signaling domain encoded by the nucleotide sequence set forth in SEQ ID NO:58 and a co-stimulatory signaling domain region encoded by the nucleotide sequence set forth in SEQ ID NO:60 wherein the second CAR comprises a second antigen binding domain that binds to GPRC5D, optionally wherein the second antigen binding domain is encoded by the nucleotide sequence set forth in SEQ ID NO:311, a spacer encoded by the nucleotide set forth in SEQ ID NO:305, a transmembrane domain encoded by the nucleotide sequence set forth in SEQ ID NO:307, and an intracellular signaling region comprising an intracellular signaling domain encoded by the nucleotide sequence set forth in SEQ ID NO:309 and a co-stimulatory signaling region encoded by the nucleotide sequence set forth in SEQ ID NO:308; wherein the first nucleic acid encoding the first CAR is located toward the 5° end of the polynucleotide relative to the second nucleic acid sequence encoding the second CAR.

117. The polynucleotide of any one of claims 80-116, wherein the nucleotide sequence encoding the first chimeric antigen receptor and the nucleotide sequence encoding the second chimeric antigen receptor have no more than about 30, no more than about 20, or no more than about 10 consecutive base pairs of sequence homology.

118. A vector comprising the polynucleotide of any of claims 68-117.

119. The vector of claim 118, which is a viral vector.

120. A cell comprising the chimeric antigen receptor of any of claims 1-67.

121. The cell of claim 120, wherein the chimeric antigen receptor is a first chimeric receptor and the cell further comprises a polynucleotide comprising a nucleotide encoding a second chimeric antigen receptor.

122. A cell comprising the polynucleotide of any of claims 68-117.

123. A cell comprising the polynucleotide of any of claims 68-79, which is the first polynucleotide, wherein the cell further comprises a second polynucleotide comprising a nucleotide sequence encoding a second chimeric antigen receptor (CAR).

124. The cell of claim 121 or claim 123, wherein the second chimeric antigen receptor (CAR) comprises an extracellular antigen-binding domain that specifically binds a second antigen expressed on or associated with multiple myeloma.

125. The cell of claim 124, wherein the second CAR further comprises a spacer, a transmembrane domain, and an intracellular signaling region.

126. The cell of claim 124 or claim 125, wherein the second antigen is selected from B cell maturation antigen (BCMA), CD38, CD138, CS-1, BAFF-R, TACI, and FcRHS.

127. The cell of any of claims 124-126, wherein the second antigen is BCMA.

128. The cell of any of claims 121-127, wherein the second CAR comprises: (1) an extracellular antigen-binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain comprises: (1) a variable heavy chain (Vu) region comprising an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NOs: 189, 191, 193, 195 or 197; and (ii) a variable light chain (V1) region comprising an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 190, 192, 194, 196 or 198; (2) a spacer, optionally a spacer comprising an IgG4 / 2 chimeric hinge or a modified IgG4 hinge; an IgG2 / 4 chimeric Cu2 region; and an IgG4 Cu3 region, optionally that is at or about 228 amino acids in length, or a spacer set forth in SEQ ID NO:17; (3) a transmembrane domain; and (4) an intracellular signaling region.

129. The cell of claim 128, wherein the Vy region of the second CAR comprises a CDR-HI1, CDR-H2 and CDR-H3 contained within the Vx region amino acid sequence set forth in SEQ ID NO: 189, 191, 193, 195 or 197; and the Vi region comprises a CDR-L1, CDR-L2 and CDR-L3 contained within the Vi region amino acid sequence set forth in SEQ ID NO: 190, 192, 194, 196 or 198.

130. The cell of any of claims 121-127, wherein the second CAR comprises: (1) an extracellular antigen-binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain comprises: (1) a variable heavy chain (Vu) region comprising a heavy chain complementarity determining region 1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 199, 202, 206, or 209; (b) a heavy chain complementarity determining region 2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 200, 203, 207, or 210; and (c) a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 201, 204, 205, 208, or 211; and (ii) a variable light chain (V1) region comprising a light chain complementarity determining region 1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 218, 221, 224,227, or 230; (b) a light chain complementarity determining region 2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 219, 222, 225, 228, or 231; and (c) a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 220, 223, or 226; (2) a spacer, optionally a spacer comprising an IgG4 / 2 chimeric hinge or a modified IgG4 hinge; an IgG2 / 4 chimeric Cy2 region; and an IgG4 C3 region, optionally that is about 228 amino acids in length, or a spacer set forth in SEQ ID NO:17; (3) a transmembrane domain; and (4) an intracellular signaling region.

131. The cell of any of claims 128-130, wherein: the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:199, 200 and 201, respectively, and the Viregion of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:218, 219 and 220, respectively; the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:202, 203, 204, respectively, and the Vi region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:221, 222 and 223, respectively; the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:199, 200, 205, respectively, and the Vi region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:224, 225, and 226, respectively; the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:206, 207, 208, respectively, and the Vi region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:227, 228 and 229, respectively; or the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Vy region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively.

132. The cell of any of claims 128-131, wherein: the Vg region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Viregion of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively.

133. The cell of any of claims 128-132, wherein: the Vg region and VL region of the second CAR comprises (a) the amino acid sequences set forth in SEQ ID NO:189 and SEQ ID NO:190, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:189 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:190; the Vy region and Vy, region of the second CAR comprises (a) the amino acid sequences set forth in SEQ ID NO:191 and SEQ ID NO:192, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:191 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:192; the Vy region and V1 region of the second CAR comprises (a) the amino acid sequences set forth in SEQ ID NO:193 and SEQ ID NO:194, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:193 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%; at or about 98%, or at or about 99% sequence identity to SEQ ID NO:194; the Vy region and Vy, region of the second CAR comprises (a) the amino acid sequences set forth in SEQ ID NO:195 and SEQ ID NO:196, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:195 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%; at or about 98%, or at or about 99% sequence identity to SEQ ID NO:196; or the Vy region and Vy region of the second CAR comprises (a) the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:197 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:

198.

134. The cell of any of claims 128-133, wherein: the Vy region and Vi region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:189 and SEQ ID NO:190, respectively; the Vy region and Vi region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:191 and SEQ ID NO:192; the Vy region and Vi region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:193 and SEQ ID NO:194; the Vy region and Vy, region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:195 and SEQ ID NO:196; or the Vy region and Vy, region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively.

135. The cell of claim 128-134, wherein the single chain antibody fragment is or comprises a single chain variable fragment (scFv).

136. The cell of any of claims 128-135, wherein the Vy region of the second CAR is amino- terminal to the Vi region of the second CAR.

137. The cell of any of claims 128-135 wherein the Vg region of the second CAR is carboxy- terminal to the Vi region of the second CAR.

138. The cell of any of claims 128-137, wherein the antigen-binding domain of the second CAR comprises the amino acid sequence selected from SEQ ID NOs: 237, 238, 239, 240, and 241 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence selected from SEQ ID NOs: 237, 238, 239, 240, and 241.

139. The cell of any of claims 128-138, wherein the antigen-binding domain comprises the amino acid sequence selected from SEQ ID NOs: 237, 238, 239, 240, and 241.

140. The cell of any of claims 128-139, wherein: the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Viregion of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively; and / or the Vg region and VL region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively; and / or the antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO: 241 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequence set forth in SEQ ID NO:

241.

141. The cell of any of claims 125-140, wherein the transmembrane domain of the second CAR is or comprises a transmembrane domain from CD4, CD28, or CD8, optionally from human CD4, human CD28 or human CDS.

142. The cell of any of claims 125-141, wherein the intracellular signaling region of the second CAR further comprises a costimulatory signaling region.

143. The cell of claim 142, wherein the costimulatory signaling region comprises an intracellular signaling domain of CD28, 4-1BB, or ICOS, or a signaling portion thereof, optionally human CD28, human 4-1BB, or human ICOS.

144. The cell of claim 142 or claim 143, wherein the costimulatory signaling region comprises an intracellular signaling domain of 4-1BB or a signaling portion thereof, optionally human 4- 1BB.

145. A composition comprising the chimeric antigen receptor of any of claims 1-67.

146. A composition comprising the cell of any one of claims 120-144 or a plurality of the cells of any one of claims 120-144.

147. The composition of claim 143, wherein the composition comprises CD4+ and CD8+ T cells and the ratio of CD4+ to CD8+ T cells is from about 1:3 to 3:1, optionally about 1:2 to 2:

1.

148. A composition comprising: a plurality of first cells comprising a first chimeric antigen receptor that is the chimeric antigen receptor of any of claims 1-67 or encoded by the polynucleotide of any of claims 68-79; and a plurality of second cells comprising a second chimeric antigen receptor.

149. The composition of claim 148, wherein the second chimeric receptor comprises an extracellular antigen-binding domain that specifically binds a second antigen expressed on or associated with multiple myeloma.

150. The composition of claim 148 or claim 149, wherein the second CAR comprises the extracellular antigen-binding domain that binds the second antigen, a spacer, a transmembrane domain, and an intracellular signaling region.

151. The composition of claim 149 or claim 150, wherein the second antigen is selected from B cell maturation antigen (BCMA), CD38, CD138, CS-1, BAFF-R, TACI, and FcRHS5.

152. The composition of any of claims 149-151, wherein the second antigen is BCMA.

153. The composition of any of claims 148-152, wherein the second CAR comprises: (1) an extracellular antigen-binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain comprises: (i) a variable heavy chain (Vu) region comprising an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 189, 191, 193, 195 or 197; and (ii) a variable light chain (V1) region comprising an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 190, 192, 194, 196 or 198; (2) a spacer, optionally a spacer comprising an IgG4 / 2 chimeric hinge or a modified IgG4 hinge; an 1gG2 / 4 chimeric Cu2 region; and an IgG4 Cu3 region, optionally that is about 228 amino acids in length, or a spacer set forth in SEQ ID NO:17; (3) a transmembrane domain; and (4) an intracellular signaling region.

154. The composition of claim 153, wherein the Vi region of the second CAR comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the Vy region amino acid sequence set forth in SEQ ID NO: 189, 191, 193, 195 or 197; and the Vi region comprises a CDR-L1, CDR-L2 and CDR-L3 contained within the Vi region amino acid sequence set forth in SEQ ID NO: 190, 192, 194, 196, or 198.

155. The composition of any of claims 148-152, wherein the second CAR comprises: (1) an extracellular antigen-binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain comprises: (i) a variable heavy chain (Vy) region comprising a heavy chain complementarity determining region 1 (CDR-HI) comprising the amino acid sequence set forth in SEQ ID NO: 199, 202, 206, or 209; (b) a heavy chain complementarity determining region 2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 200, 203, 207, or 210; and (c) a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 201, 204, 205, 208, or 211; and (ii) a variable light chain (V1) region comprising a light chain complementarity determining region 1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 218, 221, 224,227, or 230; (b) a light chain complementarity determining region 2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 219, 222, 225, 228, or 231; and (c) a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NO: 220, 223, or 226; (2) a spacer, optionally a spacer comprising an IgG4 / 2 chimeric hinge or a modified IgG4 hinge; an IgG2 / 4 chimeric Cy2 region; and an IgG4 C3 region, optionally that is about 228 amino acids in length, or a spacer set forth in SEQ ID NO:17; (3) a transmembrane domain; and (4) an intracellular signaling region.

156. The composition of any of claims 153-155, wherein: the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:199, 200 and 201, respectively, and the Vi region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:218, 219 and 220, respectively; the Vy region of the second CAR comprise a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:202, 203, 204, respectively, and the Vyregion of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:221, 222 and 223, respectively; the Vg region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:199, 200, 205, respectively, and the Vp region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:224, 225, and 226, respectively; the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:206, 207, 208, respectively, and the Vp region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:227, 228 and 229, respectively; or the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Vi region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively.

157. The composition of any of claims 153-156, wherein: the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Viregion of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively.

158. The composition of any of claims 153-157, wherein: the Vy region and Vi region of the second CAR comprise (a) the amino acid sequences set forth in SEQ ID NO:189 and SEQ ID NO:190, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:189 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%; at or about 98%, or at or about 99% sequence identity to SEQ ID NO:190; the Vy region and Vy, region of the second CAR comprises (a) the amino acid sequences set forth in SEQ ID NO:191 and SEQ ID NO:192, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:191 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%; at or about 98%, or at or about 99% sequence identity to SEQ ID NO:192; the Vy region and Vy region of the second CAR comprises (a) the amino acid sequences set forth in SEQ ID NO:193 and SEQ ID NO:194, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:193 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:194; the Vy region and Vi region of the second CAR comprises (a) the amino acid sequences set forth in SEQ ID NO:195 and SEQ ID NO:196, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:195 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%; at or about 98%, or at or about 99% sequence identity to SEQ ID NO:196; or the Vy region and Vi region of the second CAR comprises (a) the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:197 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%; at or about 98%, or at or about 99% sequence identity to SEQ ID NO:

198.

159. The composition of any of claims 153-158, wherein: the Vy region and Vy region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:189 and SEQ ID NO:190, respectively; the Vy region and Vy, region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:191 and SEQ ID NO:192; the Vy region and Vy, region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:193 and SEQ ID NO:194; the Vy region and Vy, region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:195 and SEQ ID NO:196; or the Vy region and Vy, region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively.

160. The composition of any of claims 153-159, wherein the Vy region of the second CAR is amino-terminal to the Vi region of the second CAR.

161. The composition of any of claims 153-159, wherein the Vg region of the second CAR is carboxy-terminal to the Vp region of the second CAR.

162. The composition of any of claims 153-161, wherein the antigen-binding domain of the second CAR comprises the amino acid sequence selected from SEQ ID NOs: 237, 238, 239, 240, and 241 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence selected from SEQ ID NOs: 237, 238, 239, 240, and 241.

163. The composition of any of claims 153-162, wherein the antigen-binding domain of the second CAR comprises the amino acid sequence selected from SEQ ID NOs: 237, 238, 239, 240, and 241.

164. The composition of any of claims 153-163, wherein: the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:209, 210 and 211, respectively, and the Viregion of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:230, 231 and 232, respectively; and / or the Vu region and VL region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO: 198, respectively; and / or the antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO: 241 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequence set forth in SEQ ID NO:

241.

165. The composition of any of claims 150-164, wherein the transmembrane domain of the second CAR is or comprises a transmembrane domain from CD4, CD28, or CDS, optionally from human CD4, human CD28 or human CDS.

166. The composition of any of claims 150-165, wherein: the transmembrane domain of the second CAR is or comprises a transmembrane domain from human CD28; and / or the transmembrane domain of the second CAR is or comprises the amino acid sequence set forth in SEQ ID NO:18 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:

18.

167. The composition of any of claims 150-166, wherein the intracellular signaling region comprises an intracellular signaling domain., wherein the intracellular signaling domain is capable of inducing a primary activation signal in a T cell, is a T cell receptor (TCR) component and / or comprises an immunoreceptor tyrosine-based activation motif (ITAM).

168. The composition of claim 167, wherein the intracellular signaling domain is or comprises a cytoplasmic signaling domain of a CD3-zeta (CD3() chain or a functional variant or signaling portion thereof, optionally a human CD3 zeta chain.

169. The composition of any of claims 150-168, wherein the intracellular signaling region of the second CAR further comprises a costimulatory signaling region.

170. The composition of claim 169, wherein the costimulatory signaling region of the second CAR comprises an intracellular signaling domain of CD28, 4-1BB, or ICOS, or a signaling portion thereof, optionally human CD28, human 4-1BB, or human ICOS.

171. The composition of any of claims 148-170, wherein at least one of the first chimeric antigen receptor and the second chimeric antigen receptor comprises an intracellular signaling region comprising an intracellular signaling domain of 4-1BB or a signaling portion thereof, optionally of human 4-1BB.

172. The composition of any one of claims 169-171, wherein the costimulatory signaling region of the second CAR comprises an intracellular signaling domain of 4-1BB or a signaling portion thereof, optionally human 4-1BB.

173. The composition of any of claims 148-172, wherein the plurality of first cells comprises T cells, optionally wherein the T cells comprises CD4+ and CD8+ T cells, optionally wherein the ratio of CD4+ to CD8+ T cells is from about 1:3 to 3:1, optionally 1:2 to 2:

1.

174. The composition of any of claims 148-173, wherein the plurality of second cells comprises T cells, optionally wherein the T cells comprises CD4+ and CD8+ T cells, optionally wherein the ratio of CD4+ to CD8+ T cells is from about 1:3 to 3:1, optionally about 1:2 to 2:

1.

175. The composition of any of claims 148-174, wherein the the ratio of the first plurality of cells and the second plurality of cells in the composition is from about 1:3 to 3:1, optionally about 1:2 to 2:1, optionally about 1:

1.

176. The composition of any of claims 148-175, wherein the composition comprises the first plurality of cells expressing the first chimeric antigen receptor and the second plurality of cells expressing the second chimeric antigen receptor at a ratio that is from about 1:3 to 3:1, optionally about 1:2 to 2:1, optionally about 1:

1.

177. A pharmaceutical composition of any of claims 145-176, for use in treating a subject with a disease or condition, optionally wherein the disease or condition is a cancer.

178. A pharmaceutical composition for use in treating a disease or disorder, optionally a cancer, containing the cells of any of claims 120-144 as an active ingredient.

179. A pharmaceutical composition for use treating a disease or disorder, optionally a cancer, containing the composition of any of claims 145-176, 233 or 234 as an active ingredient.

180. A pharmaceutical composition for use in treating a disease or disorder, optionally a cancer, containing a composition comprising a first dose of a plurality of first cells comprising a first chimeric antigen receptor that is the chimeric antigen receptor of any of claims 1-67 or encoded by the polynucleotide of any of claims 68-79 and a composition comprising a second dose of a plurality of second cells comprising a second chimeric antigen receptoras an active ingredient.

181. A method of treatment, comprising administering a composition comprising a dose of cells of any of claims 120-144 or the composition of any of claims 145-180, 233 or 234 to a subject having a disease or disorder.

182. Use of the cells of any of claims 120-144 for treatment of a disease or disorder, optionally wherein the disease or condition is a cancer.

183. Use of the composition of any of claims 145-180, 233 or 234 for treatment of a disease or disorder, optionally wherein the disease or condition is a cancer.

184. The use of the cells of any of claims 120-144 for the manufacture of a medicament for treatment of a disease or disorder, optionally wherein the disease or condition is a cancer.

185. The use of the composition of any of claims 145-180, 233 or 234 for the manufacture of a medicament for treatment of a disease or disorder, optionally wherein the disease or condition is a cancer.

186. The method or use of any of claims 181-185 or the pharmaceutical composition for use of any of claims 177-180, wherein the dose of cells comprises between about 1.0 x 10” CAR-expressing T cells and 1.2 x 10° CAR-expressing T cells, between about 1.0 x 10” CAR-expressing T cells and 6.5 x 108 CAR-expressing T cells, between about 1.5 x 107 CAR-expressing T cells and 6.5 x 10° CAR- expressing T cells, between about 1.5 x 107 CAR-expressing T cells and 6.0 x 108 CAR-expressing T cells, between about 2.5 x 107 CAR-expressing T cells and 6.0 x 10% CAR-expressing T cells, between about 5.0 x 10” CAR-expressing T cells and 6.0 x 10° CAR-expressing T cells, between about 1.25 x 107 CAR-expressing T cells and 1.2 x 10° CAR-expressing T cells, between about 1.5 x 10” CAR-expressing T cells and 1.2 x 10° CAR-expressing T cells, between about 5.0 x 10” CAR-expressing T cells and 4.5 x 10° CAR-expressing T cells, or between about 1.5 x 10° CAR-expressing T cells and 3.0 x 10° CAR- expressing T cells, each inclusive.

187. The method or use of any of claims 181-186 or the pharmaceutical composition for use of any of claims 177-180, wherein the dose of cells comprises at or about 1.5 x 107, at or about 2.5 x 107, at or about 5.0 x 107, at or about 7.5 x 107, at or about 1.5 x 10%, at or about 2.25 x 10°, at or about 3.0 x 108, at or about 4.5 x 108, at or about 6.0 x 10%, at or about 8.0 x 10%, or at or about 1.2 x 10° CAR- expressing T cells.

188. A method of treatment, comprising: administering a composition comprising a first dose of a plurality of first cells comprising a first chimeric antigen receptor that is the chimeric antigen receptor of any of claims 1-67 or encoded by the polynucleotide of any of claims 68-79 to a subject having a disease or disorder; and administering to the subject a composition comprising a second dose of a plurality of second cells comprising a second chimeric antigen receptor.

189. Use of a composition comprising a first dose of a plurality of first cells comprising a first chimeric antigen receptor that is the chimeric antigen receptor of any of claims 1-67 or encoded by the polynucleotide of any of claims 68-79 and a composition comprising a second dose of a plurality of second cells comprising a second chimeric antigen receptor for treatment of a disease or disorder, optionally wherein the disease or condition is a cancer.

190. The use of a composition comprising a first dose of a plurality of first cells comprising a first chimeric antigen receptor that is the chimeric antigen receptor of any of claims 1-67 or encoded by the polynucleotide of any of claims 68-79 and a composition comprising a second dose of a plurality of second cells comprising a second chimeric antigen receptor for the manufacture of a medicament for treatment of a disease or disorder, optionally wherein the disease or condition is a cancer.

191. The method or use of any of claims 188-190, wherein the first dose of the plurality of first cells and the second dose of the plurality of second cells independently comprise between at or about 1.0 x 107 CAR-expressing T cells and at or about 1.5 x 10° CAR-expressing T cells, between at or about about 1.0 x 10” CAR-expressing T cells and at or about 6.5 x 10° CAR-expressing T cells, between at or about 1.25 x 10” CAR-expressing T cells and at or about 0.6 x 10° CAR-expressing T cells, between at or about 1.5 x 10” CAR-expressing T cells and at or about 6.5 x 10° CAR-expressing T cells, between at or about 1.5 x 10” CAR-expressing T cells and at or about 6.0 x 10% CAR-expressing T cells, between at or about 2.5 x 107 CAR-expressing T cells and at or about 2.25 x 10% CAR-expressing T cells, between at or about 2.5 x 107 CAR-expressing T cells and at or about 6.0 x 10% CAR-expressing T cells, between at or about 5.0 x 10” CAR-expressing T cells and at or about 6.0 x 10° CAR-expressing T cells, between at or about 7.5 x 107 CAR-expressing T cells and at or about 1.5 x 10% CAR-expressing T cells, between at or about 2.5 x 10” CAR-expressing T cells and at or about 1.2 x 10° CAR-expressing T cells, between at or about 5.0 x 107 CAR-expressing T cells and at or about 4.5 x 10% CAR-expressing T cells, or between at or about 1.5 x 10® CAR-expressing T cells and at or about 3.0 x 10® CAR-expressing T cells, each inclusive.

192. The method or use of any of claims claim 188-190 or the pharmaceutical composition for use of claim 180, wherein the second chimeric receptor comprises an extracellular antigen binding domain that specifically binds a second antigen expressed on or associated with multiple myeloma.

193. The method or use or pharmaceutical composition for use of claim 192, wherein the second antigen is selected from B cell maturation antigen (BCMA), CD38, CD138, CS-1, BAFF-R, TACI, and FcRHS.

194. The method or use or pharmaceutical composition for use of any of claims 188-193, wherein the second antigen is BCMA.

195. The method or use or pharmaceutical composition for use of any of claims 188-194, wherein the second CAR comprises: (1) an extracellular antigen-binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain comprises: (i) a variable heavy chain (Vu) region comprising an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 189, 191, 193, 195 or 197; and (ii) a variable light chain (V1) region comprising an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 190, 192, 194, 196 or 198; (2) a spacer, optionally a spacer comprising an IgG4 / 2 chimeric hinge or a modified IgG4 hinge; an IgG2 / 4 chimeric Cu2 region; and an IgG4 Cu3 region, optionally that is about 228 amino acids in length, or a spacer set forth in SEQ ID NO:17; (3) a transmembrane domain; and (4) an intracellular signaling region.

196. The method or use or pharmaceutical composition for use of claim 195, wherein the Vu region of the second CAR comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the Vy region amino acid sequence set forth in SEQ ID NO: 189, 191, 193, 195 or 197; and the Vr region comprises a CDR-L1, CDR-L2 and CDR-L3 contained within the Vy region amino acid sequence set forth in SEQ ID NO: 190, 192, 194, 196 or 198.

197. The method or use or pharmaceutical composition for use of any of claims 188-196, wherein the second CAR comprises: (1) an extracellular antigen-binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain comprises: (1) a variable heavy chain (Vu) region comprising a heavy chain complementarity determining region 1 (CDR-H1) comprising the amino acid sequence selected from SEQ ID NOs: 199, 202, 206, and 209; (b) a heavy chain complementarity determining region 2 (CDR-H2) comprising the amino acid sequence selected from SEQ ID NOs: 200, 203, 207, and 210; and (c) a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence selected from SEQ ID NOs: 201, 204, 205, 208, and 211; and (ii) a variable light chain (V1) region comprising a light chain complementarity determining region 1 (CDR-L1) comprising the amino acid sequence selected from SEQ ID NOs: 218, 221, 224, 227, and 230; (b) a light chain complementarity determining region 2 (CDR-L2) comprising the amino acid sequence selected from SEQ ID NOs: 219, 222, 225, 228, and 231, 234; and (c) a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence selected from SEQ ID NOs: 220, 223, and 226; (2) a spacer, optionally a spacer comprising an IgG4 / 2 chimeric hinge or a modified IgG4 hinge; an IgG2 / 4 chimeric Cu2 region; and an IgG4 Cu3 region, optionally that is about 228 amino acids in length, or a spacer set forth in SEQ ID NO:17; (3) a transmembrane domain; and (4) an intracellular signaling region.

198. The method or use or pharmaceutical composition for use of any of claims 195-197, wherein: the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:199, 200 and 201, respectively, and the Vi region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:218, 219 and 220, respectively; the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequencse of SEQ ID NOS:202, 203, 204, respectively, and the Vi region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:221, 222 and 223, respectively; the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:199, 200, 205, respectively, and the Vi region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:224, 225, and 226, respectively; the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:206, 207, 208, respectively, and the Vi region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:227, 228 and 229, respectively; or the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:209, 210 and 211, respectively, and the Viregion of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:230, 231 and 232, respectively.

199. The method or use or pharmaceutical composition for use of any of claims 195-198, wherein: the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:209, 210 and 211, respectively, and the Vi region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:230, 231 and 232, respectively.

200. The method or use or pharmaceutical composition for use of any of claims 195-199, wherein: the Vy region and VL region of the second CAR comprise (a) the amino acid sequences set forth in SEQ ID NO:189 and SEQ ID NO:190, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:189 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%; at or about 98%, or at or about 99% sequence identity to SEQ ID NO:190; the Vg region and VL region of the second CAR comprise (a) the amino acid sequences set forth in SEQ ID NO:191 and SEQ ID NO:192, respectively, or (b) an amino acid sequence having a at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:191 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%; at or about 98%, or at or about 99% sequence identity to SEQ ID NO:192; the Vg region and VL region of the second CAR comprise (a) the amino acid sequences set forth in SEQ ID NO:193 and SEQ ID NO:194, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:193 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:194; the Vy region and VL region of the second CAR comprises (a) the amino acid sequences set forth in SEQ ID NO:195 and SEQ ID NO:196, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:195 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%; at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:196; or the Vy region and VL region of the second CAR comprises (a) the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:197 and SEQ ID NO:

198.

201. The method or use or pharmaceutical composition for use of any of claims 195-200, wherein: the Vu region and VL region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:189 and SEQ ID NO:190, respectively; the Vy region and VL region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:191 and SEQ ID NO:192; the Vu region and VL region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:193 and SEQ ID NO:194; the Vy region and VL region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:195 and SEQ ID NO: 196; or the Vu region and VL region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively.

202. The method or use or pharmaceutical composition for use of any of claims 195-201, wherein the Vy region of the second CAR is carboxy-terminal to the Viregion.

203. The method or use or pharmaceutical composition for use of any of claims 195-202, wherein the antigen-binding domain of the second CAR comprises the amino acid sequence selected from SEQ ID NOs: 237, 238, 239, 240, and 241 or an amino acid sequence having a at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence selected from SEQ ID NOs: 237, 238, 239, 240, and 241.

204. The method or use or pharmaceutical composition for use of any of claims 195-203, wherein the antigen-binding domain of the second CAR comprises the amino acid sequence selected from SEQ ID NOs: 237, 238, 239, 240, and 241.

205. The method or use or pharmaceutical composition for use of any of claims 195-204, wherein: the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:209, 210 and 211, respectively, and the Vi region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:230, 231 and 232, respectively; and / or the Vg region and VL region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively; and / or the antigen-binding domain of the second CAR comprises the amino acid sequence set forth in SEQ ID NO: 241 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequence set forth in SEQ ID NO:

241.

206. The method or use or pharmaceutical compostion for use of any of claims 188-205, wherein at least one of the first chimeric antigen receptor and the second chimeric antigen receptor comprises an intracellular signaling region comprising an intracellular signaling domain of 4-1BB or a signaling portion thereof, optionally of human 4-1BB.

207. The method or use or pharmaceutical composition for use of any of claims 195-206, wherein the transmembrane domain of the second CAR is or comprises a transmembrane domain from CD4, CD28, or CDS, optionally from human CD4, human CD38 or human CDS.

208. The method or use or pharmaceutical composition for use of any of claims 195-207, wherein: the transmembrane domain of the second CAR is or comprises a transmembrane domain from human CD28; and / or the transmembrane domain of the second CAR is or comprises the amino acid sequence set forth in SEQ ID NO:18 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:

18.

209. The method or use or pharmaceutical composition for use of any of claims 195-208, wherein the intracellular signaling region of the second CAR comprises an intracellular signaling domain.

210. The method or use or pharmaceutical composition for use of claim 209, wherein the intracellular signaling domain of the second CAR is or comprises a cytoplasmic signaling domain of a CD3-zeta (CD3() chain or a functional variant or signaling portion thereof, optionally a human CD3 zeta chain.

211. The method or use or pharmaceutical composition for use of any of claims 209 or 210, wherein the intracellular signaling region of the second CAR comprises the amino acid sequence set forth in SEQ ID NO:20 or an amino acid sequence that has at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:

20.

212. The method or use or pharmaceutical composition for use of any of claims 209-211, wherein the intracellular signaling region of the second CAR further comprises a costimulatory signaling region.

213. The method or use or pharmaceutical composition for use of claim 212, wherein the costimulatory signaling region of the second CAR comprises an intracellular signaling domain of CD28, 4-1BB, or ICOS or a signaling portion thereof, optionally human CD28, human 4-1BB, or human ICOS.

214. The method or use or pharmaceutical composition for use of claim 212 or claim 213, wherein the costimulatory signaling region of the second CAR comprises an intracellular signaling domain of 4-1BB or a signaling portion thereof, optionally human 4-1BB.

215. The method or use or pharmaceutical composition for use of claim 212 or claim 213, wherein the costimulatory signaling region of the second CAR comprises: an intracellular signaling domain of human CD28; and / or the amino acid sequence set forth in SEQ ID NO:46 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequence set forth in SEQ ID NO:

46.

216. The method or use or pharmaceutical composition for use of any of claims 212-214, wherein the costimulatory signaling region of the second CAR comprises: an intracellular signaling domain of a human 4-1BB; and / or the amino acid sequence set forth in SEQ ID NO:19 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequence set forth in SEQ ID NO:

19.

217. The method or use or pharmaceutical composition for use of any of claims 181-216, wherein the disease or disorder is associated with expression of GPRC5D.

218. The method or use or pharmaceutical composition for use of claim 217, wherein the disease or disorder is further associated with expression of B cell maturation antigen (BCMA).

219. The method or use or pharmaceutical composition for use of any of claims 181-218, wherein the disease or disorder is a B cell-related disorder.

220. The method or use or pharmaceutical composition for use of any one of claims 181-219, wherein the disease or disorder associated with BCMA is an autoimmune disease or disorder.

221. The method or use or pharmaceutical composition for use of claim 220, wherein the autoimmune disease or disorder is systemic lupus erythematosus (SLE), lupus nephritis, inflammatory bowel disease, rheumatoid arthritis, ANCA associated vasculitis, idiopathic thrombocytopenia purpura (ITP), thrombotic thrombocytopenia purpura (TTP), autoimmune thrombocytopenia, Chagas’ disease, Grave's disease, Wegener's granulomatosis, poly-arteritis nodosa, Sjogren's syndrome, pemphigus vulgaris, scleroderma, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, vasculitis, diabetes mellitus, Reynaud’s syndrome, anti-phospholipid syndrome, Goodpasture’s disease, Kawasaki disease, autoimmune hemolytic anemia, myasthenia gravis, or progressive glomerulonephritis.

222. The method or use or pharmaceutical composition for use of any one of claims 181-221, wherein the disease or disorder is a cancer.

223. The method or use or pharmaceutical composition for use of claim 222, wherein the cancer is a GPRC5D-expressing cancer.

224. The method or use or pharmaceutical composition for use of claim 222 or claim 223, wherein the cancer is a plasma cell malignancy and the plasma cell malignancy is multiple myeloma (MM) or plasmacytoma.

225. The method or use or pharmaceutical composition for use of any of any of claims 222- 224, wherein the cancer is multiple myeloma (MM).

226. The method or use or pharmaceutical composition for use of claim 225, wherein the cancer is a relapsed / refractory multiple myeloma.

227. The method or use or pharmaceutical composition for use of any of claims 181-226, wherein: the subject is refractory to or has relapsed following administration of a BCMA-targeted therapy, optionally following administration of T cells comprising a CAR that specifically binds BCMA; or the method comprises selecting a subject for treatment that is refractory to or has relapsed following administration of a BCMA-targeted therapy, optionally following administration T cells comprising a CAR that specifically binds BCMA.

228. The method or use or pharmaceutical composition for use of any of claims 181-187 and 191-227, wherein prior to the administration of the dose of cells, the subject has previously received administration of a BCMA-targeted therapy for treating the disease or disorder.

229. The method or use or pharmaceutical composition for use of any of claims 188-228, wherein prior to the administration of the first dose of cells and the second dose of cells, the subject has previously received administration of a BCMA-targeted therapy for treating the disease or disorder.

230. The method or use or pharmaceutical composition for use of claim 228 or claim 229, wherein the BCMA-targeted therapy comprises a composition comprising T cells comprising a CAR that specifically binds BCMA.

231. The method or use or pharmaceutical composition for use of any of claims 228-230, wherein the subject is refractory to or has relapsed following administration of the BCMA-targeted therapy, optionally following administration of T cells comprising a CAR that specifically binds BCMA. 25 The method or use or pharmaceutical composition for use of any of claims 181-231, wherein the subject comprises multiple myeloma cells exhibiting BCMA antigen or epitope loss, BCMA downregulation and / or BCMA-negative tumor cells following a previous administration.

233. The composition of claim 146 or claim 147, wherein the composition comprises a plurality of cells, wherein at least a portion of the cells comprise the first CAR that specifically binds GPRCS5D, a portion of the cells comprise a second CAR that specifically binds a second antigen that is expressed on or associated with multiple myeloma, optionally wherein the second antigen is BCMA, and a portion of the cells comprise both the first CAR and the second CAR.

234. The composition of claim 233, wherein the ratio of cells expressing the first CAR to cells expressing the second CAR is from or from about 1:3 to 3:1, optionally 1:2 to 2:1, optionally is or is about 1:

1.

235. A combination comprising: a plurality of first cells comprising a first chimeric antigen receptor that is the chimeric antigen receptor of any of claims 1-67 and / or encoded by the polynucleotide of any of claims 68-79; and a plurality of second cells comprising a second chimeric antigen receptor.

236. The combination of claim 235, wherein the second chimeric receptor comprises an extracellular antigen binding domain that specifically binds a second antigen expressed on or associated with multiple myeloma.

237. The combination of claim 236, wherein the second antigen is selected from the group consisting of B cell maturation antigen (BCMA), CD38, CD138, CS-1, BAFF-R, TACI, and FcRHS.

238. The combination of claim 236 or claim 237, wherein the second antigen is BCMA.

239. The combination of any of claims 235-238, wherein the second CAR comprises: (1) an extracellular antigen-binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain comprises: (i) a variable heavy chain (Vy) region comprising an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 189, 191, 193, 195 or 197; and (ii) a variable light chain (V1) region comprising an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in any of SEQ ID NO: 190, 192, 194, 196 or 198; (2) a spacer, optionally a spacer comprising an IgG4 / 2 chimeric hinge or a modified IgG4 hinge; an IgG2 / 4 chimeric Cu2 region; and an IgG4 Cu3 region, optionally that is about 228 amino acids in length and / or a spacer set forth in SEQ ID NO:17; (3) a transmembrane domain; and (4) an intracellular signaling region.

240. The combination of claim 239, wherein the Vy region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the Vy region amino acid sequence set forth in SEQ ID NO: 189, 191, 193, 195 or 197; and the Vi region comprises a CDR-L1, CDR-L2 and CDR-L3 contained within the Vi region amino acid sequence set forth in SEQ ID NO: 190, 192, 194, 196 or 198.

241. The combination of any of claims 235-240, wherein the second CAR comprises: (1) an extracellular antigen-binding domain that specifically binds BCMA, wherein the extracellular antigen-binding domain comprises: (i) a variable heavy chain (Vu) comprising a heavy chain complementarity determining region 1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 199, 202, 206, or 209; (b) a heavy chain complementarity determining region 2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 200, 203, 207, or 210; and (c) a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NOs: 201, 204, 205, 208, or 211; and (ii) a variable light chain (V1) region comprising a light chain complementarity determining region 1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NOs: 218, 221, 224,227, 230, 233, or 235; (b) a light chain complementarity determining region 2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NOs: 219, 222, 225, 228, or 231; and (c) a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence set forth in SEQ ID NOs: 220, 223, or 226; (2) a spacer, optionally a spacer comprising an IgG4 / 2 chimeric hinge or a modified IgG4 hinge; an IgG2 / 4 chimeric Cu2 region; and an IgG4 Cu3 region, optionally that is about 228 amino acids in length and / or a spacer set forth in SEQ ID NO:17; (3) a transmembrane domain; and (4) an intracellular signaling region.

242. The combination of any of claims 239-241 wherein: the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:199, 200 and 201, respectively, and the Viregion of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:218, 219 and 220, respectively; the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:202, 203, 204, respectively, and the Vi region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:221, 222 and 223, respectively; the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:199, 200, 205, respectively, and the V_region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:224, 225, and 226, respectively; the Vi region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:206, 207, 208, respectively, and the Vi region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:227, 228 and 229, respectively; or the Vg region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:209, 210 and 211, respectively, and the Vi region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:230, 231 and 232, respectively.

243. The combination of any of claims 239-242, wherein: the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:209, 210 and 211, respectively, and the Vi region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:230, 231 and 232, respectively.

244. The combination of any of claims 240-243, wherein: the Vy region and Vi region of the second CAR comprise (a) the amino acid sequences set forth in SEQ ID NO:189 and SEQ ID NO:190, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, at or about 99%, or at or about 100% sequence identity to SEQ ID NO:189 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:190; the Vy region and Vy, region of the second CAR comprise (a) the amino acid sequences set forth in SEQ ID NO:191 and SEQ ID NO:192, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:191 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:192; the Vy region and Vy region of the second CAR comprises (a) the amino acid sequences set forth in SEQ ID NO:193 and SEQ ID NO:194, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:193 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:194; the Vy region and Vy region of the second CAR comprises (a) the amino acid sequences set forth in SEQ ID NO:195 and SEQ ID NO:196, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:195 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:196; or the Vy region and Vi region of the second CAR comprises (a) the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively, or (b) an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to SEQ ID NO:197 and an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%; at or about 98%, or at or about 99% sequence identity to SEQ ID NO:

198.

245. The combination of any of claims 239-244, wherein: the Vu region and Vi region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:189 and SEQ ID NO:190, respectively; the Vy region and Vi region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:191 and SEQ ID NO:192; the Vu region and Vi region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:193 and SEQ ID NO:194; the Vu region and Vi region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:195 and SEQ ID NO: 196; or the Vy region and Vi region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively.

246. The combination of any of claims 239-245, wherein the antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NOs: 237, 238, 239, 240, or 241 or an amino acid sequence having at least at or about 90%, at or about 91%; at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NOs: 227, 238, 239, 240, or 241.

247. The combination of any of claims 239-246, wherein the antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NOs: 237, 238, 239, 240, or 241.

248. The combination of any of claims 239-247, wherein: the Vy region of the second CAR comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences of SEQ ID NOS:209, 210 and 211, respectively, and the Vy region of the second CAR comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOS:230, 231 and 232, respectively; and / or the Vy region and VL region of the second CAR comprise the amino acid sequences set forth in SEQ ID NO:197 and SEQ ID NO:198, respectively; and / or the antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO: 241 or an amino acid sequence having at least at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% sequence identity to the sequence set forth in SEQ ID NO:

241.

249. The combination of any of claims 235-248, wherein at least one of the first chimeric antigen receptor and the second chimeric antigen receptor comprises an intracellular signaling region comprising an intracellular signaling domain of 4-1BB or a signaling portion thereof, optionally of a human 4-1BRB.

250. AKkit comprising the combination of any of claims 235-249 and instructions for use, optionally wherein the instructions are for administering a dose of the first and second plurality of cells, optionally in accord with the method or use or pharmaceutical composition for use of any of claims 174- 216.

251. An article of manufacture comprising the combination of any of claims 235-249 or the kit of claim 250.

252. The article of manufacture of claim 251 comprising a first container comprising a dose of the plurality of first cells and a second container comprising a dose of the plurality of second cells, optionally wherein the first and second container independently is a vial or bag.

253. Use of the combination of any of claims 235-249 for the treatment of a disease or disorder, optionally wherein the disease or disorder is a cancer.

254. The use of the combination of any of claims 235-249 for the manufacture of a medicament for treatment of a disease or disorder, optionally wherein the disease or disorder is a cancer.

255. A pharmaceutical composition for treating a disease or disorder, optionally a cance containing the combination of any of claims 235-249 as an active ingredient.

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