Chimeric antigen receptors targeting g-protein coupled receptor and uses thereof

Abstract

To provide chimeric antigen receptors targeting a G-protein coupled receptor and uses thereof.SOLUTION: The presently disclosed subject matter provides methods and compositions for treating multiple myeloma. The presently disclosed subject matter relates to chimeric antigen receptors (CARs) that specifically target a G-protein coupled receptor (e.g., a G-protein coupled receptor family C group 5 member D (GPRC5D)), and immunoresponsive cells comprising such CARs. The presently disclosed CARs targeting a G-protein coupled receptor (e.g., GPRC5D) have enhanced immune-activating properties, including anti-tumor activity.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 088,286, filed December 5, 2014, the entire contents of which are incorporated herein by reference and priority is claimed thereto.

[0002] introduction The presently disclosed subject matter provides methods and compositions for treating cancer. The presently disclosed subject matter relates to chimeric antigen receptors (CARs) that specifically target G protein-coupled receptors (e.g., G protein-coupled receptor family C group 5 member D (GPRC5D)), immunoresponsive cells comprising such CARs, and methods of using such cells to treat cancer (e.g., multiple myeloma). [Background technology]

[0003] Background of the Invention Cell-based immunotherapy is a potentially curative treatment for cancer. T cells and other immune cells can be engineered to target tumor antigens through the introduction of genetic material encoding artificial or synthetic receptors for antigens, termed chimeric antigen receptors (CARs), that are specific for selected antigens. Targeted T cell therapy using CARs has recently shown clinical success in the treatment of hematological malignancies.

[0004] Multiple myeloma (MM) is the second most common hematologic malignancy 9 Approximately 25% of patients have high-risk cytogenetic features that portend a median survival of less than two years. 10、11 Regardless of cytogenetic characteristics, although significant advances have been made in recent years, the disease remains considered refractory to treatment outside of immunotherapeutic graft-versus-myeloma (GvM) with allogeneic transplantation. However, allogeneic transplantation is limited by high rates of ineligibility and transplant-related morbidity and mortality. 12Similar to the GvM effect, potentially curative T cell effects can be achieved with minimal toxicity via autologous adoptive T cell therapy.

[0005] Myeloma may be an ideal disease for testing adoptive T cell therapy. First, as indicated above, allogeneic transplantation confirms that T cells may be a curative treatment even when concomitant chemotherapy is minimal or absent, such as after non-myeloablative transplantation or post-transplant donor lymphocyte infusion. Second, conditioning chemotherapy enhances the efficacy of adoptive T cell therapy, possibly through a mechanism of depletion of regulatory T cells (Tregs). 5、13 The period immediately following autologous transplantation may itself be an optimal time to administer T cells, and myeloma is one of the few diseases for which autologous stem cell transplantation is the standard of care. Third, the immunomodulatory drug lenalidomide may improve CAR-based therapy, as shown in mice. 14 Lenalidomide is commonly used to treat MM. Fourth, adoptive T cell therapy is more effective than solid tumors or extramedullary CLL. 5 It works best in bone marrow-driven diseases such as ALL. 7、8 Like ALL, myeloma is a disease of the bone marrow. Summary of the Invention [Problem to be solved by the invention]

[0006] Although there are many reasons to hope that adoptive T-cell therapy may work well in MM, extending adoptive T-cell therapy to myeloma also poses unique challenges. Unlike other B-cell malignancies, CD19 expression is found in only 2% of myeloma patients. 15 Furthermore, unlike CD19, the common extracellular immunophenotypic markers in myeloma (CD138, CD38, and CD56) are all co-expressed on other major cell types, and a CAR directed against any of these targets would result in unacceptable "off-tumor, on-target" toxicity. 7 For HER2-targeted CARs16 Similarly, even in targets where antibodies are well tolerated, it is predicted that they will still cause potentially fatal toxicity. To address these issues, the present inventors have identified extracellular targets that are predicted to be highly expressed in MM and have limited expression in major normal tissues, and that may be optimal targets for adoptive T cell therapy of MM. Therefore, there is a need for a new therapeutic strategy for treating multiple myeloma, in which CARs are designed to target antigens that are highly expressed in MM cells and have limited expression in normal tissues, and that can induce potent tumor eradication while minimizing toxicity and immunogenicity. [Means for solving the problem]

[0007] The subject matter of the present disclosure generally provides chimeric antigen receptors (CARs) that specifically target G protein-coupled receptors, immunoresponsive cells comprising such CARs, and uses of these CARs and immunoresponsive cells to treat multiple myeloma.

[0008] The subject matter of the present disclosure provides a CAR. In a non-limiting example, the CAR comprises an extracellular antigen-binding domain, a transmembrane domain, and an intracellular domain, and the extracellular antigen-binding domain specifically binds to a G protein-coupled receptor. In certain embodiments, the G protein-coupled receptor is G protein-coupled receptor family C group 5 member D (GPRC5D). In certain embodiments, the extracellular antigen-binding domain binds to GPRC5D at about 1 x 10 -9 M ~ approx. 3×10 -6 Binding affinity (K D) specifically binds to the extracellular antigen-binding domain. In certain embodiments, the extracellular antigen-binding domain is a single-chain variable fragment (scFv). In certain embodiments, the extracellular antigen-binding domain is a mouse scFv. In certain embodiments, the extracellular antigen-binding domain is a human scFv. In certain embodiments, the extracellular antigen-binding domain is an optionally cross-linked Fab. In certain embodiments, the extracellular binding domain is a F(ab)2. In certain embodiments, any of the foregoing molecules may be included within a fusion protein with a heterologous sequence to form the extracellular antigen-binding domain.

[0009] In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 302, 314, 326, 338, 350, 362, 374, and 386.

[0010] In certain embodiments, the extracellular antigen-binding domain comprises a light chain variable region comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 303, 315, 327, 339, 351, 363, 375, and 387.

[0011] In certain embodiments, the extracellular antigen-binding domain comprises: (a) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 302, 314, 326, 338, 350, 362, 374, and 386; and (b) a light chain variable region comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 303, 315, 327, 339, 351, 363, 375, and 387. Includes.

[0012] In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 302, 314, 326, 338, 350, 362, 374, and 386, and conservative modifications thereof.

[0013] In certain embodiments, the extracellular antigen-binding domain comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 303, 315, 327, 339, 351, 363, 375, and 387, and conservative modifications thereof.

[0014] In certain embodiments, the extracellular antigen-binding domain comprises: (a) a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 302, 314, 326, 338, 350, 362, 374, and 386, and conservative modifications thereof; and (b) a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 303, 315, 327, 339, 351, 363, 375, and 387, and conservative modifications thereof. Includes.

[0015] In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having a sequence selected from the group consisting of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 302, 314, 326, 338, 350, 362, 374, and 386. In certain embodiments, the extracellular antigen-binding domain comprises a light chain variable region comprising amino acids having a sequence selected from the group consisting of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 303, 315, 327, 339, 351, 363, 375, and 387. In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having a sequence set forth in SEQ ID NO: 53. In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having a sequence set forth in SEQ ID NO: 57. In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having a sequence set forth in SEQ ID NO: 61. In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having a sequence set forth in SEQ ID NO: 65. In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 69. In certain embodiments, the extracellular antigen-binding domain comprises a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 54. In certain embodiments, the extracellular antigen-binding domain comprises a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 58. In certain embodiments, the extracellular antigen-binding domain comprises a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 62. In certain embodiments, the extracellular antigen-binding domain comprises a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 66. In certain embodiments, the extracellular antigen-binding domain comprises a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 70. In certain embodiments, the extracellular antigen-binding domain comprises (a) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 1; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO:2; (b) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO:5; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO:6; (c) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 9; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 10; (d) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 13; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 14; (e) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 17; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 18; (f) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 21; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 22; (g) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 25; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 26; (h) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 29; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 30; (i) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 33; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 34; (j) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 37; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 38; (k) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 41; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 42; (l) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 45; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 46; (m) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 49, and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 50; (n) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 53; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 54; (o) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 57; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 58; (p) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 61; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 62; (q) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 65; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 66; (r) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 69; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 70; (s) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 73; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 74; (t) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 77; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 78; (u) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 81; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 82; (v) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 85; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 86; (w) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 89; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 90; (x) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 93, and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 94; (y) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 302, and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 303; (z) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 314; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 315; (aa) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 326, and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 327; (ab) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 338, and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 339; (ac) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 350, and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 351; (ad) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 362; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 363; (ae) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 374, and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 375; (af) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 386; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 387; In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 53; and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 54. In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 57; and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 58. In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 61; and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 62. In another embodiment, the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 65; and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 66. In yet another embodiment, the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 69; and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 70.

[0016] In certain embodiments, the extracellular antigen-binding domain comprises both the heavy and light chains, optionally with a linker sequence, e.g., a linker peptide between the heavy and light chain variable regions. For example, in certain non-limiting embodiments, the extracellular antigen-binding domain comprises (i) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 57, and (ii) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 58, optionally with (iii) a linker sequence, e.g., a linker peptide between the heavy and light chain variable regions. In certain embodiments, the extracellular antigen-binding domain comprises (i) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 61, and (ii) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 62, optionally with (iii) a linker sequence, e.g., a linker peptide between the heavy and light chain variable regions. In certain embodiments, the extracellular antigen-binding domain comprises (i) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 53, and (ii) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 54, optionally with (iii) a linker sequence, e.g., a linker peptide, between the heavy and light chain variable regions. In certain embodiments, the extracellular antigen-binding domain comprises (i) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 61, and (ii) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 62, optionally with (iii) a linker sequence, e.g., a linker peptide, between the heavy and light chain variable regions. In certain embodiments, the extracellular antigen-binding domain comprises (i) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 65, and (ii) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 66, optionally with (iii) a linker sequence, e.g., a linker peptide, between the heavy and light chain variable regions. In certain embodiments, the extracellular antigen-binding domain comprises (i) a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 69, and (ii) a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 70, optionally with (iii) a linker sequence, e.g., a linker peptide between the heavy chain variable region and the light chain variable region.

[0017] In certain embodiments, the extracellular antigen-binding domain comprises: (a) a heavy chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 126, 132, 138, 144, 150, 156, 162, 168, 174, 180, 186, 192, 198, 204, 210, 216, 222, 228, 234, 240, 246, 252, 258, 264, 306, 318, 330, 342, 354, 366, 378, and 390; and (b) a light chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 129, 135, 141, 147, 153, 159, 165, 171, 177, 183, 189, 195, 201, 207, 213, 219, 225, 231, 237, 243, 249, 255, 261, 267, 309, 321, 333, 345, 357, 369, 381, and 393.

[0018] In certain embodiments, the heavy chain variable region CDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 125, 131, 137, 143, 149, 155, 161, 167, 173, 179, 185, 191, 197, 203, 209, 215, 221, 227, 233, 239, 245, 251, 257, 263, 305, 317, 329, 341, 353, 365, 377, and 389, and conservative modifications thereof; (b) the light chain variable region CDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 128, 134, 140, 146, 152, 158, 164, 170, 176, 182, 188, 194, 200, 206, 212, 218, 224, 230, 236, 242, 248, 254, 260, 266, 308, 320, 332, 344, 356, 368, 380, and 392, and conservative modifications thereof.

[0019] In certain embodiments, the heavy chain variable region CDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 124, 130, 136, 142, 148, 154, 160, 166, 172, 178, 184, 190, 196, 202, 208, 214, 220, 226, 232, 238, 244, 250, 256, 262, 304, 316, 328, 340, 352, 364, 376, and 388, and conservative modifications thereof; (b) the light chain variable region CDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 127, 133, 139, 145, 151, 157, 163, 169, 175, 181, 187, 193, 199, 205, 211, 217, 223, 229, 235, 241, 247, 253, 259, 265, 307, 319, 331, 343, 355, 367, 379, and 391, and conservative modifications thereof.

[0020] In certain embodiments, the extracellular antigen-binding domain comprises: (a) a heavy chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124, 130, 136, 142, 148, 154, 160, 166, 172, 178, 184, 190, 196, 202, 208, 214, 220, 226, 232, 238, 244, 250, 256, 262, 304, 316, 328, 340, 352, 364, 376, and 388; (b) a heavy chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 125, 131, 137, 143, 149, 155, 161, 167, 173, 179, 185, 191, 197, 203, 209, 215, 221, 227, 233, 239, 245, 251, 257, 263, 305, 317, 329, 341, 353, 365, 377, and 389; (c) a heavy chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 126, 132, 138, 144, 150, 156, 162, 168, 174, 180, 186, 192, 198, 204, 210, 216, 222, 228, 234, 240, 246, 252, 258, 264, 306, 318, 330, 342, 354, 366, 378, and 390; (d) a light chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 127, 133, 139, 145, 151, 157, 163, 169, 175, 181, 187, 193, 199, 205, 211, 217, 223, 229, 235, 241, 247, 253, 259, 265, 307, 319, 331, 343, 355, 367, 379, and 391; (e) a light chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 128, 134, 140, 146, 152, 158, 164, 170, 176, 182, 188, 194, 200, 206, 212, 218, 224, 230, 236, 242, 248, 254, 260, 266, 308, 320, 332, 344, 356, 368, 380, and 392; and (f) a light chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 129, 135, 141, 147, 153, 159, 165, 171, 177, 183, 189, 195, 201, 207, 213, 219, 225, 231, 237, 243, 249, 255, 261, 267, 309, 321, 333, 345, 357, 369, 381, and 393. Includes.

[0021] In certain embodiments, the extracellular antigen-binding domain comprises: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 124 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 125 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 126 or amino acids having a conservative modification thereof; (b) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 130 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 131 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 132 or a conservative modification thereof; (c) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 136 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 137 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 138 or amino acids having a conservative modification thereof; (d) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 142 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 143 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 144 or amino acids having a conservative modification thereof; (e) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 148 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 149 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 150 or amino acids having a conservative modification thereof; (f) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 154 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 155 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 156 or a conservative modification thereof; (g) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 160 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 161 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 162 or a conservative modification thereof; (h) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 166 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 167 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 168 or amino acids having a conservative modification thereof; (i) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 172 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 173 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 174 or amino acids having a conservative modification thereof; (j) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 178 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 179 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 180 or amino acids having a conservative modification thereof; (k) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 184 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 185 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 186 or amino acids having a conservative modification thereof; (l) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 190 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 191 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 192 or amino acids having a conservative modification thereof; (m) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 196 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 197 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 198 or amino acids having a conservative modification thereof; (n) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 202 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 203 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 204 or amino acids having a conservative modification thereof; (o) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 208 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 209 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210 or a conservative modification thereof; (p) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 214 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 215 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 216 or amino acids having a conservative modification thereof; (q) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 220 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 221 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 222 or amino acids having a conservative modification thereof; (r) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 226 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 227 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 228 or amino acids having a conservative modification thereof; (s) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 232 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 233 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 234 or amino acids having a conservative modification thereof; (t) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 238 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 239 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 240 or amino acids having a conservative modification thereof; (u) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 244 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 245 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 246 or a conservative modification thereof; (v) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 250 or an amino acid sequence having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 251 or an amino acid sequence having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 252 or an amino acid sequence having a conservative modification thereof; (w) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 256 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 257 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 258 or a conservative modification thereof; (x) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 262 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 263 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 264 or amino acids having a conservative modification thereof; (y) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 304 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 305 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 306 or amino acids having a conservative modification thereof; (z) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 316 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 317 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 318 or a conservative modification thereof; (aa) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 328 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 329 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 330 or a conservative modification thereof; (ab) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 340 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 341 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 342 or a conservative modification thereof; (ac) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 352 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 353 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 354 or a conservative modification thereof; (ad) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 364 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 365 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 366 or a conservative modification thereof; (ae) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 376 or amino acids having conservative modifications thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 377 or amino acids having conservative modifications thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 378 or amino acids having conservative modifications thereof; or (af) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 388 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 389 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 390 or a conservative modification thereof; In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 202; a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 203; and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 204. In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 208; a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 209; and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 210. In another non-limiting embodiment, the extracellular antigen-binding domain comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 214; a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 215; and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 216. In yet another non-limiting embodiment, the extracellular antigen-binding domain comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 220; a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 221; and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 222. In another embodiment, the extracellular antigen-binding domain comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 226; a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 227; and a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 228.

[0022] In certain embodiments, the extracellular antigen-binding domain comprises: (a) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 127 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 129 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 130 or amino acids having a conservative modification thereof; (b) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 133 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134 or a conservative modification thereof; and a light chain variable region CDR3 comprising SEQ ID NO: 135 or a conservative modification thereof; (c) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 139 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 140 or a conservative modification thereof; and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 141 or a conservative modification thereof; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 145 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 146 or a conservative modification thereof; and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 147 or a conservative modification thereof; (e) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 151 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 152 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 153 or amino acids having a conservative modification thereof; (f) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 157 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 158 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 159 or amino acids having a conservative modification thereof; (g) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 163 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 164 or a conservative modification thereof; and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 165 or a conservative modification thereof; (h) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 169 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 170 or a conservative modification thereof; and a light chain variable region CDR3 comprising SEQ ID NO: 171 or a conservative modification thereof; (i) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 175 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 176 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 177 or amino acids having a conservative modification thereof; (j) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 181 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 182 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 183 or amino acids having a conservative modification thereof; (k) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 187 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 188 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 189 or amino acids having a conservative modification thereof; (l) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 193 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 194 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 195 or amino acids having a conservative modification thereof; (m) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 199 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 200 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 201 or amino acids having a conservative modification thereof; (n) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 205 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 206 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 207 or amino acids having a conservative modification thereof; (o) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 211 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 212 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 213 or amino acids having a conservative modification thereof; (p) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 217 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 218 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 219 or amino acids having a conservative modification thereof; (q) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 223 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 224 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 225 or amino acids having a conservative modification thereof; (r) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 229 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 230 or a conservative modification thereof; and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 231 or a conservative modification thereof; (s) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 235 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 236 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 237 or amino acids having a conservative modification thereof; (t) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 241 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 242 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 243 or amino acids having a conservative modification thereof; (u) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 247 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 248 or a conservative modification thereof; and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 249 or a conservative modification thereof; (v) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 253 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 254 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 255 or amino acids having a conservative modification thereof; (w) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 259 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 260 or a conservative modification thereof; and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 261 or a conservative modification thereof; (x) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 265 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 266 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 267 or amino acids having a conservative modification thereof; (y) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 307 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 308 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 309 or amino acids having a conservative modification thereof; (z) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 319 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 320 or a conservative modification thereof; and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 321 or a conservative modification thereof; (aa) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 331 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 332 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 333 or amino acids having a conservative modification thereof; (ab) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 343 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 344 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 345 or amino acids having a conservative modification thereof; (ac) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 355 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 356 or a conservative modification thereof; and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 357 or a conservative modification thereof; (ad) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 367 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 368 or a conservative modification thereof; and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 369 or a conservative modification thereof; (ae) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 379 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 380 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 381 or amino acids having a conservative modification thereof; or (af) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 391 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 392 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 393 or amino acids having a conservative modification thereof; In certain embodiments, the extracellular antigen-binding domain comprises a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 205; a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 206; and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 207. In certain embodiments, the extracellular antigen-binding domain comprises a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 211; a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 212; and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 213. In certain embodiments, the extracellular antigen-binding domain comprises a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 217; a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 218; and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 219. In another non-limiting embodiment, the extracellular antigen-binding domain comprises a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 223; a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 224; and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 225. In yet another non-limiting embodiment, the extracellular antigen-binding domain comprises a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 229; a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 230; and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 231.

[0023] In certain embodiments, the extracellular antigen-binding domain comprises: (a) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 124; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 125; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 126; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 127; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 128; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 129; (b) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 130; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 131; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 132; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 133; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 134; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 135; (c) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 136; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 137; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 138; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 139; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 140; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 141; (d) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 142; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 143; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 144; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 145; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 146; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 147; (e) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 148; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 149; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 150; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 151; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 152; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 153; (f) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 154; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 155; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 156; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 157; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 158; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 159; (g) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 160; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 161; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 162; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 163; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 164; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 165; (h) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 166; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 167; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 168; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 169; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 170; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 171; (i) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 172; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 173; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 174; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 175; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 176; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 177; (j) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 178; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 179; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 180; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 181; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 182; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 183; (k) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 184; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 185; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 186; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 187; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 188; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 189; (l) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 190; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 191; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 192; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 193; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 194; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 195; (m) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 196; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 197; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 198; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 199; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 200; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 201; (n) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 202; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 203; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 204; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 205; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 206; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 207; (o) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 208; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 209; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 210; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 211; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 212; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 213; (p) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 214; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 215; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 216; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 217; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 218; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 219; (q) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 220; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 221; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 222; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 223; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 224; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 225; (r) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 226; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 227; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 228; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 229; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 230; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 231; (s) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 232; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 233; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 234; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 235; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 236; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 237; (t) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 238; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 239; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 240; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 241; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 242; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 243; (u) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 244; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 245; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 246; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 247; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 248; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 249; (v) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 250; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 251; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 252; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 253; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 254; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 255; (w) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 256; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 257; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 258; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 259; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 260; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 261; (x) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 262; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 263; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 264; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 265; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 266; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 267; (y) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 304; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 305; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 306; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 307; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 308; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 309; (z) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 316; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 317; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 318; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 319; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 320; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 321; (aa) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 328; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 329; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 330; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 331; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 332; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 333; (ab) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 340; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 341; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 342; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 343; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 344; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 345; (ac) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 352; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 353; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 354; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 355; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 356; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 357; (ad) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 364; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 365; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 366; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 367; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 368; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 369; (ae) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 376; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 377; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 378; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 379; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 380; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 381; or (af) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 388; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 389; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 390; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 391; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 392; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 393; In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 202; a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 203; a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 204; a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 205; a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 206; and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 207. In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 208; a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 209; a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 210; a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 211; a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 212; and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 213. In certain embodiments, the extracellular antigen-binding domain comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 214; a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 215; a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 216; a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 217; a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 218; and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 219. In another non-limiting embodiment, the extracellular antigen-binding domain comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 220; a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 221; a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 222; a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 223; a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 224; and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 225.In yet another non-limiting embodiment, the extracellular antigen-binding domain comprises a heavy chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 226; a heavy chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 227; a heavy chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 228; a light chain variable region CDR1 comprising amino acids having the sequence set forth in SEQ ID NO: 229; a light chain variable region CDR2 comprising amino acids having the sequence set forth in SEQ ID NO: 230; and a light chain variable region CDR3 comprising amino acids having the sequence set forth in SEQ ID NO: 231. In certain embodiments, the human scFv comprises a heavy chain variable region, a light chain variable region, a linker peptide between the heavy and light chain variable regions, a His tag, and an HA tag. In certain embodiments, the amino acid sequences of the His tag and the HA tag are as follows: [ka] The amino acid sequence of SEQ ID NO: 275 is presented in

[0024] The nucleotide sequence encoding SEQ ID NO:275 is as follows: [ka] The sequence is sequence number 276 presented in

[0025] In certain embodiments, GPRC5D comprises the amino acid sequence set forth in SEQ ID NO: 97. In certain embodiments, the extracellular antigen-binding domain binds to one, two, three, or four epitope regions selected from the group consisting of an epitope region in the N-terminal region comprising amino acids 1-27 of SEQ ID NO: 97, an epitope region in the ECL1 region comprising amino acids 85-93 of SEQ ID NO: 97, an epitope region in the ECL2 region comprising amino acids 145-167 of SEQ ID NO: 97, and an epitope region in the ECL3 region comprising amino acids 226-239 of SEQ ID NO: 97. In certain embodiments, the extracellular antigen-binding domain binds to an epitope region comprising amino acids 16-23 of SEQ ID NO: 97. In certain embodiments, the extracellular antigen-binding domain binds to an epitope region comprising amino acids 15-23 of SEQ ID NO: 97. In certain embodiments, the extracellular antigen-binding domain binds to an epitope region comprising amino acids 16-25 of SEQ ID NO: 97. In certain embodiments, the extracellular antigen-binding domain binds to an epitope region comprising amino acids 10-17 of SEQ ID NO: 97. In certain embodiments, the extracellular antigen-binding domain binds to an epitope region comprising amino acids 5-17 of SEQ ID NO: 97. In certain embodiments, the extracellular antigen-binding domain binds to an epitope region comprising amino acids 85-95 of SEQ ID NO: 97. In certain embodiments, the extracellular antigen-binding domain binds to an epitope region comprising amino acids 157-164 of SEQ ID NO: 97. In certain embodiments, the extracellular antigen-binding domain binds to an epitope region comprising amino acids 157-167 of SEQ ID NO: 97. In certain embodiments, the extracellular antigen-binding domain binds to an epitope region comprising amino acids 230-237 of SEQ ID NO: 97. In certain embodiments, the extracellular antigen-binding domain binds to an epitope region comprising amino acids 229-237 of SEQ ID NO: 97. In certain embodiments, the extracellular antigen-binding domain binds to an epitope region comprising amino acids 230-243 of SEQ ID NO: 97. In certain embodiments, the extracellular antigen-binding domain binds to an epitope region comprising amino acids 227-237 of SEQ ID NO:97.

[0026] In certain embodiments, the extracellular antigen-binding domain binds to one, two, or three epitope regions selected from the group consisting of the epitope region comprising amino acids 16-25 of SEQ ID NO: 97, the epitope region comprising amino acids 157-164 of SEQ ID NO: 97, and the epitope region comprising amino acids 229-237 of SEQ ID NO: 97. For example, the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 57 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 58. For example, the extracellular antigen-binding domain comprises a V chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 208. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 209 H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 210 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 211 L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 212 L CDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 213 L Includes CDR3.

[0027] In certain embodiments, the extracellular antigen-binding domain binds to one, two, or three epitope regions selected from the group consisting of an epitope region comprising amino acids 5-17 of SEQ ID NO: 97, an epitope region comprising amino acids 85-95 of SEQ ID NO: 97, and an epitope region comprising amino acids 157-164 of SEQ ID NO: 97. For example, the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 61 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 62. For example, the extracellular antigen-binding domain comprises a V chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 214. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 215 H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 216 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 217 LCDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 218 L CDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 219 L Includes CDR3.

[0028] In certain embodiments, the extracellular antigen-binding domain binds to one or two epitope regions selected from the group consisting of the epitope region comprising amino acids 15-23 of SEQ ID NO: 97 and the epitope region comprising amino acids 230-243 of SEQ ID NO: 97. For example, the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 65 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 66. For example, the extracellular antigen-binding domain comprises a V chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 220. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 221 H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 222 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 223 L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 224 L CDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 225 L Includes CDR3.

[0029] In certain embodiments, the extracellular antigen-binding domain binds to one, two, or three epitope regions selected from the group consisting of an epitope region comprising amino acids 10-17 of SEQ ID NO: 97, an epitope region comprising amino acids 157-167 of SEQ ID NO: 97, and an epitope region comprising amino acids 227-237 of SEQ ID NO: 97. For example, the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 69 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 70. For example, the extracellular antigen-binding domain comprises a V chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 226. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 227 HCDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 228 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 229 L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 230 L CDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 231 L Includes CDR3.

[0030] According to the subject matter of the present disclosure, the extracellular antigen-binding domain is covalently linked to the transmembrane domain. The extracellular antigen-binding domain may include a signal peptide covalently linked to the 5' end of the extracellular antigen-binding domain. In certain embodiments, the transmembrane domain of the CAR comprises a CD8 polypeptide, a CD28 polypeptide, a CD3ζ polypeptide, a CD4 polypeptide, a 4-1BB polypeptide, an OX40 polypeptide, an ICOS polypeptide, a CTLA-4 polypeptide, a PD-1 polypeptide, a LAG-3 polypeptide, a 2B4 polypeptide, a BTLA polypeptide, a synthetic peptide (not based on a protein associated with an immune response), or a combination thereof. In certain embodiments, the transmembrane domain comprises a CD8 polypeptide. In certain embodiments, the transmembrane domain comprises a CD28 polypeptide.

[0031] In accordance with the subject matter of the present disclosure, the intracellular domain comprises a CD3ζ polypeptide. In certain embodiments, the intracellular domain further comprises at least one signaling region. In certain embodiments, the at least one signaling region comprises a CD28 polypeptide, a 4-1BB polypeptide, an OX40 polypeptide, an ICOS polypeptide, a DAP-10 polypeptide, a PD-1 polypeptide, a CTLA-4 polypeptide, a LAG-3 polypeptide, a 2B4 polypeptide, a BTLA polypeptide, a synthetic peptide (not based on a protein associated with an immune response), or a combination thereof. In certain embodiments, the signaling region is a costimulatory signaling region. In certain embodiments, the costimulatory signaling region comprises a CD28 polypeptide, a 4-1BB polypeptide, an OX40 polypeptide, an ICOS polypeptide, a DAP-10 polypeptide, or a combination thereof. In certain embodiments, at least one costimulatory signaling region comprises a CD28 polypeptide. In certain embodiments, at least one costimulatory signaling region comprises a 4-1BB polypeptide. In certain embodiments, the transmembrane domain comprises a CD28 polypeptide, the intracellular domain comprises a CD3ζ polypeptide, and the costimulatory signaling domain comprises a CD28 polypeptide.

[0032] In certain embodiments, the CAR is recombinantly expressed. The CAR can be expressed from a vector. In certain embodiments, the vector is a gamma-retroviral vector.

[0033] The presently disclosed subject matter also provides isolated immunoresponsive cells comprising the above-described CAR. In certain embodiments, the isolated immunoresponsive cells are transduced with the CAR, e.g., the CAR is constitutively expressed on the surface of the immunoresponsive cells. In certain embodiments, the isolated immunoresponsive cells are further transduced with at least one costimulatory ligand to express the at least one costimulatory ligand. In certain embodiments, the at least one costimulatory ligand is selected from the group consisting of 4-1BBL, CD80, CD86, CD70, OX40L, CD48, TNFRSF14, and combinations thereof. In certain embodiments, the isolated immunoresponsive cells are further transduced with at least one cytokine to secrete at least one cytokine. In certain embodiments, the at least one cytokine is selected from the group consisting of IL-2, IL-3, IL-6, IL-7, IL-11, IL-12, IL-15, IL-17, IL-21, and combinations thereof. In some embodiments, the isolated immunoresponsive cell is selected from the group consisting of a T cell, a natural killer (NK) cell, a cytotoxic T lymphocyte (CTL), a regulatory T cell, a human embryonic stem cell, a lymphoid progenitor cell, a T cell precursor cell, and a pluripotent stem cell from which lymphoid cells can differentiate. In certain embodiments, the immunoresponsive cell is a T cell.

[0034] The presently disclosed subject matter further provides nucleic acid molecules encoding the CARs of the present disclosure, vectors comprising the nucleic acid molecules, and host cells expressing such nucleic acid molecules. In certain embodiments, the nucleic acid molecule comprises a nucleic acid having a sequence set forth in SEQ ID NO: 397. In certain embodiments, the nucleic acid molecule comprises a nucleic acid having a sequence set forth in SEQ ID NO: 398. In certain embodiments, the nucleic acid molecule comprises a nucleic acid having a sequence set forth in SEQ ID NO: 399. In certain embodiments, the nucleic acid molecule comprises a nucleic acid having a sequence set forth in SEQ ID NO: 400. In certain embodiments, the nucleic acid molecule comprises a nucleic acid having a sequence set forth in SEQ ID NO: 401. In certain embodiments, the nucleic acid molecule comprises a nucleic acid having a sequence set forth in SEQ ID NO: 402. In certain embodiments, the nucleic acid molecule comprises a nucleic acid having a sequence set forth in SEQ ID NO: 403. In certain embodiments, the nucleic acid molecule comprises a nucleic acid having a sequence set forth in SEQ ID NO: 406. In certain embodiments, the nucleic acid molecule comprises a nucleic acid having a sequence set forth in SEQ ID NO: 407. In certain embodiments, the nucleic acid molecule comprises a nucleic acid having a sequence set forth in SEQ ID NO: 408. In certain embodiments, the vector is a gamma-retroviral vector. In certain embodiments, the host cell is a T cell.

[0035] Furthermore, the presently disclosed subject matter provides methods of using the immunoresponsive cells described above to reduce tumor burden in a subject. For example, the presently disclosed subject matter provides a method of treating reducing tumor burden in a subject, comprising administering to the subject an effective amount of the immunoresponsive cells of the present disclosure, thereby inducing tumor cell death in the subject. In certain embodiments, the method reduces the number of tumor cells. In other embodiments, the method reduces tumor size. In yet other embodiments, the method eradicates tumors in the subject. In certain embodiments, the subject is human. In certain embodiments, the immunoresponsive cells are T cells. In certain embodiments, the tumor is multiple myeloma or Waldenstrom's macroglobulinemia. In certain embodiments, the tumor is multiple myeloma.

[0036] Furthermore, the presently disclosed subject matter provides methods of using the immunoresponsive cells described above to prolong or extend the survival of a subject with neoplasia. For example, the presently disclosed subject matter provides a method of prolonging or extending the survival of a subject with neoplasia, comprising administering to the subject an effective amount of an immunoresponsive cell of the present disclosure, thereby prolonging or extending the survival of the subject. In certain embodiments, the neoplasia is multiple myeloma or Waldenstrom's macroglobulinemia. In certain embodiments, the neoplasia is multiple myeloma. In certain embodiments, the method reduces or eradicates tumor burden in the subject.

[0037] The presently disclosed subject matter also provides a method for producing an immunoresponsive cell that binds to a G protein-coupled receptor. In one non-limiting example, the method includes introducing into the immunoresponsive cell a nucleic acid sequence encoding a chimeric antigen receptor (CAR) that includes an extracellular antigen-binding domain, a transmembrane domain, and an intracellular domain, wherein the extracellular antigen-binding domain specifically binds to the G protein-coupled receptor. In a specific embodiment, the G protein-coupled receptor is G protein-coupled receptor family C group 5 member D (GPRC5D). In a specific non-limiting embodiment, the extracellular antigen-binding domain is an scFv.

[0038] The presently disclosed subject matter further provides a pharmaceutical composition comprising an effective amount of the immunoresponsive cells of the present disclosure and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition is for treating neoplasia. In certain embodiments, the neoplasia is multiple myeloma or Waldenstrom's macroglobulinemia. In certain embodiments, the neoplasia is multiple myeloma.

[0039] The presently disclosed subject matter further provides a kit for treating neoplasia, the kit comprising the immunoresponsive cells of the present disclosure. In certain embodiments, the kit further comprises instructions for using the immunoresponsive cells to treat neoplasia. In certain embodiments, the neoplasia is multiple myeloma or Waldenstrom's macroglobulinemia. In certain embodiments, the neoplasia is multiple myeloma. In certain embodiments, for example, the following items are provided: (Item 1) A chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain, a transmembrane domain, and an intracellular domain, wherein the extracellular antigen-binding domain specifically binds to a G protein-coupled receptor. (Item 2) 2. The CAR of item 1, wherein the G protein-coupled receptor is G protein-coupled receptor family C group 5 member D (GPRC5D). (Item 3) The extracellular antigen-binding domain of the CAR binds to GPRC5D at a concentration of about 1×10 -9 M ~ approx. 3×10 -6 The binding affinity (K d ) The CAR according to item 2, wherein the CAR is bound by (Item 4) 2. The CAR of item 1, wherein the extracellular antigen-binding domain is a single-chain variable fragment (scFv). (Item 5) 5. The CAR of item 4, wherein the extracellular antigen-binding domain is a mouse scFv. (Item 6) 5. The CAR of item 4, wherein the extracellular antigen-binding domain is a human scFv. (Item 7) 2. The CAR of item 1, wherein the extracellular antigen-binding domain is an optionally cross-linked Fab. (Item 8) 2. The CAR of item 1, wherein the extracellular antigen-binding domain is F(ab)2. (Item 9) 9. The CAR of any one of items 2 to 8, wherein one or more of the scFv, Fab, and F(ab)2 are comprised within a fusion protein with a heterologous sequence to form the extracellular antigen-binding domain. (Item 10) 10. The CAR of any one of paragraphs 1 to 9, wherein the extracellular antigen-binding domain comprises a heavy chain variable region comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 302, 314, 326, 338, 350, 362, 374, and 386. (Item 11) 11. The CAR of any one of items 1 to 10, wherein the extracellular antigen-binding domain comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 302, 314, 326, 338, 350, 362, 374, and 386, and conservative modifications thereof. (Item 12) 12. The CAR of any one of items 1 to 11, wherein the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having a sequence selected from the group consisting of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 302, 314, 326, 338, 350, 362, 374, and 386. (Item 13) 13. The CAR of item 12, wherein the extracellular antigen-binding domain comprises a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 53. (Item 14) 13. The CAR of item 12, wherein the extracellular antigen-binding domain comprises a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 57. (Item 15) 13. The CAR of item 12, wherein the extracellular antigen-binding domain comprises a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 61. (Item 16) 13. The CAR of item 12, wherein the extracellular antigen-binding domain comprises a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 65. (Item 17) 13. The CAR of item 12, wherein the extracellular antigen-binding domain comprises a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 69. (Item 18) 18. The CAR of any one of items 1 to 17, wherein the extracellular antigen-binding domain comprises a light chain variable region comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 303, 315, 327, 339, 351, 363, 375, and 387. (Item 19) 19. The CAR of any one of items 1 to 18, wherein the extracellular antigen-binding domain comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 303, 315, 327, 339, 351, 363, 375, and 387, and conservative modifications thereof. (Item 20) 20. The CAR of any one of items 1 to 19, wherein the extracellular antigen-binding domain comprises a light chain variable region comprising amino acids having a sequence selected from the group consisting of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 303, 315, 327, 339, 351, 363, 375, and 387. (Item 21) 21. The CAR of item 20, wherein the extracellular antigen-binding domain comprises a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 54. (Item 22) 21. The CAR of item 20, wherein the extracellular antigen-binding domain comprises a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 58. (Item 23) 21. The CAR of item 20, wherein the extracellular antigen-binding domain comprises a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 62. (Item 24) 21. The CAR of item 20, wherein the extracellular antigen-binding domain comprises a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 66. (Item 25) 21. The CAR of item 20, wherein the extracellular antigen-binding domain comprises a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 70. (Item 26) the extracellular antigen-binding domain (a) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 302, 314, 326, 338, 350, 362, 374, and 386; and (b) a light chain variable region comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 303, 315, 327, 339, 351, 363, 375, and 387. 26. The CAR of any one of items 1 to 25, comprising: (Item 27) the extracellular antigen-binding domain (a) a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 302, 314, 326, 338, 350, 362, 374, and 386, and conservative modifications thereof; and (b) a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 303, 315, 327, 339, 351, 363, 375, and 387, and conservative modifications thereof. 27. The CAR of any one of items 1 to 26, comprising: (Item 28) the extracellular antigen-binding domain (a) a heavy chain variable region comprising amino acids having a sequence selected from the group consisting of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 302, 314, 326, 338, 350, 362, 374, and 386; and (b) a light chain variable region comprising amino acids having a sequence selected from the group consisting of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 303, 315, 327, 339, 351, 363, 375, and 387. 28. The CAR of any one of items 1 to 27, comprising: (Item 29) the extracellular antigen-binding domain (a) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 1; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO:2; (b) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO:5; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO:6; (c) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 9; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 10; (d) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 13; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 14; (e) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 17; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 18; (f) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 21; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 22; (g) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 25; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 26; (h) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 29; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 30; (i) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 33; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 34; (j) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 37; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 38; (k) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 41; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 42; (l) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 45; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 46; (m) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 49, and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 50; (n) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 53; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 54; (o) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 57; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 58; (p) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 61; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 62; (q) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 65; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 66; (r) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 69; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 70; (s) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 73; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 74; (t) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 77; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 78; (u) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 81; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 82; (v) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 85; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 86; (w) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 89; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 90; (x) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 93, and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 94; (y) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 302, and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 303; (z) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 314; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 315; (aa) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 326, and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 327; (ab) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 338, and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 339; (ac) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 350, and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 351; (ad) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 362; and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 363; (ae) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 374, and a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 375; (af) a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 386; and A light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 387. 29. The CAR of item 28, comprising: (Item 30) 30. The CAR of item 29, wherein the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 53; and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 54. (Item 31) 30. The CAR of item 29, wherein the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 57; and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 58. (Item 32) 30. The CAR of item 29, wherein the extracellular antigen-binding domain comprises a heavy chain variable region comprising an amino acid having the sequence set forth in SEQ ID NO: 61; and a light chain variable region comprising an amino acid having the sequence set forth in SEQ ID NO: 62. (Item 33) 30. The CAR of item 29, wherein the extracellular antigen-binding domain comprises a heavy chain variable region comprising an amino acid having the sequence set forth in SEQ ID NO: 65; and a light chain variable region comprising an amino acid having the sequence set forth in SEQ ID NO: 66. (Item 34) 30. The CAR of item 29, wherein the extracellular antigen-binding domain comprises a heavy chain variable region comprising an amino acid having the sequence set forth in SEQ ID NO: 69; and a light chain variable region comprising an amino acid having the sequence set forth in SEQ ID NO: 70. (Item 35) 35. The CAR of any one of items 1 to 34, wherein the extracellular antigen-binding domain comprises a linker between the heavy chain variable region and the light chain variable region of the extracellular antigen-binding domain. (Item 36) the extracellular antigen-binding domain (a) a heavy chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 126, 132, 138, 144, 150, 156, 162, 168, 174, 180, 186, 192, 198, 204, 210, 216, 222, 228, 234, 240, 246, 252, 258, 264, 306, 318, 330, 342, 354, 366, 378, and 390, and conservative modifications thereof; and (b) a light chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 129, 135, 141, 147, 153, 159, 165, 171, 177, 183, 189, 195, 201, 207, 213, 219, 225, 231, 237, 243, 249, 255, 261, 267, 309, 321, 333, 345, 357, 369, 381, and 393, and conservative modifications thereof. 36. The CAR of any one of items 1 to 35, comprising: (Item 37) the extracellular antigen-binding domain (a) a heavy chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 125, 131, 137, 143, 149, 155, 161, 167, 173, 179, 185, 191, 197, 203, 209, 215, 221, 227, 233, 239, 245, 251, 257, 263, 305, 317, 329, 341, 353, 365, 377, and 389, and conservative modifications thereof; and (b) a light chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 128, 134, 140, 146, 152, 158, 164, 170, 176, 182, 188, 194, 200, 206, 212, 218, 224, 230, 236, 242, 248, 254, 260, 266, 308, 320, 332, 344, 356, 368, 380, and 392, and conservative modifications thereof; 37. The CAR of item 36, comprising: (Item 38) the extracellular antigen-binding domain (a) a heavy chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124, 130, 136, 142, 148, 154, 160, 166, 172, 178, 184, 190, 196, 202, 208, 214, 220, 226, 232, 238, 244, 250, 256, 262, 304, 316, 328, 340, 352, 364, 376, and 388, and conservative modifications thereof; and (b) a light chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 127, 133, 139, 145, 151, 157, 163, 169, 175, 181, 187, 193, 199, 205, 211, 217, 223, 229, 235, 241, 247, 253, 259, 265, 307, 319, 331, 343, 355, 367, 379, and 391, and conservative modifications thereof; 38. The CAR according to item 36 or 37, comprising: (Item 39) the extracellular antigen-binding domain (a) a heavy chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124, 130, 136, 142, 148, 154, 160, 166, 172, 178, 184, 190, 196, 202, 208, 214, 220, 226, 232, 238, 244, 250, 256, 262, 304, 316, 328, 340, 352, 364, 376, and 388; (b) a heavy chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 125, 131, 137, 143, 149, 155, 161, 167, 173, 179, 185, 191, 197, 203, 209, 215, 221, 227, 233, 239, 245, 251, 257, 263, 305, 317, 329, 341, 353, 365, 377, and 389; (c) a heavy chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 126, 132, 138, 144, 150, 156, 162, 168, 174, 180, 186, 192, 198, 204, 210, 216, 222, 228, 234, 240, 246, 252, 258, 264, 306, 318, 330, 342, 354, 366, 378, and 390; (d) a light chain variable region CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 127, 133, 139, 145, 151, 157, 163, 169, 175, 181, 187, 193, 199, 205, 211, 217, 223, 229, 235, 241, 247, 253, 259, 265, 307, 319, 331, 343, 355, 367, 379, and 391; (e) a light chain variable region CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 128, 134, 140, 146, 152, 158, 164, 170, 176, 182, 188, 194, 200, 206, 212, 218, 224, 230, 236, 242, 248, 254, 260, 266, 308, 320, 332, 344, 356, 368, 380, and 392; and (f) a light chain variable region CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 129, 135, 141, 147, 153, 159, 165, 171, 177, 183, 189, 195, 201, 207, 213, 219, 225, 231, 237, 243, 249, 255, 261, 267, 309, 321, 333, 345, 357, 369, 381, and 393. 39. The CAR of any one of items 1 to 38, comprising: (Item 40) the extracellular antigen-binding domain (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 124 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 125 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 126 or amino acids having a conservative modification thereof; (b) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 130 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 131 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 132 or a conservative modification thereof; (c) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 136 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 137 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 138 or amino acids having a conservative modification thereof; (d) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 142 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 143 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 144 or amino acids having a conservative modification thereof; (e) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 148 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 149 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 150 or a conservative modification thereof; (f) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 154 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 155 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 156 or a conservative modification thereof; (g) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 160 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 161 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 162 or a conservative modification thereof; (h) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 166 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 167 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 168 or amino acids having a conservative modification thereof; (i) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 172 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 173 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 174 or amino acids having a conservative modification thereof; (j) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 178 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 179 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 180 or amino acids having a conservative modification thereof; (k) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 184 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 185 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 186 or amino acids having a conservative modification thereof; (l) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 190 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 191 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 192 or amino acids having a conservative modification thereof; (m) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 196 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 197 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 198 or amino acids having a conservative modification thereof; (n) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 202 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 203 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 204 or amino acids having a conservative modification thereof; (o) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 208 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 209 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210 or a conservative modification thereof; (p) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 214 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 215 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 216 or amino acids having a conservative modification thereof; (q) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 220 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 221 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 222 or amino acids having a conservative modification thereof; (r) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 226 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 227 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 228 or amino acids having a conservative modification thereof; (s) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 232 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 233 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 234 or amino acids having a conservative modification thereof; (t) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 238 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 239 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 240 or amino acids having a conservative modification thereof; (u) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 244 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 245 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 246 or a conservative modification thereof; (v) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 250 or an amino acid sequence having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 251 or an amino acid sequence having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 252 or an amino acid sequence having a conservative modification thereof; (w) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 256 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 257 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 258 or a conservative modification thereof; (x) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 262 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 263 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 264 or amino acids having a conservative modification thereof; (y) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 304 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 305 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 306 or amino acids having a conservative modification thereof; (z) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 316 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 317 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 318 or a conservative modification thereof; (aa) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 328 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 329 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 330 or a conservative modification thereof; (ab) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 340 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 341 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 342 or a conservative modification thereof; (ac) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 352 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 353 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 354 or a conservative modification thereof; (ad) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 364 or a conservative modification thereof; a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 365 or a conservative modification thereof; and a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 366 or a conservative modification thereof; (ae) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 376 or amino acids having conservative modifications thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 377 or amino acids having conservative modifications thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 378 or amino acids having conservative modifications thereof; or (af) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 388 or amino acids having a conservative modification thereof; a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 389 or amino acids having a conservative modification thereof; and a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 390 or amino acids having a conservative modification thereof. 40. The CAR of any one of items 1 to 39, comprising: (Item 41) the extracellular antigen-binding domain a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 202; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 203; and Heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 204 41. The CAR according to item 40, comprising: (Item 42) the extracellular antigen-binding domain a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 208; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 209; and Heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 210 41. The CAR according to item 40, comprising: (Item 43) the extracellular antigen-binding domain a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 214; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 215; and Heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 216 41. The CAR according to item 40, comprising: (Item 44) the extracellular antigen-binding domain a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 220; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 221; and Heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 222 41. The CAR according to item 40, comprising: (Item 45) the extracellular antigen-binding domain a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 226; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 227; and Heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 228 41. The CAR according to item 40, comprising: (Item 46) the extracellular antigen-binding domain (a) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 127 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 129 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 130 or amino acids having a conservative modification thereof; (b) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 133 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 134 or a conservative modification thereof; and a light chain variable region CDR3 comprising SEQ ID NO: 135 or a conservative modification thereof; (c) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 139 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 140 or a conservative modification thereof; and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 141 or a conservative modification thereof; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 145 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 146 or a conservative modification thereof; and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 147 or a conservative modification thereof; (e) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 151 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 152 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 153 or amino acids having a conservative modification thereof; (f) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 157 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 158 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 159 or amino acids having a conservative modification thereof; (g) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 163 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 164 or a conservative modification thereof; and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 165 or a conservative modification thereof; (h) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 169 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 170 or a conservative modification thereof; and a light chain variable region CDR3 comprising SEQ ID NO: 171 or a conservative modification thereof; (i) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 175 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 176 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 177 or amino acids having a conservative modification thereof; (j) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 181 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 182 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 183 or amino acids having a conservative modification thereof; (k) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 187 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 188 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 189 or amino acids having a conservative modification thereof; (l) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 193 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 194 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 195 or amino acids having a conservative modification thereof; (m) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 199 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 200 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 201 or amino acids having a conservative modification thereof; (n) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 205 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 206 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 207 or amino acids having a conservative modification thereof; (o) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 211 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 212 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 213 or amino acids having a conservative modification thereof; (p) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 217 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 218 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 219 or amino acids having a conservative modification thereof; (q) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 223 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 224 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 225 or amino acids having a conservative modification thereof; (r) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 229 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 230 or a conservative modification thereof; and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 231 or a conservative modification thereof; (s) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 235 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 236 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 237 or amino acids having a conservative modification thereof; (t) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 241 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 242 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 243 or amino acids having a conservative modification thereof; (u) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 247 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 248 or a conservative modification thereof; and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 249 or a conservative modification thereof; (v) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 253 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 254 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 255 or amino acids having a conservative modification thereof; (w) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 259 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 260 or a conservative modification thereof; and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 261 or a conservative modification thereof; (x) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 265 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 266 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 267 or amino acids having a conservative modification thereof; (y) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 307 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 308 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 309 or amino acids having a conservative modification thereof; (z) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 319 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 320 or a conservative modification thereof; and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 321 or a conservative modification thereof; (aa) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 331 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 332 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 333 or amino acids having a conservative modification thereof; (ab) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 343 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 344 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 345 or amino acids having a conservative modification thereof; (ac) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 355 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 356 or a conservative modification thereof; and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 357 or a conservative modification thereof; (ad) a light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 367 or a conservative modification thereof; a light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 368 or a conservative modification thereof; and a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 369 or a conservative modification thereof; (ae) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 379 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 380 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 381 or amino acids having a conservative modification thereof; or (af) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 391 or amino acids having a conservative modification thereof; a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 392 or amino acids having a conservative modification thereof; and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 393 or amino acids having a conservative modification thereof. 46. ​​The CAR of any one of items 1 to 45, comprising: (Item 47) the extracellular antigen-binding domain a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 205; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 206; and Light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 207 47. The CAR of item 46, comprising: (Item 48) the extracellular antigen-binding domain a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 211; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 212; and A light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 213 47. The CAR of item 46, comprising: (Item 49) the extracellular antigen-binding domain a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 217; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 218; and A light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 219 47. The CAR of item 46, comprising: (Item 50) the extracellular antigen-binding domain a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 223; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 224; and Light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225 47. The CAR of item 46, comprising: (Item 51) the extracellular antigen-binding domain a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 229; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 230; and Light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 231 47. The CAR of item 46, comprising: (Item 52) the extracellular antigen-binding domain (a) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 124; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 125; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 126; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 127; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 128; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 129; (b) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 130; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 131; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 132; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 133; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 134; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 135; (c) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 136; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 137; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 138; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 139; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 140; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 141; (d) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 142; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 143; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 144; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 145; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 146; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 147; (e) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 148; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 149; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 150; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 151; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 152; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 153; (f) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 154; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 155; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 156; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 157; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 158; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 159; (g) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 160; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 161; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 162; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 163; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 164; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 165; (h) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 166; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 167; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 168; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 169; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 170; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 171; (i) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 172; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 173; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 174; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 175; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 176; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 177; (j) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 178; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 179; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 180; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 181; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 182; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 183; (k) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 184; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 185; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 186; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 187; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 188; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 189; (l) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 190; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 191; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 192; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 193; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 194; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 195; (m) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 196; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 197; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 198; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 199; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 200; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 201; (n) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 202; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 203; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 204; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 205; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 206; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 207; (o) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 208; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 209; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 210; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 211; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 212; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 213; (p) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 214; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 215; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 216; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 217; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 218; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 219; (q) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 220; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 221; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 222; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 223; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 224; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 225; (r) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 226; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 227; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 228; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 229; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 230; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 231; (s) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 232; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 233; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 234; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 235; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 236; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 237; (t) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 238; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 239; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 240; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 241; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 242; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 243; (u) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 244; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 245; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 246; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 247; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 248; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 249; (v) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 250; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 251; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 252; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 253; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 254; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 255; (w) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 256; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 257; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 258; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 259; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 260; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 261; (x) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 262; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 263; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 264; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 265; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 266; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 267; (y) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 304; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 305; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 306; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 307; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 308; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 309; (z) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 316; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 317; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 318; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 319; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 320; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 321; (aa) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 328; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 329; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 330; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 331; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 332; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 333; (ab) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 340; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 341; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 342; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 343; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 344; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 345; (ac) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 352; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 353; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 354; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 355; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 356; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 357; (ad) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 364; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 365; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 366; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 367; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 368; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 369; (ae) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 376; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 377; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 378; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 379; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 380; and a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 381; or (af) a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 388; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 389; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 390; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 391; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 392; and 52. The CAR of any one of items 1 to 51, comprising a light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 393. (Item 53) the extracellular antigen-binding domain a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 202; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 203; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 204; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 205; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 206; and Light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 207 53. The CAR of item 52, comprising: (Item 54) the extracellular antigen-binding domain a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 208; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 209; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 210; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 211; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 212; and A light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 213 53. The CAR of item 52, comprising: (Item 55) the extracellular antigen-binding domain a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 214; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 215; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 216; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 217; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 218; and A light chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 219 53. The CAR of item 52, comprising: (Item 56) the extracellular antigen-binding domain a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 220; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 221; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 222; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 223; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 224; and Light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 225 53. The CAR of item 52, comprising: (Item 57) the extracellular antigen-binding domain a heavy chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 226; a heavy chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 227; a heavy chain variable region CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 228; a light chain variable region CDR1 comprising an amino acid sequence set forth in SEQ ID NO: 229; a light chain variable region CDR2 comprising an amino acid sequence set forth in SEQ ID NO: 230; and Light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 231 53. The CAR of item 52, comprising: (Item 58) 58. The CAR of any one of items 1 to 57, wherein the extracellular antigen-binding domain comprises a signal peptide covalently attached to the 5' end of the extracellular antigen-binding domain. (Item 59) 59. The CAR of any one of items 2 to 58, wherein the GPRC5D comprises the amino acid sequence set forth in SEQ ID NO: 97. (Item 60) 60. The CAR of item 59, wherein the extracellular antigen-binding domain binds to one, two, three, or four epitope regions selected from the group consisting of: an epitope region in the N-terminal region comprising amino acids 1 to 27 of SEQ ID NO: 97; an epitope region in the ECL1 region comprising amino acids 85 to 93 of SEQ ID NO: 97; an epitope region in the ECL2 region comprising amino acids 145 to 167 of SEQ ID NO: 97; and an epitope region in the ECL3 region comprising amino acids 226 to 239 of SEQ ID NO: 97. (Item 61) 61. The CAR of item 60, wherein the extracellular antigen-binding domain binds to an epitope region comprising amino acids 16 to 23 of SEQ ID NO: 97. (Item 62) 62. The CAR of item 61, wherein the extracellular antigen-binding domain binds to an epitope region comprising amino acids 15 to 23 of SEQ ID NO: 97. (Item 63) 62. The CAR of item 61, wherein the extracellular antigen-binding domain binds to an epitope region comprising amino acids 16 to 25 of SEQ ID NO: 97. (Item 64) 61. The CAR of item 60, wherein the extracellular antigen-binding domain binds to an epitope region comprising amino acids 10 to 17 of SEQ ID NO: 97. (Item 65) 65. The CAR of item 64, wherein the extracellular antigen-binding domain binds to an epitope region comprising amino acids 5 to 17 of SEQ ID NO: 97. (Item 66) 61. The CAR of item 60, wherein the extracellular antigen-binding domain binds to an epitope region comprising amino acids 85 to 95 of SEQ ID NO: 97. (Item 67) 61. The CAR of item 60, wherein the extracellular antigen-binding domain binds to an epitope region comprising amino acids 157 to 164 of SEQ ID NO: 97. (Item 68) 68. The CAR of Item 67, wherein the extracellular antigen-binding domain binds to an epitope region comprising amino acids 157 to 167 of SEQ ID NO: 97. (Item 69) 61. The CAR of item 60, wherein the extracellular antigen-binding domain binds to an epitope region comprising amino acids 230 to 237 of SEQ ID NO: 97. (Item 70) 70. The CAR of item 69, wherein the extracellular antigen-binding domain binds to an epitope region comprising amino acids 229 to 237 of SEQ ID NO: 97. (Item 71) 70. The CAR of item 69, wherein the extracellular antigen-binding domain binds to an epitope region comprising amino acids 230 to 243 of SEQ ID NO: 97. (Item 72) 70. The CAR of item 69, wherein the extracellular antigen-binding domain binds to an epitope region comprising amino acids 227 to 237 of SEQ ID NO: 97. (Item 73) 61. The CAR of item 60, wherein the extracellular antigen-binding domain binds to one, two, or three epitope regions selected from the group consisting of an epitope region comprising amino acids 16 to 25 of SEQ ID NO: 97, an epitope region comprising amino acids 157 to 164 of SEQ ID NO: 97, and an epitope region comprising amino acids 229 to 237 of SEQ ID NO: 97. (Item 74) 74. The CAR of item 73, wherein the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 57, and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 58. (Item 75) the extracellular antigen-binding domain comprises an amino acid sequence set forth in SEQ ID NO: 208 H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 209 H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 210 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 211 L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 212 L CDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 213 L 75. The CAR of item 73 or item 74, comprising CDR3. (Item 76) 61. The CAR of item 60, wherein the extracellular antigen-binding domain binds to one, two, or three epitope regions selected from the group consisting of an epitope region comprising amino acids 5 to 17 of SEQ ID NO: 97, an epitope region comprising amino acids 85 to 95 of SEQ ID NO: 97, and an epitope region comprising amino acids 157 to 164 of SEQ ID NO: 97. (Item 77) 77. The CAR of item 76, wherein the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 61, and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 62. (Item 78) the extracellular antigen-binding domain comprises an amino acid sequence set forth in SEQ ID NO: 214 HCDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 215 H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 216 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 217 L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 218 L CDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 219 L 78. The CAR of item 76 or item 77, comprising CDR3. (Item 79) 61. The CAR of item 60, wherein the extracellular antigen-binding domain binds to one or two epitope regions selected from the group consisting of an epitope region comprising amino acids 15 to 23 of SEQ ID NO: 97 and an epitope region comprising amino acids 230 to 243 of SEQ ID NO: 97. (Item 80) 80. The CAR of item 79, wherein the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 65, and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 66. (Item 81) the extracellular antigen-binding domain comprises an amino acid sequence having the sequence set forth in SEQ ID NO: 220 H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 221 H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 222 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 223 L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 224 L CDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 225 L The CAR of item 79 or item 80, comprising CDR3. (Item 82) 61. The CAR of item 60, wherein the extracellular antigen-binding domain binds to one, two, or three epitope regions selected from the group consisting of an epitope region comprising amino acids 10 to 17 of SEQ ID NO: 97, an epitope region comprising amino acids 157 to 167 of SEQ ID NO: 97, and an epitope region comprising amino acids 227 to 237 of SEQ ID NO: 97. (Item 83) 83. The CAR of claim 82, wherein the extracellular antigen-binding domain comprises a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 69, and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 70. (Item 84) the extracellular antigen-binding domain comprises an amino acid sequence set forth in SEQ ID NO: 226 H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 227 H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 228 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 229 L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 230 L CDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 231 L The CAR of item 82 or item 83, comprising a CDR3. (Item 85) 85. The CAR of any one of paragraphs 1 to 84, wherein the transmembrane domain comprises a CD8 polypeptide, a CD28 polypeptide, a CD3ζ polypeptide, a CD4 polypeptide, a 4-1BB polypeptide, an OX40 polypeptide, an ICOS polypeptide, a CTLA-4 polypeptide, a PD-1 polypeptide, a LAG-3 polypeptide, a 2B4 polypeptide, a BTLA polypeptide, a synthetic peptide (not based on a protein associated with an immune response), or a combination thereof. (Item 86) 86. The CAR of item 85, wherein the transmembrane domain comprises a CD8 polypeptide. (Item 87) 86. The CAR of item 85, wherein the transmembrane domain comprises a CD28 polypeptide. (Item 88) 88. The CAR of any one of items 1 to 87, wherein the intracellular domain comprises a CD3ζ polypeptide. (Item 89) 89. The CAR of any one of paragraphs 1 to 88, wherein the intracellular domain further comprises at least one signaling region. (Item 90) 90. The CAR of item 89, wherein the at least one signaling region comprises a CD28 polypeptide, a 4-1BB polypeptide, an OX40 polypeptide, an ICOS polypeptide, a DAP-10 polypeptide, a PD-1 polypeptide, a CTLA-4 polypeptide, a LAG-3 polypeptide, a 2B4 polypeptide, a BTLA polypeptide, a synthetic peptide (not based on a protein associated with an immune response), or a combination thereof. (Item 91) The CAR of paragraph 89 or paragraph 90, wherein the signaling region is a costimulatory signaling region. (Item 92) 92. The CAR of item 91, wherein the at least one costimulatory signaling region comprises a CD28 polypeptide, a 4-1BB polypeptide, an OX40 polypeptide, an ICOS polypeptide, a DAP-10 polypeptide, or a combination thereof. (Item 93) 93. The CAR of paragraph 92, wherein the at least one costimulatory signaling region comprises a CD28 polypeptide. (Item 94) 93. The CAR of item 92, wherein the at least one costimulatory signaling region comprises a 4-1BB polypeptide. (Item 95) 94. The CAR of any one of paragraphs 89 to 93, wherein the transmembrane domain comprises a CD28 polypeptide, the intracellular domain comprises a CD3ζ polypeptide, and the signaling domain comprises a CD28 polypeptide. (Item 96) 95. The CAR of any one of paragraphs 89 to 92 and 94, wherein the transmembrane domain comprises a CD8 polypeptide, the intracellular domain comprises a CD3ζ polypeptide, and the signaling domain comprises a 4-1BB polypeptide. (Item 97) 97. The CAR of any one of items 1 to 96, which is recombinantly expressed. (Item 98) 98. The CAR of any one of items 1 to 97, which is expressed from a vector. (Item 99) 99. The CAR of item 98, wherein the vector is a gamma-retroviral vector. (Item 100) An isolated immunoresponsive cell comprising the CAR of any one of the preceding items. (Item 101) 101. The isolated immunoresponsive cell of paragraph 100, transduced with the CAR. (Item 102) 102. The isolated immunoresponsive cell of paragraph 100 or 101, wherein the CAR is constitutively expressed on the surface of the immunoresponsive cell. (Item 103) 103. The isolated immunoresponsive cell of any one of paragraphs 100 to 102, further transduced with at least one costimulatory ligand to express said at least one costimulatory ligand. (Item 104) 104. The isolated immunoresponsive cell of paragraph 103, wherein the at least one costimulatory ligand is selected from the group consisting of 4-1BBL, CD80, CD86, CD70, OX40L, CD48, TNFRSF14, and combinations thereof. (Item 105) 105. The isolated immunoresponsive cell of any one of paragraphs 100 to 104, further transduced with at least one cytokine such that the cell secretes said at least one cytokine. (Item 106) 106. The isolated immunoresponsive cell of claim 105, wherein the at least one cytokine is selected from the group consisting of IL-2, IL-3, IL-6, IL-7, IL-11, IL-12, IL-15, IL-17, IL-21, and combinations thereof. (Item 107) 107. The isolated immunoresponsive cell of any one of paragraphs 100 to 106, wherein the isolated immunoresponsive cell is selected from the group consisting of a T cell, a natural killer (NK) cell, a cytotoxic T lymphocyte (CTL), a regulatory T cell, a human embryonic stem cell, a lymphoid progenitor cell, a T cell precursor cell, and a pluripotent stem cell from which lymphoid cells can be differentiated. (Item 108) 108. The isolated immunoresponsive cell of paragraph 107, which is a T cell. (Item 109) 99. An isolated nucleic acid molecule encoding the chimeric antigen receptor (CAR) of any one of items 1 to 99. (Item 110) 109. The isolated nucleic acid molecule of claim 109, comprising a nucleic acid having the sequence set forth in SEQ ID NO: 397. (Item 111) 109. The isolated nucleic acid molecule of claim 109, comprising a nucleic acid having the sequence set forth in SEQ ID NO: 398. (Item 112) 109. The isolated nucleic acid molecule of claim 109, comprising a nucleic acid having the sequence set forth in SEQ ID NO: 399. (Item 113) 110. The isolated nucleic acid molecule of item 109, comprising a nucleic acid having the sequence set forth in SEQ ID NO: 400. (Item 114) 110. The isolated nucleic acid molecule of Item 109, comprising a nucleic acid having the sequence set forth in SEQ ID NO: 401. (Item 115) 110. The isolated nucleic acid molecule of item 109, comprising a nucleic acid having the sequence set forth in SEQ ID NO: 402. (Item 116) 110. The isolated nucleic acid molecule of item 109, comprising a nucleic acid having the sequence set forth in SEQ ID NO: 403. (Item 117) 109. The isolated nucleic acid molecule of claim 109, comprising a nucleic acid having the sequence set forth in SEQ ID NO: 406. (Item 118) 109. The isolated nucleic acid molecule of claim 109, comprising a nucleic acid having the sequence set forth in SEQ ID NO: 407. (Item 119) 109. The isolated nucleic acid molecule of claim 109, comprising a nucleic acid having the sequence set forth in SEQ ID NO: 408. (Item 120) 120. A vector comprising the isolated nucleic acid molecule of any one of items 109 to 119. (Item 121) Item 122. The vector according to Item 120, wherein the vector is a gamma-retroviral vector. 120. A host cell expressing the nucleic acid molecule of any one of items 109 to 119. (Item 123) 123. The host cell of item 122, which is a T cell. (Item 124) 109. A method of reducing tumor burden in a subject, comprising administering to the subject an effective amount of the immunoresponsive cell of any one of paragraphs 100 to 108, thereby inducing tumor cell death in the subject. (Item 125) 125. The method of claim 124, wherein the number of tumor cells is reduced. (Item 126) The method of item 124, wherein the tumor size is reduced. (Item 127) 125. The method of claim 124, wherein the tumor is eradicated in the subject. (Item 128) 128. The method of any one of items 124 to 127, wherein the tumor is multiple myeloma or Waldenstrom's macroglobulinemia. (Item 129) Item 129. The method of item 128, wherein the tumor is multiple myeloma. (Item 130) 130. The method of any one of items 124 to 129, wherein the subject is a human. (Item 131) 131. The method of any one of items 124 to 130, wherein the immunoresponsive cells are T cells. (Item 132) 109. A method for prolonging or extending the survival of a subject having a neoplasia, comprising administering to the subject an effective amount of an immunoresponsive cell according to any one of paragraphs 100 to 108, thereby prolonging or extending the survival of the subject. (Item 133) 133. The method of claim 132, wherein the neoplasia is multiple myeloma or Waldenstrom's macroglobulinemia. (Item 134) Item 134. The method of item 133, wherein the neoplasia is multiple myeloma. (Item 135) 135. The method of any one of items 132 to 134, wherein the method reduces or eradicates tumor burden in the subject. (Item 136) 1. A method for generating an immunoresponsive cell that binds to a G protein-coupled receptor, comprising administering to the immunoresponsive cell: A nucleic acid sequence encoding a chimeric antigen receptor (CAR) comprising an extracellular antigen-binding domain, a transmembrane domain, and an intracellular domain, wherein the extracellular antigen-binding domain specifically binds to a G protein-coupled receptor. 20. A method comprising: (Item 137) Item 137. The method of item 136, wherein the G protein-coupled receptor is G protein-coupled receptor family C group 5 member D (GPRC5D). (Item 138) 109. A pharmaceutical composition comprising an effective amount of the immunoresponsive cells of any one of items 100 to 108 and a pharmaceutically acceptable excipient. (Item 139) 139. The pharmaceutical composition according to item 138, which is for treating neoplasia. (Item 140) 140. The pharmaceutical composition of item 139, wherein the neoplasia is multiple myeloma or Waldenstrom's macroglobulinemia. (Item 141) 141. The pharmaceutical composition of item 140, wherein the neoplasia is multiple myeloma. (Item 142) 109. A kit for treating multiple myeloma, comprising the immunoresponsive cell of any one of items 100 to 108. (Item 143) 143. The kit of claim 142, further comprising instructions for using the immunoresponsive cells to treat a subject with a neoplasia. (Item 144) 144. The kit of item 142 or 143, wherein the neoplasia is multiple myeloma or Waldenstrom's macroglobulinemia. (Item 145) Item 145. The kit of item 144, wherein the neoplasia is multiple myeloma.

[0040] The following detailed description, given by way of example and not intended to limit the invention to the particular embodiments described, may be understood in conjunction with the accompanying drawings. [Brief explanation of the drawings]

[0041] [Figure 1] FIG. 1 shows a chimeric antigen receptor targeting a G protein-coupled receptor according to one non-limiting embodiment of the presently disclosed subject matter.

[0042] [Figure 2] FIG. 2 shows human GPRC5D expression in normal tissues and human cancer cell lines.

[0043] [Figure 3] FIG. 3 shows the expression of the GPRC5D CAR of the present disclosure on human T cells.

[0044] [Figure 4] FIG. 4 shows the killing activity of GPRC5D of the present disclosure on 3T3 cells overexpressing GPRC5D.

[0045] [Figure 5] FIG. 5 shows the killing activity of GPRC5D of the present disclosure on human multiple myeloma cell lines.

[0046] [Figure 6] FIG. 6 shows a chimeric antigen receptor that targets GPRC5D according to one non-limiting embodiment of the presently disclosed subject matter.

[0047] [Figure 7] FIG. 7 shows a nucleic acid molecule encoding a GPRC5D-targeting CAR according to one non-limiting embodiment of the presently disclosed subject matter.

[0048] [Figure 8] FIG. 8 shows a nucleic acid molecule encoding a GPRC5D-targeting CAR according to one non-limiting embodiment of the presently disclosed subject matter.

[0049] [Figure 9] FIG. 9 shows a nucleic acid molecule encoding a GPRC5D-targeting CAR according to one non-limiting embodiment of the presently disclosed subject matter.

[0050] [Figure 10] Figure 10 shows the cytotoxicity of GPRC5D-targeted CAR T cells on human multiple myeloma cell lines.

[0051] [Figure 11] Figure 11 shows induction of cytokine secretion of GPRC5D-targeted CAR T cells.

[0052] [Figure 12] Figure 12 shows the anti-tumor activity of GPRC5D-targeted CAR T cells.

[0053] [Figure 13A] Figures 13A and 13B show the killing activity of GPRC5D-targeted CAR T cells. (A) shows the percentage of GFP+ tumor lines at time 0. (B) shows the percentage killing of GFP+ tumor lines at 36 hours. [Figure 13B] Figures 13A and 13B show the killing activity of GPRC5D-targeted CAR T cells. (A) shows the percentage of GFP+ tumor lines at time 0. (B) shows the percentage killing of GFP+ tumor lines at 36 hours.

[0054] [Figure 14] Figure 14 illustrates the CLIPS technology. The CLIPS reaction occurs between the bromo group of the CLIPS scaffold and the thiol side chain of cysteine. The reaction is fast and specific under mild conditions. This elegant chemistry is used to transform natural protein sequences into CLIPS constructs with a range of structures. From left to right: two different single T2 loops, a T3 double loop, a conjugated T2+T3 loop, a stabilized beta sheet, and a stabilized alpha helix (Timmerman et al., J. Mol. Recognit. 2007;20:283-29).

[0055] [Figure 15] Figure 15 illustrates combinatorial CLIPS library screening. A target protein containing discontinuous conformational epitopes (left) is converted into a matrix library (center). Combinatorial peptides are synthesized on unique minicards and chemically converted into spatially defined CLIPS constructs (right).

[0056] [Figure 16] FIG. 16 shows the T3 looped CLIPS™ construct.

[0057] [Figure 17] 17A-D illustrate the heatmap technique. (A) Table of combined peptides with two subsequences designated "Loop 1" and "Loop 2." (B) Data from A shown as a matrix. (C) Color bar presentation of the heatmap depiction. (D) Heatmap visualization of data from A.

[0058] [Figure 18] Figure 18 shows the intensity profile recorded for ET150-2, with a line drawn from the starting to the ending residue of a single peptide to the height at which the signal is recorded for that peptide.

[0059] [Figure 19] FIG. 19 shows a heat map analysis of the data recorded for ET150-5 under high stringency conditions.

[0060] [Figure 20] FIG. 20 shows the intensity profile recorded for ET150-18.

[0061] [Figure 21] FIG. 21 shows the intensity profile recorded for ET150-8.

[0062] [Figure 22] Figure 22 shows a schematic diagram of a GPCR containing seven transmembrane helices (TM) and three extracellular domains (ECLs). Colored arrows indicate the binding sites for each antibody.

[0063] [Figure 23] Figure 23 shows a scatterplot analysis of all the data recorded for each sample. The statistical data distribution is on the diagonal.

[0064] [Figure 24] FIG. 24 shows FACS analysis of anti-GPRC5D antibodies.

[0065] [Figure 25] FIG. 25 shows FACS analysis of anti-GPRC5D antibodies.

[0066] [Figure 26]FIG. 26 shows a nucleic acid molecule encoding a GPRC5D-targeting CAR according to one non-limiting embodiment of the presently disclosed subject matter.

[0067] [Figure 27] FIG. 27 shows a nucleic acid molecule encoding a GPRC5D-targeting CAR according to one non-limiting embodiment of the presently disclosed subject matter. DETAILED DESCRIPTION OF THE INVENTION

[0068] Detailed Description of the Invention The presently disclosed subject matter generally provides chimeric antigen receptors (CARs) that target G protein-coupled receptors (e.g., G protein-coupled receptor family C group 5 member D (GPRC5D)). In one non-limiting example, the CAR comprises an extracellular antigen-binding domain, a transmembrane domain, and an intracellular domain, where the extracellular antigen-binding domain specifically binds to the G protein-coupled receptor. The presently disclosed subject matter also provides immunoresponsive cells (e.g., T cells, natural killer (NK) cells, cytotoxic T lymphocytes (CTLs), regulatory T cells, human embryonic stem cells, lymphoid progenitor cells, T cell precursor cells, and pluripotent stem cells from which lymphoid cells can differentiate) that express CARs that target G protein-coupled receptors, and methods of using such immunoresponsive cells to treat cancer, e.g., multiple myeloma.

[0069] I. Definition Unless otherwise specified, all scientific and technical terms used herein have the meanings commonly understood by those skilled in the art to which this invention belongs. The following references: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed., 1994); The Cambridge Dictionary of Science and Technology (Walker, ed., 1988); The Glossary of Genetics, 5th ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale and Marham, The Harper Collins Dictionary of Biology (1991) provide those skilled in the art with general definitions for many of the terms used in this invention. As used herein, the following terms have the meanings ascribed to them below, unless otherwise specified.

[0070] As used herein, the term "about" or "approximately" refers to an acceptable error range for a particular value, as determined by a person skilled in the art, that depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 3 or more standard deviations, according to the practice in the art. Alternatively, "about" can mean within a range of up to 20%, preferably up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. Alternatively, particularly with respect to biological systems or biological processes, the term can mean within one order of magnitude, preferably within 5-fold, and more preferably within 2-fold of a value.

[0071] As used herein, the term "cell population" refers to a group of at least two cells that express similar or different phenotypes. In a non-limiting example, a cell population can include at least about 10, at least about 100, at least about 200, at least about 300, at least about 400, at least about 500, at least about 600, at least about 700, at least about 800, at least about 900, or at least about 1000 cells that express similar or different phenotypes.

[0072] As used herein, the term "antibody" refers not only to intact antibody molecules but also to fragments of antibody molecules that retain immunogen-binding ability. Such fragments are also well known in the art and are routinely used both in vitro and in vivo. Thus, as used herein, the term "antibody" refers not only to intact immunoglobulin molecules but also to the well-known active fragments, F(ab')2 and Fab. F(ab')2 and Fab fragments, which lack the Fe fragment from intact antibodies, clear more rapidly from the circulation and may exhibit less nonspecific tissue binding than intact antibodies (Wahl et al., J. Nucl. Med., 24:316-325 (1983)). Antibodies of the present invention include natural whole antibodies, bispecific antibodies; chimeric antibodies; Fab, Fab', single-chain V-region fragments (scFv), fusion polypeptides, and non-conventional antibodies.

[0073] As used herein, the term "single-chain variable fragment" or "scFv" refers to a V H A heavy chain (VL) of an immunoglobulin (e.g., murine or human) covalently linked to form a VL heterodimer. H ) and light chain (V L ) is a fusion protein of the variable region of the heavy chain (V H ) and light chain (V L ) is directly attached or is a peptide-encoding linker (e.g., 10, 15, 20, 25 amino acids), and V H The N-terminus of V L or V H The C-terminus of VL The heavy chain variable region and the light chain variable region of the extracellular antigen-binding domain are connected by a linker that connects the heavy chain variable region and the light chain variable region of the extracellular antigen-binding domain. The linker is typically rich in glycine for flexibility and also rich in serine or threonine for solubility. The linker can connect the heavy chain variable region and the light chain variable region of the extracellular antigen-binding domain. Non-limiting examples of linkers are disclosed in Shen et al., Anal. Chem., Vol. 80(6):1910-1917 (2008) and WO2014 / 087010, the contents of which are hereby incorporated by reference in their entireties. In certain embodiments, the linker is a G4S linker.

[0074] In a non-limiting example, the linker may be: [ka] As set forth in SEQ ID NO: 897, it comprises amino acids having the sequence set forth in SEQ ID NO: 897. In certain embodiments, a nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 284 is selected from the group consisting of: [ka] The sequence of the present invention is shown in SEQ ID NO: 285.

[0075] In another non-limiting example, the linker may be: [ka] As set forth in SEQ ID NO: 98, it comprises amino acids having the sequence set forth in SEQ ID NO: 98.

[0076] In certain embodiments, a nucleic acid sequence encoding the amino acid sequence of SEQ ID NO: 98 is selected from the group consisting of: [ka] The sequence of the present invention is shown in SEQ ID NO: 99.

[0077] Despite the removal of the constant region and the introduction of the linker, the scFv protein retains the specificity of the original immunoglobulin. Single-chain Fv polypeptide antibodies are composed of V, V- ... H Coding sequence and V L It can be expressed from a nucleic acid containing the coding sequence. See also U.S. Patent Nos. 5,091,513, 5,132,405, and 4,956,778; and U.S. Patent Application Publication Nos. 20050196754 and 20050196754. Antagonistic scFvs with inhibitory activity have been described (e.g., Zhao et al., Hyrbidoma (Larchmt), 2008, 27(6):455-51; Peter et al., J Cachexia Sarcopenia Muscle, 2012, August 12; Shieh et al., J Imunol, 2009, 183(4):2277-85; Giomarelli et al., Thromb Haemost, 2007, 97(6):955-63; Fife et al., J Clin Invest, 2006, 116(8):2252-61; Brocks et al., Immunotechnology, 1997, 3(3):173-84; Moosmayer et al., Ther Immunol, 1995, 2(10):31-40. Agonistic scFvs with stimulatory activity have been described (see, e.g., Peter et al., J Bioi Chern, 2003, 25278(38):36740-7; Xie et al., Nat Biotech, 1997, 15(8):768-71; Ledbetter et al., Crit Rev Immunol, 1997, 17(5-6):427-55; Ho et al., BioChim Biophys Acta, 2003, 1638(3):257-66).

[0078] As used herein, "F(ab)" refers to a fragment of the antibody structure that binds to an antigen but is monovalent and does not have the Fc portion; for example, digestion of an antibody with the enzyme papain yields two F(ab) fragments and an Fc fragment (e.g., heavy (H) chain constant region; the Fc region that does not bind to antigen).

[0079] As used herein, "F(ab')2" refers to an antibody fragment produced by pepsin digestion of a whole IgG antibody, which fragment has two antigen-binding F(ab') (bivalent) regions, each of which contains two individual amino acid chains, a portion of an H chain and a light (L) chain, linked by an S-linkage for antigen binding, with the remaining H chain portions linked together. The "F(ab')2" fragment can be split into two individual Fab' fragments.

[0080] As used herein, the term "vector" refers to any genetic element, such as a plasmid, phage, transposon, cosmid, chromosome, virus, virion, etc., which, when associated with the proper control elements, is capable of replication and the transfer of genetic sequences to a cell. Thus, the term includes cloning and expression vehicles, as well as viral and plasmid vectors.

[0081] As used herein, the term "expression vector" refers to a recombinant nucleic acid sequence, i.e., a recombinant DNA molecule containing a desired coding sequence and appropriate nucleic acid sequences necessary for the expression of the operably linked coding sequence in a particular host organism. Nucleic acid sequences necessary for expression in prokaryotes typically include a promoter, an operator (optional), and a ribosome binding site, often along with other sequences. Eukaryotic cells are known to utilize promoters, enhancers, and termination and polyadenylation signals.

[0082] As used herein, "CDR" is defined as the amino acid sequence of the complementarity determining region of an antibody, which is the hypervariable region of the heavy and light chains of an immunoglobulin. See, for example, Kabat et al., Sequences of Proteins of Immunological Interest, 4th ed., US Department of Health and Human Services, National Institutes of Health (1987). Generally, an antibody contains three heavy chain CDRs or heavy chain CDR regions and three light chain CDRs or light chain CDR regions within the variable region. CDRs provide the majority of contact residues for antibody binding to an antigen or epitope. In certain embodiments, the CDR regions are detailed using the Kabat system (Kabat, EA et al. (1991) Sequences of Proteins of Immunological Interest, 5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242).

[0083] The term "affinity" as used herein refers to a measure of binding strength. Without being bound by theory, affinity depends on the tightness of the stereochemical fit between the antibody binding site and the antigenic determinant, the size of the contact area between them, and the distribution of charged and hydrophobic groups. Affinity also includes the term "avidity," which refers to the strength of antigen-antibody binding after the formation of a reversible complex. Methods for calculating the affinity of an antibody for an antigen are known in the art, including the use of binding experiments to calculate affinity. Antibody activity in functional assays (e.g., flow cytometry assays) also reflects antibody affinity. Antibodies and affinities can be phenotypically characterized and compared using functional assays (e.g., flow cytometry assays).

[0084] Nucleic acid molecules useful in the methods of the present invention include any nucleic acid molecule encoding a polypeptide of the present invention or a fragment thereof. Such nucleic acid molecules need not be 100% identical to an endogenous nucleic acid sequence, but typically exhibit substantial identity. A polynucleotide having "substantial identity" to an endogenous sequence is typically capable of hybridizing to at least one strand of a double-stranded nucleic acid molecule. "Hybridizing" refers to pairing between complementary polynucleotide sequences (e.g., genes described herein) or portions thereof to form a double-stranded molecule under various stringency conditions (see, e.g., Wahl, GM and SL Berger (1987), Methods Enzymol., 152:399; Kimmel, AR (1987), Methods Enzymol., 152:507).

[0085] For example, stringent salt concentrations are typically less than about 750 mM NaCl and less than 75 mM trisodium citrate, preferably less than about 500 mM NaCl and less than 50 mM trisodium citrate, and more preferably less than about 250 mM NaCl and less than 25 mM trisodium citrate. Low stringency hybridization can be achieved in the absence of organic solvents, such as formamide, while high stringency hybridization can be achieved in the presence of at least about 35% formamide, more preferably at least about 50% formamide. Stringent temperature conditions typically include a temperature of at least about 30°C, more preferably at least about 37°C, and most preferably at least about 42°C. Those skilled in the art will also be familiar with varying additional parameters, such as hybridization time, the concentration of detergents, e.g., sodium dodecyl sulfate (SDS), and the inclusion or exclusion of carrier DNA. Various levels of stringency can be achieved by combining these various conditions as needed. In a preferred embodiment, hybridization occurs at 30°C in 750 mM NaCl, 75 mM trisodium citrate, and 1% SDS. In a more preferred embodiment, hybridization occurs at 37°C in 500 mM NaCl, 50 mM trisodium citrate, 1% SDS, 35% formamide, and 100 μg / ml denatured salmon sperm DNA (ssDNA). In a most preferred embodiment, hybridization occurs at 42°C in 250 mM NaCl, 25 mM trisodium citrate, 1% SDS, 50% formamide, and 200 μg / ml ssDNA. Useful variations in these conditions will be readily apparent to those skilled in the art.

[0086] In most applications, the stringency of the washing step following hybridization also varies. The stringency of the washing can be determined by salt concentration and temperature. As described above, the stringency of the washing can be increased by decreasing the salt concentration or by increasing the temperature. For example, stringent salt concentrations for the washing step are preferably less than about 30 mM NaCl and less than 3 mM trisodium citrate, and most preferably less than about 15 mM NaCl and less than 1.5 mM trisodium citrate. Stringent temperature conditions for the washing step typically include a temperature of at least about 25°C, more preferably at least about 42°C, and even more preferably at least about 68°C. In a preferred embodiment, the washing step occurs at 25°C in 30 mM NaCl, 3 mM trisodium citrate, and 0.1% SDS. In a more preferred embodiment, the wash step occurs at 42°C in 15 mM NaCl, 1.5 mM trisodium citrate, and 0.1% SDS. In a more preferred embodiment, the wash step occurs at 68°C in 15 mM NaCl, 1.5 mM trisodium citrate, and 0.1% SDS. Further variations in these conditions will be readily apparent to those of skill in the art. Hybridization methods are well known to those of skill in the art and include those described, for example, by Benton and Davis (Science, 196:180, 1977); Grunstein and Rogness (Proc. Natl. Acad. Sci. USA, 72:3961, 1975); Ausubel et al. (Current Protocols in Molecular Biology, Wiley Interscience, New York, 2001); Berger and Kimmel (Guide to Molecular Cloning Techniques, 1987, Academic Press, New York); and Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, New York.

[0087] By "substantially identical" is meant a polypeptide or nucleic acid molecule that exhibits at least 50% identity to a reference amino acid sequence (e.g., any one of the amino acid sequences described herein) or a reference nucleic acid sequence (e.g., any one of the nucleic acid sequences described herein). Preferably, such a sequence is at least 60%, more preferably 80%, or 85% identical, and more preferably 90%, 95%, or even 99% identical at the amino acid or nucleic acid level to the sequence used for comparison.

[0088] Sequence identity can be determined using sequence analysis software (e.g., Sequence Analysis Typically, homology is measured using the Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis. 53705, BLAST program, BESTFIT program, GAP program, or PILEUP / PRETTYBOX program. Such software matches identical or similar sequences by assigning degrees of homology to various substitutions, deletions, and / or other modifications. An exemplary method for determining the degree of identity is to use the BLAST program, in which a probability score between e-3 and e-100 indicates closely related sequences.

[0089] As used herein, the term "analog" refers to a structurally related polypeptide or nucleic acid molecule that has the function of a reference polypeptide or nucleic acid molecule.

[0090] As used herein, the term "ligand" refers to a molecule that binds to a receptor. In particular, a ligand binds to a receptor on another cell, allowing recognition and / or interaction between the cells.

[0091] As used herein, the term "disease" refers to any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ. Examples of diseases include neoplasia or pathogenic infection of cells.

[0092] As used herein, the term "effective amount" refers to an amount sufficient to have a therapeutic effect. In certain embodiments, an "effective amount" is an amount sufficient to stop, ameliorate, or inhibit the persistent proliferation, growth, or metastasis (e.g., invasion or migration) of a neoplasia.

[0093] As used herein, the term "heterologous nucleic acid molecule or heterologous polypeptide" refers to a nucleic acid molecule (e.g., a cDNA molecule, a DNA molecule, or an RNA molecule) or a polypeptide that is not normally present in a cell or in a sample obtained from a cell. The nucleic acid may be derived from another organism, for example, an mRNA molecule that is not normally expressed in the cell or sample.

[0094] As used herein, the term "immunoresponsive cell" refers to a cell that functions in the immune response, or a precursor or progeny thereof.

[0095] As used herein, the term "modulate" refers to a positive or negative change. Exemplary modulations include changes of about 1%, about 2%, about 5%, about 10%, about 25%, about 50%, about 75%, or about 100%.

[0096] As used herein, the term "increase" refers to a positive alteration of at least about 5%, including but not limited to a positive alteration of about 5%, about 10%, about 25%, about 30%, about 50%, about 75%, or about 100%.

[0097] As used herein, the term "reduce" refers to a negative alteration of at least about 5%, including but not limited to a negative alteration of about 5%, about 10%, about 25%, about 30%, about 50%, about 75%, or about 100%.

[0098] As used herein, the term "isolated cell" refers to a cell that has been separated from the molecular and / or cellular components that naturally associate with the cell.

[0099] As used herein, the terms "isolated," "purified," or "biologically pure" refer to a material that is free, to varying degrees, from components that normally accompany it as found in its natural state. "Isolated" refers to some degree of separation from the original source or environment. "Purified" refers to a greater degree of separation than isolation. A "purified" or "biologically pure" protein is sufficiently free from other materials so that any impurities do not substantially affect the biological properties of the protein or cause other adverse consequences. That is, a nucleic acid or peptide of the invention is purified when it is substantially free from cellular material, viral material, or culture medium, if produced by recombinant DNA methodology, or chemical precursors or other chemicals, if chemically synthesized. Purity and homogeneity are typically determined using analytical chemistry methods, such as polyacrylamide gel electrophoresis or high-performance liquid chromatography. The term "purified" can refer to a nucleic acid or protein giving rise to essentially one band in an electrophoretic gel. In proteins that are subject to modifications, such as phosphorylation or glycosylation, different modifications may result in different isolated proteins that can be individually purified.

[0100] As used herein, the term "secreted" refers to a polypeptide that is released from the cell via the secretory pathway as vesicles that pass through the endoplasmic reticulum, the Golgi apparatus, and then transiently fuse with the plasma membrane to release the protein outside the cell.

[0101] As used herein, the terms "specifically binds" or "specifically binds to" or "specifically targets" refer to a polypeptide or fragment thereof that recognizes and binds to a biological molecule of interest (e.g., a polypeptide) but does not substantially recognize or substantially bind to other molecules in a sample that naturally contains the polypeptide of the invention, e.g., a biological sample.

[0102] As used herein, the term "treating" or "treatment" refers to clinical intervention in an attempt to alter the disease course of the individual or cell being treated, and can be performed for prophylaxis or during the course of a clinical condition. The therapeutic effects of treatment include, without limitation, preventing the occurrence or recurrence of the disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, improving or alleviating the disease state, and remission or improving prognosis. By preventing the progression of a disease or disorder, treatment can prevent the progression caused by the disorder in an affected subject or a subject diagnosed or suspected of having the disorder, but treatment can also prevent the onset of the disorder or symptoms of the disorder in a subject at risk of or suspected of having the disorder.

[0103] As used herein, the term "subject" refers to any animal (e.g., a mammal), including, but not limited to, a human, a non-human primate, a rodent, etc. (e.g., an animal that will be the recipient of a particular treatment or from which cells are obtained).

[0104] II. G protein-coupled receptors G protein-coupled receptors ("GPRs"), also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors, constitute a large protein family of receptors that sense molecules outside the cell, activate internal signaling pathways, and ultimately activate cellular responses. Based on sequence homology and functional similarity, GPCRs can be categorized into six classes: class A (rhodopsin-like), class B (secretin receptor family), class C (metabotropic glutamate / pheromone), class D (fungal mating pheromone receptor), class E (cyclic AMP receptor), and class F (Frizzled / Smoothened). In certain embodiments, the GRP is a class C GRP. In certain non-limiting embodiments, the class C GRP is a G protein-coupled receptor family C group 5 member D.

[0105] G protein-coupled receptor family C group 5 member D (GPRC5D) is an orphan receptor with no known ligand or function in humans. GPRC5D is a member of the family of retinoic acid-inducible G protein-coupled receptors. GPRC5D is overexpressed in multiple myeloma (MM) cells, as shown in Figure 2, but is not expressed or expressed at significantly lower levels in any other cell types, benign or malignant. Several groups have identified this gene by gene expression profiling of primary MM cells, as well as in normal tissues. 1 or other hematologic malignancies 2~4 High mRNA expression has been shown to correlate with poor overall survival. 1 Surface staining of bone marrow aspirates from patients with MM clearly shows plasma cell-specific staining. 4 To our knowledge, this is the first time that GPRC5D has been targeted by any therapeutic agent. In addition, to our knowledge, this is the first time that a CAR has been generated that targets any G protein-coupled receptor.

[0106] In certain non-limiting embodiments, the GPRC5D is human GPRC5D having the amino acid sequence set forth in SEQ ID NO: 97, or a fragment thereof.

[0107] SEQ ID NO: 97 is as follows: [ka] Provided to.

[0108] The N-terminal region of human GPRC5D has amino acids 1 to 27 of SEQ ID NO: 97. The extracellular loop 1 (ECL1) region of human GPRC5D has amino acids 85 to 93 of SEQ ID NO: 97. The extracellular loop 2 (ECL2) region of human GPRC5D has amino acids 145 to 167 of SEQ ID NO: 97. The extracellular loop 3 (ECL3) region of human GPRC5D has amino acids 226 to 239 of SEQ ID NO: 97.

[0109] III. Chimeric Antigen Receptor (CAR) Chimeric antigen receptors (CARs) are engineered receptors that transfer or confer a specificity of interest onto immune effector cells. CARs can be used to transfer the specificity of monoclonal antibodies into T cells, and the transfer of their coding sequences can be facilitated by retroviral vectors.

[0110] There are three generations of CARs. "First generation" CARs are typically composed of an extracellular antigen-binding domain (e.g., a single-chain variable fragment (scFv)) fused to a transmembrane domain fused to the cytoplasmic / intracellular domain of a T cell receptor chain. "First generation" CARs typically have an intracellular domain derived from the CD3 ζ chain, which is the primary transmitter of signals from endogenous TCRs. "First generation" CARs are capable of providing de novo antigen recognition and are independent of HLA-mediated antigen presentation via their CD3 ζ chain signaling domain, within a single fusion molecule. + T cells and CD8 +"Second-generation" CARs can activate both T cells and induce T cell activation. "Second-generation" CARs add intracellular domains derived from various costimulatory molecules (e.g., CD28, 4-1BB, ICOS, OX40) to the cytoplasmic tail of the CAR to provide additional signals to T cells. "Second-generation" CARs include CARs that provide both costimulation (e.g., CD28 or 4-1BB) and activation (CD3ζ). Preclinical studies indicate that "second-generation" CARs can improve the antitumor activity of T cells. For example, clinical trials targeting the CD19 molecule in patients with chronic lymphoblastic leukemia (CLL) and acute lymphoblastic leukemia (ALL) demonstrated robust efficacy of T cells engineered with "second-generation" CARs. "Third-generation" CARs include CARs that provide multiple costimulatory (e.g., CD28 and 4-1BB) and activation (CD3ζ).

[0111] In accordance with the subject matter of the present disclosure, a CAR comprises an extracellular antigen-binding domain, a transmembrane domain, and an intracellular domain, wherein the extracellular antigen-binding domain binds to a G protein-coupled receptor. In certain embodiments, the G protein-coupled receptor is GPRC5D. In non-limiting specific embodiments, the extracellular antigen-binding domain is an scFv. In non-limiting specific embodiments, the extracellular antigen-binding domain is an optionally cross-linked Fab. In non-limiting specific embodiments, the extracellular binding domain is an F(ab)2. In non-limiting specific embodiments, any of the foregoing molecules can be included in a fusion protein with a heterologous sequence to form the extracellular antigen-binding domain.

[0112] In certain non-limiting embodiments, the extracellular antigen-binding domain of a CAR of the present disclosure has high binding specificity as well as high binding affinity to a G protein-coupled receptor (e.g., GPRC5D). For example, in such embodiments, the extracellular antigen-binding domain of the CAR (e.g., embodied by an scFv or analog thereof) binds to GPRC5D at a binding affinity of about 3×10 -6 M or less dissociation constant (K D In certain embodiments, K Dis approximately 1 x 10 -6 M or less, approximately 1 x 10 -7 M or less, approximately 1 x 10 -8 M or less, or about 1 x 10 -9 M or less, approximately 1 x 10 -10 M or less, or about 1 x 10 -11 M or less. In certain embodiments, K D is approximately 1 x 10 -8 M or less. In certain embodiments, K D is approximately 1 x 10 -11 M ~ approx. 1×10 -10 M, about 1 x 10 -10 M ~ approx. 1×10 -9 M, about 1 x 10 -9 M ~ approx. 1×10 -8 M, about 1 x 10 -8 M ~ approx. 1×10 -7 M, or approximately 1 x 10 -7 M ~ approx. 1×10 -6 M, or approximately 1 x 10 -6 M ~ approx. 3×10 -6 M, etc., approximately 1 x 10 -11 M ~ approx. 3×10 -6 M. In certain embodiments, K D is approximately 1 x 10 -9 M ~ approx. 1×10 -8 M. In certain embodiments, K D is approximately 1 x 10 -9 M ~ approx. 1.5×10 -9 M. In certain embodiments, K D is approximately 1.2 x 10 -9 M. In certain embodiments, K D is about 4 x 10 -9 M ~ approx. 5×10 -9 M. In certain embodiments, K D is about 5 x 10 -9 M. In certain embodiments, K D is approximately 4.8 x 10 -9 M. In certain embodiments, K D is about 8 x 10 -9 M ~ approx. 9×10 -9M. In certain embodiments, K D is about 8 x 10 -9 M. In certain embodiments, K D is approximately 8.1 x 10 -9 I am M.

[0113] Binding of the extracellular antigen-binding domain of a CAR of the present disclosure (e.g., an scFv or analog thereof in embodiments) to a G protein-coupled receptor (e.g., GPRC5D) can be confirmed, for example, by enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), FACS analysis, bioassay (e.g., growth inhibition), or Western blot assay. Each of these assays generally detects the presence of a protein-antibody complex of interest by using a labeled reagent (e.g., an antibody or scFv) specific for the complex of interest. For example, scFvs can be radiolabeled and used in radioimmunoassays (RIA) (see, e.g., Weintraub, B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March 1986, incorporated herein by reference). Radioisotopes can be detected by means such as a gamma counter or scintillation counter, or by autoradiography. In certain embodiments, the GPRC5D-targeting extracellular antigen binding domain is labeled with a fluorescent marker. Non-limiting examples of fluorescent markers include green fluorescent protein (GFP), blue fluorescent protein (e.g., EBFP, EBFP2, Azurite, and mKalama1), cyan fluorescent protein (e.g., ECFP, Cerulean, and CyPet), and yellow fluorescent protein (e.g., YFP, Citrine, Venus, and YPet). In certain embodiments, the GPRC5D-targeting human scFv is labeled with GFP.

[0114] In certain embodiments, the extracellular antigen-binding domain of a CAR of the present disclosure comprises a single-chain variable fragment (scFv). In one specific embodiment, the extracellular antigen-binding domain of a CAR of the present disclosure comprises a human scFv that specifically binds to human GPRC5D. In another specific embodiment, the extracellular antigen-binding domain of a CAR of the present disclosure comprises a mouse scFv that specifically binds to human GPRC5D. In certain embodiments, the scFv is identified by screening an scFv phage library using cells that express GPRC5D (e.g., 3T3 cells).

[0115] Extracellular antigen-binding domain of CAR In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a heavy chain variable region comprising amino acids having a sequence selected from the group consisting of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, and 93. The nucleic acid sequences encoding the amino acid sequences of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, and 93 are SEQ ID NOs: 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51, 55, 59, 63, 67, 71, 75, 79, 83, 87, 91, and 95, respectively. In some embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a light chain variable region comprising amino acids having a sequence selected from the group consisting of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, and 94. The nucleic acid sequences encoding the amino acid sequences of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, and 94 are SEQ ID NOs: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, and 96, respectively. The sequences of SEQ ID NOs: 1 to 96 are set forth in Tables 1 to 24 below.

[0116] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences homologous to the amino acid sequences described herein and disclosed in Tables 1-24. For example, the extracellular antigen-binding domain (e.g., scFv) may comprise a heavy chain variable region and a light chain variable region comprising amino acid sequences homologous to the amino acid sequences described herein and disclosed in Tables 1-24. , 302, 314, 326, 338, 350, 362, 374, and 386.

[0117] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a light chain variable region comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 303, 315, 327, 339, 351, 363, 375, and 387.

[0118] In certain embodiments, the extracellular antigen binding domain (e.g., scFv) comprises: (a) a heavy chain variable region comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 302, 314, 326, 338, 350, 362, 374, and 386; and (b) a light chain variable region comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 303, 315, 327, 339, 351, 363, 375, and 387. Includes.

[0119] The presently disclosed subject matter further provides extracellular antigen-binding domains (e.g., scFvs) comprising the CDRs of the heavy and light chain variable regions, e.g., CDR1, CDR2, and CDR3, as disclosed in Tables 1-24 herein. The CDR regions are sequenced according to the Kabat system (Kabat, EA et al. (1991), Sequences of Proteins of Immunological Interest, 5th ed., US Pat. No. 6,623,199). Department of Health and Human Services, NIH Publication No. 91-3242). The presently disclosed subject matter further provides extracellular antigen-binding domains (e.g., scFvs) comprising conservative modifications of the antibody sequences disclosed herein. For example, the presently disclosed subject matter's extracellular antigen-binding domains (e.g., scFvs) comprise, but are not limited to, a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences, wherein one or more of these CDR sequences comprise the designated amino acid sequences disclosed herein, or conservative modifications thereof, and the extracellular antigen-binding domain retains desired functional properties.

[0120] In certain embodiments, the presently disclosed subject matter provides an extracellular antigen-binding domain (e.g., scFv) comprising a heavy chain variable region, wherein the heavy chain variable region is (a) a CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 124, 130, 136, 142, 148, 154, 160, 166, 172, 178, 184, 190, 196, 202, 208, 214, 220, 226, 232, 238, 244, 250, 256, 262, 304, 316, 328, 340, 352, 364, 376, and 388, and conservative modifications thereof; (b) a CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 125, 131, 137, 143, 149, 155, 161, 167, 173, 179, 185, 191, 197, 203, 209, 215, 221, 227, 233, 239, 245, 251, 257, 263, 305, 317, 329, 341, 353, 365, 377, and 389, and conservative modifications thereof; and (c) a CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 126, 132, 138, 144, 150, 156, 162, 168, 174, 180, 186, 192, 198, 204, 210, 216, 222, 228, 234, 240, 246, 252, 258, 264, 306, 318, 330, 342, 354, 366, 378, and 390, and conservative modifications thereof. Includes.

[0121] In certain embodiments, the extracellular antigen-binding domain (e.g., scFv) comprises a light chain variable region, wherein the light chain variable region is (a) a CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 127, 133, 139, 145, 151, 157, 163, 169, 175, 181, 187, 193, 199, 205, 211, 217, 223, 229, 235, 241, 247, 253, 259, 265, 307, 319, 331, 343, 355, 367, 379, and 391, and conservative modifications thereof; (b) a CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 128, 134, 140, 146, 152, 158, 164, 170, 176, 182, 188, 194, 200, 206, 212, 218, 224, 230, 236, 242, 248, 254, 260, 266, 308, 320, 332, 344, 356, 368, 380, and 392, and conservative modifications thereof; and (c) a CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 129, 135, 141, 147, 153, 159, 165, 171, 177, 183, 189, 195, 201, 207, 213, 219, 225, 231, 237, 243, 249, 255, 261, 267, 309, 321, 333, 345, 357, 369, 381, and 393, and conservative modifications thereof. Includes.

[0122] The presently disclosed subject matter provides an extracellular antigen-binding domain (e.g., scFv) comprising a heavy chain variable region comprising a CDR1 sequence, a CDR2 sequence, and a CDR3 sequence, and a light chain variable region comprising a CDR1 sequence, a CDR2 sequence, and a CDR3 sequence; (a) the heavy chain variable region CDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 126, 132, 138, 144, 150, 156, 162, 168, 174, 180, 186, 192, 198, 204, 210, 216, 222, 228, 234, 240, 246, 252, 258, 264, 306, 318, 330, 342, 354, 366, 378, and 390, and conservative modifications thereof; (b) the light chain variable region CDR3 is an amino acid sequence selected from the group consisting of SEQ ID NOs: 129, 135, 141, 147, 153, 159, 165, 171, 177, 183, 189, 195, 201, 207, 213, 219, 225, 231, 237, 243, 249, 255, 261, 267, 309, 321, 333, 345, 357, 369, 381, and 393, and conservative modifications thereof; and the extracellular antigen-binding domain specifically binds to a GPRC5D polypeptide (e.g., a human GPRC5D polypeptide). In certain embodiments, the heavy chain variable region CDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 125, 131, 137, 143, 149, 155, 161, 167, 173, 179, 185, 191, 197, 203, 209, 215, 221, 227, 233, 239, 245, 251, 257, 263, 305, 317, 329, 341, 353, 365, 377, and 389, and conservative modifications thereof; (b) the light chain variable region CDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 128, 134, 140, 146, 152, 158, 164, 170, 176, 182, 188, 194, 200, 206, 212, 218, 224, 230, 236, 242, 248, 254, 260, 266, 308, 320, 332, 344, 356, 368, 380, and 392, and conservative modifications thereof, and the extracellular antigen-binding domain specifically binds to a GPRC5D polypeptide (e.g., a human GPRC5D polypeptide). In certain embodiments, the heavy chain variable region CDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 124, 130, 136, 142, 148, 154, 160, 166, 172, 178, 184, 190, 196, 202, 208, 214, 220, 226, 232, 238, 244, 250, 256, 262, 304, 316, 328, 340, 352, 364, 376, and 388, and conservative modifications thereof; (b) the light chain variable region CDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 127, 133, 139, 145, 151, 157, 163, 169, 175, 181, 187, 193, 199, 205, 211, 217, 223, 229, 235, 241, 247, 253, 259, 265, 307, 319, 331, 343, 355, 367, 379, and 391, and conservative modifications thereof, and the extracellular antigen-binding domain specifically binds to a GPRC5D polypeptide (e.g., a human GPRC5D polypeptide).

[0123] In certain embodiments, the extracellular antigen-binding domain is an scFv that comprises the amino acid sequence of SEQ ID NO: 100 and specifically binds to a GPRC5D polypeptide (e.g., a GPRC5D polypeptide having the amino acid sequence of SEQ ID NO: 97, or a fragment thereof), and is designated ET150-153 scFv (also referred to as "ET150-3 scFv").

[0124] In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 1, and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 2, optionally with (iii) a linker sequence, e.g., a linker peptide between the heavy chain variable region and the light chain variable region. In certain embodiments, the linker comprises amino acids having the sequence set forth in SEQ ID NO: 98. In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a V H Area and V L In certain embodiments, the extracellular antigen-binding domain is a scFv-Fc fusion protein or a full-length human IgG, with a region or CDR. In certain embodiments, the extracellular antigen-binding domain is a VFv comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO: 1, as shown in Table 1. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 1, as shown in Table 1. H In certain embodiments, the extracellular antigen-binding domain comprises a V that comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO:2, as shown in Table 1. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO:2, as shown in Table 1. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 1, as shown in Table 1. H and V comprising an amino acid sequence set forth in SEQ ID NO:2 LIn certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 124, or conservative modifications thereof, as shown in Table 1. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 125 or a conservative modification thereof H CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 126 or a conservative modification thereof H In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 127, or a conservative modification thereof, as shown in Table 1. L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 128 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 129 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 124, or a conservative modification thereof, as shown in Table 1. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 125 or a conservative modification thereof H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 126 or a conservative modification thereof H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 127 or a conservative modification thereof L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 128 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 129 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 124. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 125 H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 126 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 127 L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 128 LCDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 129 L Includes CDR3. [Table 1]

[0125] In certain embodiments, the extracellular antigen-binding domain is an scFv comprising the amino acid sequence of SEQ ID NO: 101 and specifically binding to a GPRC5D polypeptide (e.g., a GPRC5D polypeptide having the amino acid sequence of SEQ ID NO: 97, or a fragment thereof), and is designated ET150-166 scFv (also referred to as "ET150-16 scFv").

[0126] In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 5, and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 6, optionally with (iii) a linker sequence, e.g., a linker peptide between the heavy chain variable region and the light chain variable region. In certain embodiments, the linker comprises amino acids having the sequence set forth in SEQ ID NO: 98. In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a V H Area and V L The extracellular antigen-binding domain is an scFv-Fc fusion protein or a full-length human IgG, with a region or CDR. In certain embodiments, the extracellular antigen-binding domain is a human scFv. In certain embodiments, the extracellular antigen-binding domain is a V comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO: 5, as shown in Table 2. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO:5, as shown in Table 2. HIn certain embodiments, the extracellular antigen-binding domain comprises a V that comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO:6, as shown in Table 2. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO:6, as shown in Table 2. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO:5, as shown in Table 2. H and V comprising an amino acid sequence set forth in SEQ ID NO:6 L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 130, or a conservative modification thereof, as shown in Table 2. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 131 or a conservative modification thereof H CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 132 or a conservative modification thereof H In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 133, or a conservative modification thereof, as shown in Table 2. L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 134 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 130, or a conservative modification thereof, as shown in Table 2. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 131 or a conservative modification thereof H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 132 or a conservative modification thereof HCDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 133 or a conservative modification thereof L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 134 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 135 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 130. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 131 H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 132 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 133 L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 134 L CDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 135 L Includes CDR3. [Table 2]

[0127] In certain embodiments, the extracellular antigen-binding domain is an scFv that comprises the amino acid sequence of SEQ ID NO: 102 and specifically binds to a GPRC5D polypeptide (e.g., a GPRC5D polypeptide having the amino acid sequence of SEQ ID NO: 97, or a fragment thereof), and is designated ET150-170 scFv (also referred to as "ET150-20 scFv").

[0128] In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 9, and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 10, optionally with (iii) a linker sequence, e.g., a linker peptide between the heavy chain variable region and the light chain variable region. In certain embodiments, the linker comprises amino acids having the sequence set forth in SEQ ID NO: 98. In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a VH Area and V L In certain embodiments, the extracellular antigen-binding domain is a scFv-Fc fusion protein or a full-length human IgG, with a region or CDR. In certain embodiments, the extracellular antigen-binding domain is a VFv comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO:9, as shown in Table 3. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO:9, as shown in Table 3. H In certain embodiments, the extracellular antigen-binding domain comprises a V that comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO: 10, as shown in Table 3. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 10, as shown in Table 3. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO:9, as shown in Table 3. H and V comprising an amino acid sequence set forth in SEQ ID NO: 10. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising an amino acid sequence set forth in SEQ ID NO: 136, or a conservative modification thereof, as shown in Table 3. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 137 or a conservative modification thereof H CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 138 or a conservative modification thereof H In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 139, or a conservative modification thereof, as shown in Table 3.L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 140 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 141 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 136, or a conservative modification thereof, as shown in Table 3. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 137 or a conservative modification thereof H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 138 or a conservative modification thereof H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 139 or a conservative modification thereof L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 140 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 141 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 136. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 137 H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 138 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 139 L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 140 L CDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 141 L Includes CDR3. [Table 3]

[0129] In certain embodiments, the extracellular antigen-binding domain is an scFv that comprises the amino acid sequence of SEQ ID NO: 103 and specifically binds to a GPRC5D polypeptide (e.g., a GPRC5D polypeptide having the amino acid sequence of SEQ ID NO: 97, or a fragment thereof), and is designated ET150-171 scFv (also referred to as "ET150-21 scFv").

[0130] In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 13, and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 14, optionally with (iii) a linker sequence, e.g., a linker peptide between the heavy chain variable region and the light chain variable region. In certain embodiments, the linker comprises amino acids having the sequence set forth in SEQ ID NO: 98. In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a V H Area and V L In certain embodiments, the extracellular antigen-binding domain is a scFv-Fc fusion protein or a full-length human IgG, with a region or CDR. In certain embodiments, the extracellular antigen-binding domain is a VFv comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO: 13, as shown in Table 4. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 13, as shown in Table 4. H In certain embodiments, the extracellular antigen-binding domain comprises a V that comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO: 14, as shown in Table 4. LIn certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 14, as shown in Table 4. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 13, as shown in Table 4. H and V comprising an amino acid sequence set forth in SEQ ID NO: 14. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising an amino acid sequence set forth in SEQ ID NO: 142, or a conservative modification thereof, as shown in Table 4. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 143 or a conservative modification thereof H CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 144 or a conservative modification thereof H In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 145, or a conservative modification thereof, as shown in Table 4. L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 146 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 147 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 142, or a conservative modification thereof, as shown in Table 4. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 143 or a conservative modification thereof H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 144 or a conservative modification thereof H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 145 or a conservative modification thereof L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 146 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 147 or a conservative modification thereof LIn certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 142. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 143 H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 144 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 145 L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 146 L CDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 147 L Includes CDR3. [Table 4]

[0131] In certain embodiments, the extracellular antigen-binding domain is an scFv that comprises the amino acid sequence of SEQ ID NO: 104 and specifically binds to a GPRC5D polypeptide (e.g., a GPRC5D polypeptide having the amino acid sequence of SEQ ID NO: 97, or a fragment thereof), and is designated ET150-175 scFv (also referred to as "ET150-25 scFv").

[0132] In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 17, and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 18, optionally with (iii) a linker sequence, e.g., a linker peptide between the heavy chain variable region and the light chain variable region. In certain embodiments, the linker comprises amino acids having the sequence set forth in SEQ ID NO: 98. In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a V H Area and V LIn certain embodiments, the extracellular antigen-binding domain is a scFv-Fc fusion protein or a full-length human IgG, with a region or CDR. In certain embodiments, the extracellular antigen-binding domain is a VFv comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO: 17, as shown in Table 5. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 17, as shown in Table 5. H In certain embodiments, the extracellular antigen-binding domain comprises a V that comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO: 18, as shown in Table 5. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 18, as shown in Table 5. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 17, as shown in Table 5. H and V comprising an amino acid sequence set forth in SEQ ID NO: 18 L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising an amino acid sequence set forth in SEQ ID NO: 148, or a conservative modification thereof, as shown in Table 5. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 149 or a conservative modification thereof H CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 150 or a conservative modification thereof H In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 151, or a conservative modification thereof, as shown in Table 5. LCDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 152 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 153 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 148, or a conservative modification thereof, as shown in Table 5. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 149 or a conservative modification thereof H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 150 or a conservative modification thereof H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 151 or a conservative modification thereof L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 152 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 153 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 148. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 149 H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 150 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 151 L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 152 L CDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 153 L Includes CDR3. [Table 5]

[0133] In certain embodiments, the extracellular antigen-binding domain is an scFv that comprises the amino acid sequence of SEQ ID NO: 105 and specifically binds to a GPRC5D polypeptide (e.g., a GPRC5D polypeptide having the amino acid sequence of SEQ ID NO: 97, or a fragment thereof), and is designated ET150-154 scFv (also referred to as "ET150-4 scFv").

[0134] In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 21, and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 22, optionally with (iii) a linker sequence, e.g., a linker peptide between the heavy chain variable region and the light chain variable region. In certain embodiments, the linker comprises amino acids having the sequence set forth in SEQ ID NO: 98. In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a V H Area and V L In certain embodiments, the extracellular antigen-binding domain is a scFv-Fc fusion protein or a full-length human IgG, with a region or CDR. In certain embodiments, the extracellular antigen-binding domain is a VFv comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO: 21, as shown in Table 6. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 21, as shown in Table 6. H In certain embodiments, the extracellular antigen-binding domain comprises a V that comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO: 22, as shown in Table 6. LIn certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 22, as shown in Table 6. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 21, as shown in Table 6. H and V comprising an amino acid sequence set forth in SEQ ID NO: 22. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising an amino acid sequence set forth in SEQ ID NO: 154, or a conservative modification thereof, as shown in Table 6. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 155 or a conservative modification thereof H CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 156 or a conservative modification thereof H In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 157, or a conservative modification thereof, as shown in Table 6. L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 158 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 159 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 154, or a conservative modification thereof, as shown in Table 6. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 155 or a conservative modification thereof H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 156 or a conservative modification thereof H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 157 or a conservative modification thereof L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 158 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 159 or a conservative modification thereof LIn certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 154. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 155 H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 156 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 157 L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 158 L CDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 159 L Includes CDR3. [Table 6]

[0135] In certain embodiments, the extracellular antigen-binding domain is an scFv that comprises the amino acid sequence of SEQ ID NO: 106 and specifically binds to a GPRC5D polypeptide (e.g., a GPRC5D polypeptide having the amino acid sequence of SEQ ID NO: 97, or a fragment thereof), and is designated ET150-156 scFv (also referred to as "ET150-6 scFv").

[0136] In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 25, and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 26, optionally with (iii) a linker sequence, e.g., a linker peptide between the heavy chain variable region and the light chain variable region. In certain embodiments, the linker comprises amino acids having the sequence set forth in SEQ ID NO: 98. In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a V H Area and V LIn certain embodiments, the extracellular antigen-binding domain is an scFv-Fc fusion protein or a full-length human IgG, with a region or CDR. In certain embodiments, the extracellular antigen-binding domain is a VFv comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO:25, as shown in Table 7. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 25, as shown in Table 7. H In certain embodiments, the extracellular antigen-binding domain comprises a V that comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO: 26, as shown in Table 7. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 26, as shown in Table 7. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 25, as shown in Table 7. H and V comprising an amino acid sequence set forth in SEQ ID NO: 26 L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising an amino acid sequence set forth in SEQ ID NO: 160, or a conservative modification thereof, as shown in Table 7. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 161 or a conservative modification thereof H CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 162 or a conservative modification thereof H In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 163, or a conservative modification thereof, as shown in Table 7. LCDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 164 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 165 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 160, or a conservative modification thereof, as shown in Table 7. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 161 or a conservative modification thereof H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 162 or a conservative modification thereof H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 163 or a conservative modification thereof L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 164 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 165 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 160. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 161 H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 162 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 163 L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 164 L CDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 165 L Includes CDR3. [Table 7]

[0137] In certain embodiments, the extracellular antigen-binding domain is an scFv that comprises the amino acid sequence of SEQ ID NO: 107 and specifically binds to a GPRC5D polypeptide (e.g., a GPRC5D polypeptide having the amino acid sequence of SEQ ID NO: 97, or a fragment thereof), and is designated ET150-157 scFv (also referred to as "ET150-7 scFv").

[0138] In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 29, and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 30, optionally with (iii) a linker sequence, e.g., a linker peptide between the heavy chain variable region and the light chain variable region. In certain embodiments, the linker comprises amino acids having the sequence set forth in SEQ ID NO: 98. In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a V H Area and V L In certain embodiments, the extracellular antigen-binding domain is a scFv-Fc fusion protein or a full-length human IgG, with a region or CDR. In certain embodiments, the extracellular antigen-binding domain is a VFv comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO:29, as shown in Table 8. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO:29, as shown in Table 8. H In certain embodiments, the extracellular antigen-binding domain comprises a V that comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO: 30, as shown in Table 8. LIn certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 30, as shown in Table 8. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO:29, as shown in Table 8. H and V comprising an amino acid sequence set forth in SEQ ID NO: 30 L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising an amino acid sequence set forth in SEQ ID NO: 166, or a conservative modification thereof, as shown in Table 8. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 167 or a conservative modification thereof H CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 168 or a conservative modification thereof H In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 169, or a conservative modification thereof, as shown in Table 8. L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 170 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 171 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 166, or a conservative modification thereof, as shown in Table 8. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 167 or a conservative modification thereof H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 168 or a conservative modification thereof H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 169 or a conservative modification thereof L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 170 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 171 or a conservative modification thereof LIn certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 166. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 167 H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 168 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 169 L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 170 L CDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 171 L Includes CDR3. [Table 8]

[0139] In certain embodiments, the extracellular antigen-binding domain is an scFv that comprises the amino acid sequence of SEQ ID NO: 108 and specifically binds to a GPRC5D polypeptide (e.g., a GPRC5D polypeptide having the amino acid sequence of SEQ ID NO: 97, or a fragment thereof), and is designated ET150-159 scFv (also referred to as "ET150-9 scFv").

[0140] In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 33, and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 34, optionally with (iii) a linker sequence, e.g., a linker peptide between the heavy chain variable region and the light chain variable region. In certain embodiments, the linker comprises amino acids having the sequence set forth in SEQ ID NO: 98. In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a V H Area and V LIn certain embodiments, the extracellular antigen-binding domain is an scFv-Fc fusion protein or a full-length human IgG, with a region or CDR. In certain embodiments, the extracellular antigen-binding domain is a VFv comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO: 33, as shown in Table 9. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 33, as shown in Table 9. H In certain embodiments, the extracellular antigen-binding domain comprises a V that comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO: 34, as shown in Table 9. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 34, as shown in Table 9. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 33, as shown in Table 9. H and V comprising an amino acid sequence set forth in SEQ ID NO: 34. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising an amino acid sequence set forth in SEQ ID NO: 172, or a conservative modification thereof, as shown in Table 9. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 173 or a conservative modification thereof H CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 174 or a conservative modification thereof H In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 175, or a conservative modification thereof, as shown in Table 9. LCDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 176 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 177 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 172, or a conservative modification thereof, as shown in Table 9. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 173 or a conservative modification thereof H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 174 or a conservative modification thereof H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 175 or a conservative modification thereof L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 176 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 177 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 172. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 173 H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 174 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 175 L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 176 L CDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 177 L Includes CDR3. [Table 9]

[0141] In certain embodiments, the extracellular antigen-binding domain is an scFv that comprises the amino acid sequence of SEQ ID NO: 109 and specifically binds to a GPRC5D polypeptide (e.g., a GPRC5D polypeptide having the amino acid sequence of SEQ ID NO: 97, or a fragment thereof), and is designated ET150-160 scFv (also referred to as "ET150-10 scFv").

[0142] In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 37, and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 38, optionally with (iii) a linker sequence, e.g., a linker peptide between the heavy chain variable region and the light chain variable region. In certain embodiments, the linker comprises amino acids having the sequence set forth in SEQ ID NO: 98. In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a V H Area and V L In certain embodiments, the extracellular antigen-binding domain is an scFv-Fc fusion protein or a full-length human IgG, with a region or CDR. In certain embodiments, the extracellular antigen-binding domain is a VFv comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO: 37, as shown in Table 10. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 37, as shown in Table 10. H In certain embodiments, the extracellular antigen-binding domain comprises a V that comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO: 38, as shown in Table 10. LIn certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 38, as shown in Table 10. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 37, as shown in Table 10. H and V comprising an amino acid sequence set forth in SEQ ID NO: 38 L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising an amino acid sequence set forth in SEQ ID NO: 178, or a conservative modification thereof, as shown in Table 10. H CDR1, V comprising the amino acid sequence set forth in SEQ ID NO: 179 or a conservative modification thereof H CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 180 or a conservative modification thereof H In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 181, or a conservative modification thereof, as shown in Table 10. L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 182 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 183 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 178, or a conservative modification thereof, as shown in Table 10. H CDR1, V comprising the amino acid sequence set forth in SEQ ID NO: 179 or a conservative modification thereof H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 180 or a conservative modification thereof H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 181 or a conservative modification thereof L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 182 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 183 or a conservative modification thereof LIn certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 178. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 179 H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 180 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 181 L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 182 L CDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 183 L Includes CDR3. [Table 10]

[0143] In certain embodiments, the extracellular antigen-binding domain is an scFv that comprises the amino acid sequence of SEQ ID NO: 110 and specifically binds to a GPRC5D polypeptide (e.g., a GPRC5D polypeptide having the amino acid sequence of SEQ ID NO: 97, or a fragment thereof), and is designated ET150-161 scFv (also referred to as "ET150-11 scFv").

[0144] In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 41, and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 42, optionally with (iii) a linker sequence, e.g., a linker peptide between the heavy chain variable region and the light chain variable region. In certain embodiments, the linker comprises amino acids having the sequence set forth in SEQ ID NO: 98. In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a V H Area and V LIn certain embodiments, the extracellular antigen-binding domain is a scFv-Fc fusion protein or a full-length human IgG, with a region or CDR. In certain embodiments, the extracellular antigen-binding domain is a VFv comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO:41, as shown in Table 11. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO:41, as shown in Table 11. H In certain embodiments, the extracellular antigen-binding domain comprises a V that comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO: 42, as shown in Table 11. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 42, as shown in Table 11. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO:41, as shown in Table 11. H and V comprising an amino acid sequence set forth in SEQ ID NO: 42 L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising an amino acid sequence set forth in SEQ ID NO: 184, or a conservative modification thereof, as shown in Table 11. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 185 or a conservative modification thereof H CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 186 or a conservative modification thereof H In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 187, or a conservative modification thereof, as shown in Table 11. LCDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 188 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 189 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 184, or a conservative modification thereof, as shown in Table 11. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 185 or a conservative modification thereof H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 186 or a conservative modification thereof H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 187 or a conservative modification thereof L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 188 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 189 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 184. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 185 H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 186 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 187 L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 188 L CDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 189 L Includes CDR3. [Table 11]

[0145] In certain embodiments, the extracellular antigen-binding domain is an scFv comprising the amino acid sequence of SEQ ID NO: 111 and specifically binding to a GPRC5D polypeptide (e.g., a GPRC5D polypeptide having the amino acid sequence of SEQ ID NO: 97, or a fragment thereof), and is designated ET150-162 scFv (also referred to as "ET150-12 scFv").

[0146] In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 45, and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 46, optionally with (iii) a linker sequence, e.g., a linker peptide between the heavy chain variable region and the light chain variable region. In certain embodiments, the linker comprises amino acids having the sequence set forth in SEQ ID NO: 98. In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a V H Area and V L In certain embodiments, the extracellular antigen-binding domain is an scFv-Fc fusion protein or a full-length human IgG, with a region or CDR. In certain embodiments, the extracellular antigen-binding domain is a VFv comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO:45, as shown in Table 12. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO:45, as shown in Table 12. H In certain embodiments, the extracellular antigen-binding domain comprises a V that comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO: 46, as shown in Table 12. LIn certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 46, as shown in Table 12. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO:45, as shown in Table 12. H and V comprising an amino acid sequence set forth in SEQ ID NO: 46 L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising an amino acid sequence set forth in SEQ ID NO: 190, or a conservative modification thereof, as shown in Table 12. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 191 or a conservative modification thereof H CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 192 or a conservative modification thereof H In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 193, or a conservative modification thereof, as shown in Table 12. L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 194 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 195 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 190, or a conservative modification thereof, as shown in Table 12. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 191 or a conservative modification thereof H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 192 or a conservative modification thereof H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 193 or a conservative modification thereof L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 194 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 195 or a conservative modification thereof LIn certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 190. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 191 H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 192 H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 193 L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 194 L CDR2, and V comprising an amino acid sequence set forth in SEQ ID NO: 195 L Includes CDR3. [Table 12]

[0147] In certain embodiments, the extracellular antigen-binding domain is an scFv that comprises the amino acid sequence of SEQ ID NO: 112 and specifically binds to a GPRC5D polypeptide (e.g., a GPRC5D polypeptide having the amino acid sequence of SEQ ID NO: 97, or a fragment thereof), and is designated ET150-163 scFv (also referred to as "ET150-13 scFv").

[0148] In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a heavy chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 49, and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 50, optionally with (iii) a linker sequence, e.g., a linker peptide between the heavy chain variable region and the light chain variable region. In certain embodiments, the linker comprises amino acids having the sequence set forth in SEQ ID NO: 98. In certain embodiments, the extracellular antigen-binding domain is an scFv comprising a V H Area and V LIn certain embodiments, the extracellular antigen-binding domain is a scFv-Fc fusion protein or a full-length human IgG, with a region or CDR. In certain embodiments, the extracellular antigen-binding domain is a VFv comprising an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO:49, as shown in Table 13. H In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO:49, as shown in Table 13. H In certain embodiments, the extracellular antigen-binding domain comprises a V that comprises an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to the amino acid sequence set forth in SEQ ID NO: 50, as shown in Table 13. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO: 50, as shown in Table 13. L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising amino acids having the sequence set forth in SEQ ID NO:49, as shown in Table 13. H and V comprising an amino acid sequence set forth in SEQ ID NO: 50 L In certain embodiments, the extracellular antigen-binding domain comprises a V comprising an amino acid sequence set forth in SEQ ID NO: 196, or a conservative modification thereof, as shown in Table 13. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 197 or a conservative modification thereof H CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 198 or a conservative modification thereof H In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 199, or a conservative modification thereof, as shown in Table 13. LCDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 200 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 201 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth in SEQ ID NO: 196, or a conservative modification thereof, as shown in Table 13. H CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 197 or a conservative modification thereof H CDR2, V comprising an amino acid sequence set forth in SEQ ID NO: 198 or a conservative modification thereof H CDR3, V comprising an amino acid sequence set forth in SEQ ID NO: 199 or a conservative modification thereof L CDR1, V comprising an amino acid sequence set forth in SEQ ID NO: 200 or a conservative modification thereof L CDR2 and V comprising an amino acid sequence set forth in SEQ ID NO: 201 or a conservative modification thereof L In certain embodiments, the extracellular antigen-binding domain comprises a V CDR3 comprising an amino acid sequence set forth ...

Claims

[Claim 1] A method or composition as described in the specification.

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