Methods of using chimeric antigen receptors targeting b-cell maturation antigen and uses thereof

Abstract

The presently disclosed subject matter provides for methods and compositions for treating multiple myeloma. It relates to chimeric antigen receptors (CARs) that specifically target B cell maturation antigen (BCMA), and immunoresponsive cells comprising such CARs. The presently disclosed BCMA-specific CARs have enhanced immune-activating properties, including anti-tumor activity.

1 - 58 . (canceled) 
     
     
         59 . A chimeric antigen receptor (CAR), comprising an extracellular antigen-binding domain that binds to B cell maturation antigen (BCMA), a transmembrane domain and an intracellular domain, wherein the extracellular antigen-binding domain comprises:
 (a) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:1, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:2;   (b) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:5, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:6;   (c) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:9, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:10;   (d) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:13, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:14;   (e) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:17, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:18;   (f) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:21, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth SEQ ID NO:22;   (g) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:25, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:26;   (h) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:29, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:30;   (i) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:33, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:34;   (j) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:37, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:38;   (k) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:41, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:42;   (l) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:45, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:46;   (m) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:49, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:50;   (n) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:53, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:54;   (o) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:57, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:58;   (p) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:61, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:62; or   (q) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:65, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:66.   
     
     
         60 . A chimeric antigen receptor (CAR), comprising an extracellular antigen-binding domain that binds to B cell maturation antigen (BCMA), a transmembrane domain, and an intracellular domain, wherein the extracellular antigen-binding domain comprises:
 (a) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 89, 90 and 91, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 92, 93, and 94, respectively;   (b) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 95, 96, and 97, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 98, 99, and 100, respectively;   (c) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 101, 102 and 103, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 104, 105, and 106, respectively;   (d) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 107, 108, and 109, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 110, 111, and 112, respectively;   (e) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 113, 114, and 115, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 116, 117, and 118, respectively;   (f) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 119, 120, and 121, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 122, 123, and 124, respectively;   (g) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 125, 126, and 127, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 128, 129, and 130, respectively;   (h) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 131, 132, and 133, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 134, 135, and 136, respectively;   (i) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 137, 138, and 139, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 140, 141, and 142, respectively;   (j) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 143, 144, and 145, respectively; the light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 146, 147 and 148, respectively;   (k) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 149, 150, and 151, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 152, 153, and 154, respectively;   (l) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 155, 156, and 157, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 158, 159, and 160, respectively;   (m) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 161, 162, and 163, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 164, 165, and 166, respectively;   (n) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 167, 168, and 169, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 170, 171, and 172, respectively   (o) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 173, 174, and 175, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 176, 177, and 178, respectively;   (p) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 179, 180, and 181, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 182, 183, and 184, respectively; or   (q) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 185, 186, and 187, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 188, 189, and 190, respectively.   
     
     
         61 . The CAR of  claim 59 , wherein:
 (a) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:1, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:2;   (b) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:5, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:6;   (c) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:9, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:10;   (d) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:13, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:14;   (e) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:17, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:18;   (f) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:21, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:22;   (g) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:25, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:26;   (h) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:29, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:30;   (i) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:33, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:34;   (j) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:37, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:38;   (k) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:41, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:42;   (l) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:45, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:46;   (m) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:49, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:50;   (n) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:53, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:54   (o) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:57, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:58;   (p) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:61, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:62; or   (q) the heavy chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:65, and the light chain variable region comprises an amino acid sequence that has at least about 90% sequence identity to the sequence set forth in SEQ ID NO:66.   
     
     
         62 . The CAR of  claim 59 , wherein:
 (a) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:1, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:2;   (b) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:5, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:6;   (c) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:9, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:10;   (d) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:13, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:14;   (e) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:17, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:18;   (f) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:21, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:22;   (g) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:25, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:26;   (h) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:29, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:30;   (i) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:33, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:34;   (j) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:37, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:38;   (k) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:41, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:42;   (l) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:45, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:46;   (m) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:49, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:50;   (n) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:53, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:54;   (o) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:57, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:58;   (p) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:61, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:62; or   (q) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:65, and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:66.   
     
     
         63 . The CAR of  claim 59 , wherein the extracellular antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, or SEQ ID NO: 88. 
     
     
         64 . An immunoresponsive cell comprising the CAR of  claim 59 . 
     
     
         65 . An immunoresponsive cell comprising the CAR of  claim 60 . 
     
     
         66 . A nucleic acid molecule encoding the CAR of  claim 59 . 
     
     
         67 . A nucleic acid molecule encoding the CAR of  claim 60 . 
     
     
         68 . A vector comprising the nucleic acid molecule of  claim 66 . 
     
     
         69 . A vector comprising the nucleic acid molecule of  claim 67 . 
     
     
         70 . A host cell comprising the nucleic acid molecule of  claim 66 . 
     
     
         71 . A host cell comprising the nucleic acid molecule of  claim 67 . 
     
     
         72 . A T cell comprising the CAR of  claim 59 . 
     
     
         73 . The T cell of  claim 72 , wherein the T cell is a CD4+ T cell and/or a CD8+ T cell. 
     
     
         74 . A T cell comprising the CAR of  claim 60 . 
     
     
         75 . The T cell of  claim 74 , wherein the T cell is a CD4+ T cell and/or a CD8+ T cell. 
     
     
         76 . A pharmaceutical composition comprising an effective amount of the immunoresponsive cell of  claim 64  and a pharmaceutically acceptable excipient. 
     
     
         77 . A pharmaceutical composition comprising an effective amount of the immunoresponsive cell of  claim 65  and a pharmaceutically acceptable excipient. 
     
     
         78 . A pharmaceutical composition comprising an effective amount of the T cell of  claim 72  and a pharmaceutically acceptable excipient. 
     
     
         79 . A pharmaceutical composition comprising an effective amount of the T cell of  claim 73  and a pharmaceutically acceptable excipient. 
     
     
         80 . A method for producing an immunoresponsive cell that binds to B cell maturation antigen (BMCA), comprising introducing into the immunoresponsive cell a nucleic acid sequence that encodes the chimeric antigen receptor (CAR) of  claim 59 . 
     
     
         81 . A kit for treating a tumor, the kit comprising the immunoresponsive cell of  claim 64  and written instructions for using the immunoresponsive cell for treating a subject having a tumor. 
     
     
         82 . A kit for treating a tumor, the kit comprising the T cell of  claim 72  and written instructions for using the immunoresponsive cell for treating a subject having a tumor. 
     
     
         83 . The kit of  claim 82 , wherein the tumor is selected from the group consisting of multiple myeloma, Non-Hodgkin Lymphoma, Hodgkin Lymphoma, Chronic Lymphocytic Leukemia (CLL), glioblastoma, and Waldenstrom's Macroglobulinemia. 
     
     
         84 . A method of reducing tumor burden in a subject, the method comprising administering a composition comprising an immunoresponsive cell, wherein the immunoresponsive cell comprises an extracellular antigen-binding domain that binds to B cell maturation antigen (BCMA), a transmembrane domain and an intracellular domain, and wherein the extracellular antigen-binding domain comprises:
 (a) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:1, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:2;   (b) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:5, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:6;   (c) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:9, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:10;   (d) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:13, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:14;   (e) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:17, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:18;   (f) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:21, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:22;   (g) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:25, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:26;   (h) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:29, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:30;   (i) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:33, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:34;   (j) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:37, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:38;   (k) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:41, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:42;   (l) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:45, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:46;   (m) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:49, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:50;   (n) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:53, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:54;   (o) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:57, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:58;   (p) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:61, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:62; or   (q) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:65, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:66.   
     
     
         85 . A method of reducing tumor burden in a subject, the method comprising administering a composition comprising an immunoresponsive cell, wherein the immunoresponsive cell comprises an extracellular antigen-binding domain that binds to B cell maturation antigen (BCMA), a transmembrane domain and an intracellular domain, and wherein the extracellular antigen-binding domain comprises:
 (a) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 89, 90 and 91, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 92, 93, and 94, respectively;   (b) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 95, 96, and 97, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 98, 99, and 100, respectively;   (c) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 101, 102 and 103, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 104, 105, and 106, respectively;   (d) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 107, 108, and 109, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 110, 111, and 112, respectively;   (e) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 113, 114, and 115, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 116, 117, and 118, respectively;   (f) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 119, 120, and 121, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 122, 123, and 124, respectively;   (g) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 125, 126, and 127, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 128, 129, and 130, respectively;   (h) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 131, 132, and 133, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 134, 135, and 136, respectively;   (i) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 137, 138, and 139, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 140, 141, and 142, respectively;   (j) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 143, 144, and 145, respectively; the light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 146, 147 and 148, respectively;   (k) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 149, 150, and 151, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 152, 153, and 154, respectively;   (l) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 155, 156, and 157, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 158, 159, and 160, respectively;   (m) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 161, 162, and 163, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 164, 165, and 166, respectively;   (n) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 167, 168, and 169, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 170, 171, and 172, respectively   (o) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 173, 174, and 175, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 176, 177, and 178, respectively;   (p) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 179, 180, and 181, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 182, 183, and 184, respectively; or   (q) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 185, 186, and 187, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 188, 189, and 190, respectively.   
     
     
         86 . A method of reducing tumor burden in a subject, the method comprising administering a composition comprising a T cell, wherein the T cell comprises an extracellular antigen-binding domain that binds to B cell maturation antigen (BCMA), a transmembrane domain and an intracellular domain, and wherein the extracellular antigen-binding domain comprises:
 (a) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:1, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:2;   (b) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:5, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:6;   (c) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:9, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:10;   (d) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:13, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:14;   (e) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:17, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:18;   (f) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:21, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:22;   (g) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:25, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:26;   (h) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:29, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:30;   (i) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:33, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:34;   (j) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:37, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:38;   (k) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:41, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:42;   (l) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:45, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:46;   (m) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:49, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:50;   (n) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:53, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:54;   (o) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:57, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:58;   (p) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:61, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:62; or   (q) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 of the heavy chain variable region sequence set forth in SEQ ID NO:65, and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 of the light chain variable region sequence set forth in SEQ ID NO:66.   
     
     
         87 . A method of reducing tumor burden in a subject, the method comprising administering a composition comprising a T cell, wherein the T cell comprises an extracellular antigen-binding domain that binds to B cell maturation antigen (BCMA), a transmembrane domain and an intracellular domain, and wherein the extracellular antigen-binding domain comprises:
 (a) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 89, 90 and 91, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 92, 93, and 94, respectively;   (b) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 95, 96, and 97, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 98, 99, and 100, respectively;   (c) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 101, 102 and 103, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 104, 105, and 106, respectively;   (d) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 107, 108, and 109, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 110, 111, and 112, respectively;   (e) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 113, 114, and 115, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 116, 117, and 118, respectively;   (f) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 119, 120, and 121, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 122, 123, and 124, respectively;   (g) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 125, 126, and 127, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 128, 129, and 130, respectively;   (h) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 131, 132, and 133, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 134, 135, and 136, respectively;   (i) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 137, 138, and 139, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 140, 141, and 142, respectively;   (j) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 143, 144, and 145, respectively; the light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 146, 147 and 148, respectively;   (k) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 149, 150, and 151, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 152, 153, and 154, respectively;   (l) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 155, 156, and 157, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 158, 159, and 160, respectively;   (m) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 161, 162, and 163, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 164, 165, and 166, respectively;   (n) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 167, 168, and 169, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 170, 171, and 172, respectively   (o) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 173, 174, and 175, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 176, 177, and 178, respectively;   (p) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 179, 180, and 181, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 182, 183, and 184, respectively; or   (q) a heavy chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 185, 186, and 187, respectively; and a light chain variable region comprising a CDR1, a CDR2, and a CDR3 sequence set forth in SEQ ID NOs: 188, 189, and 190, respectively.   
     
     
         88 . The method of  claim 86 , wherein the T cell is a CD4+ T cell and/or a CD8+ T cell. 
     
     
         89 . The method of  claim 87 , wherein the T cell is a CD4+ T cell and/or a CD8+ T cell. 
     
     
         90 . The method of  claim 84 , wherein the method reduces the number of tumor cells, reduces tumor size, or eradicates the tumor in the subject. 
     
     
         91 . The method of  claim 84 , wherein the tumor is selected from the group consisting of multiple myeloma, Non-Hodgkin Lymphoma, Hodgkin Lymphoma, Chronic Lymphocytic Leukemia (CLL), glioblastoma, and Waldenstrom's Macroglobulinemia. 
     
     
         92 . The method of  claim 86 , wherein the method reduces the number of tumor cells, reduces tumor size, or eradicates the tumor in the subject. 
     
     
         93 . The method of  claim 86 , wherein the tumor is selected from the group consisting of multiple myeloma, Non-Hodgkin Lymphoma, Hodgkin Lymphoma, Chronic Lymphocytic Leukemia (CLL), glioblastoma, and Waldenstrom's Macroglobulinemia. 
     
     
         94 . The method of  claim 84 , wherein from about 10 4  to about 10 10 , from about 10 5  to about 10 9 , or from about 10 6  to about 10 8  immunoresponsive cells are administered to the subject. 
     
     
         95 . The method of  claim 86 , wherein from about 10 4  to about 10 10 , from about 10 5  to about 10 9 , or from about 10 6  to about 10 8  T cells are administered to the subject.