Chimeric antigen receptors specific for B cell maturation antigen (BCMA)

Abstract

The present invention provides a chimeric antigen receptor (CAR) comprising an extracellular BCMA binding domain, in particular an scFv. The CAR further comprises a spacer having a length of at least 125 amino acids, a transmembrane domain, and an intracellular signaling region. It may also comprise an intracellular co-stimulation domain. Also provided are genetically engineered cells expressing the CARs and their use in, for example, adoptive cell therapy.

Description

[0001] This application is a divisional application of Chinese patent application No. 201880084824.8, filed on November 1, 2018, entitled "Chimeric antigen receptor specific to B cell maturation antigen (BCMA)".

[0002] Cross-references to related applications

[0003] This application claims priority to the following U.S. provisional application: filed November 1, 2017, entitled "Chimeric Antigen Receptor Speccifidic for B-Cell Maturation Antigen and Encoding". U.S. Provisional Application No. 62 / 580,439 entitled "a chimeric antigen receptor specific to B-cell maturation antigen and encoding a polynucleotide", filed November 1, 2017; U.S. Provisional Application No. 62 / 580,445 entitled "a chimeric antigen receptor specific to B-cell maturation antigen and encoding a polynucleotide", filed November 7, 2017; U.S. Provisional Application No. 62 / 582,932 entitled "a chimeric antigen receptor specific to B-cell maturation antigen and encoding a polynucleotide", filed November 7, 2017; and U.S. Provisional Application No. 62 / 596,765 entitled "a chimeric antigen receptor specific to B-cell maturation antigen and encoding a polynucleotide", filed December 8, 2017. U.S. Provisional Application No. 62 / 596,763, filed December 8, 2017, entitled "A chimeric antigen receptor specific to B-cell maturation antigen and encoding a polynucleotide"; U.S. Provisional Application No. 62 / 614,960, filed January 8, 2018, entitled "A chimeric antigen receptor specific to B-cell maturation antigen and encoding a polynucleotide"; U.S. Provisional Application No. 62 / 614,963, filed January 8, 2018, entitled "A chimeric antigen receptor specific to B-cell maturation antigen and encoding a polynucleotide"; U.S. Provisional Application No. 62 / 665,442, filed May 1, 2018, entitled "A chimeric antigen receptor specific to B-cell maturation antigen and encoding a polynucleotide"; and U.S. Provisional Application No. 62 / 665,442, filed May 1, 2018, entitled "A method for assessing the activity of a recombinant antigen receptor (METHOD)". The contents of U.S. Provisional Application No. 62 / 665,447, entitled “The assuring activity of recombinant antigen recertors,” are incorporated herein by reference in their entirety.

[0004] The sequence list is incorporated by reference.

[0005] This application is submitted together with the electronic sequence list. The sequence list is provided as a file named 735042009940SeqList.txt, generated on November 1, 2018, and is 593 kilobytes in size. The information in the electronic sequence list is incorporated herein by reference in its entirety. Technical Field

[0006] This disclosure relates in several aspects to a chimeric antigen receptor (CAR) containing an antibody moiety specific to B-cell maturation antigen (BCMA); and a polynucleotide encoding a CAR specific to BCMA. This disclosure further relates to genetically engineered cells containing such BCMA-binding receptors, and their use in adoptive cell therapy. Background Technology

[0007] B cell maturation antigen (BCMA) is a type III transmembrane protein expressed on mature B lymphocytes. Upon binding to its ligands (B cell activator of the TNF family (BAFF) or proliferation-inducing ligand (APRIL)), BCMA delivers pro-survival cell signals to B cells, a delivery found essential for plasma cell survival. BCMA expression has been associated with several diseases, including cancer, autoimmune diseases, and infectious diseases. Due to its role in various diseases and conditions, including cancer, BCMA is a therapeutic target. Various BCMA-binding chimeric antigen receptors (CARs) and cells expressing these CARs are available. However, there remains a need for modified BCMA-binding CARs and engineered BCMA-CAR-expressing target cells, such as those used in adoptive cell therapy. This article provides implementation methods that meet these needs. Summary of the Invention

[0008] A polynucleotide encoding a chimeric antigen receptor is provided, comprising a nucleic acid encoding: (a) an extracellular antigen-binding domain that specifically recognizes an antigen; (b) a spacer of at least 125 amino acids in length; (c) a transmembrane domain; and (d) an intracellular signal transduction region, wherein, when the polynucleotide is expressed in a cell, the transcribed RNA (optionally, messenger RNA (mRNA)) derived from the polynucleotide exhibits at least 70%, 75%, 80%, 85%, 90%, or 95% RNA homogeneity. In some cases, the spacer is derived from an immunoglobulin. In some embodiments, the spacer includes a hinge region, C... H 2 and C H The sequence of zone 3. In some implementations, the hinge, C H 2 and C HOne or more of the three are wholly or partially derived from IgG4 or IgG2. In some cases, the hinge, C H 2 and C H 3 originates from IgG4. In some aspects, hinges, C H 2 and C H One or more of the three are chimeric and contain sequences derived from IgG4 and IgG2. In some instances, the spacer contains an IgG4 / 2 chimeric hinge and an IgG2 / 4C... H 2 and IgG4 C H Region 3. In some embodiments, the encoded spacer is or contains (i) the sequence shown in SEQ ID NO:649; (ii) a functional variant of SEQ ID NO:649 having at least 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO:649; or (iii) a continuous portion of (i) or (ii) of at least 125 amino acids in length. In some embodiments, the encoded spacer is or includes the sequence shown in SEQ ID NO:649.

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

[0010] In some embodiments of any of the polynucleotides described herein, the nucleic acid encoding the spacer includes at least one modified splice donor and / or splice acceptor site containing one or more nucleotide modifications corresponding to a reference splice donor and / or reference splice acceptor site contained in the sequence shown in SEQ ID NO:621. In some cases, the one or more nucleotide modifications contain insertions, deletions, substitutions, or combinations thereof. In some cases, the reference splice acceptor and / or reference splice donor site is a typical, atypical, or hidden splice site. In some instances, the splicing site prediction score for the reference splice donor and / or reference splice acceptor sites is at least or about 0.4, 0.5, 0.6, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 0.99, or 1.0; and / or the probability prediction of the reference splice donor and / or reference splice acceptor sites being involved in splicing events is at least 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%.

[0011] In some embodiments of any of the polynucleotides described herein, reference splicing donor sites include the sequences aatctaagtacggac (SEQ ID NO:705), tcaactggtacgtgg (SEQ ID NO:706), acaattagtaaggca (SEQ ID NO:707), and / or accacaggtgtatac (SEQ ID NO:708); and / or reference splicing acceptor sites include the sequences aagtttctttctgtattccaggctgaccgtggataaatctc (SEQ ID NO:742) and / or gggcaacgtgttctcttgcagtgtcatgcacgaagccctgc (SEQ ID NO:743). In some instances, the splicing site prediction score of the reference splice donor and / or reference splice acceptor sites is at least or about 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 0.99, or 1.0; and / or the probability prediction that the reference splice donor and / or one or more reference splice acceptor sites are involved in splicing events is at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In some embodiments, the reference splice donor site contains the sequence tcaactggtacgtgg (SEQ ID NO: 706); and / or the reference splice acceptor site contains the sequence aagtttctttctgtattccaggctgaccgtggataaatctc (SEQ ID NO: 742).

[0012] In some embodiments of any of the polynucleotides described herein, at least one of the one or more nucleotide modifications is located within residues 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the splice junction of the reference splice acceptor and / or reference splice donor site. In some aspects, the one or more nucleotide modifications are silent, and / or produce a degenerate codon compared to SEQ ID NO:621, and / or do not alter the amino acid sequence of the encoded spacer. In some embodiments, modified splice donor sites are shown in agtctaaatacggac (SEQ ID NO:661), tcaactggtatgtgg (SEQ ID NO:662), accatctccaaggcc (SEQ ID NO:663), and / or gccccaggtttacac (SEQ ID NO:664); and / or modified splice acceptor sites are shown in cagttcttcctgtatagtagactcaccgtggataaatcaa (SEQ ID NO:672), gggcaacgtgttcagctgcagcgtgatgcacgaggccctgc (SEQ ID NO:673), and / or aagtttctttctgtattccagactgaccgtggataaatctc (SEQ ID NO:854). In some cases, the modified splice donor site is shown in tcaactggtatgtgg (SEQ ID NO:662), and / or the modified acceptor site is shown in cagttcttcctgtatagtagactcaccgtggataaatcaa (SEQ ID NO:672). In some of any such embodiments, the spacer is encoded by the nucleotide sequence shown in SEQ ID NO:622 or a portion thereof.

[0013] A polynucleotide encoding a chimeric antigen receptor is provided, wherein the polynucleotide includes a nucleic acid encoding: (a) an extracellular antigen-binding domain that specifically recognizes an antigen; (b) a spacer, wherein the encoding nucleic acid is or includes the sequence shown in SEQ ID NO:622 or the amino acid sequence shown in SEQ ID NO:649; (c) a transmembrane domain; and (d) an intracellular signal transduction region.

[0014] Also provided is a polynucleotide encoding a chimeric antigen receptor, wherein the polynucleotide includes a nucleic acid encoding: (a) an extracellular antigen-binding domain that specifically recognizes an antigen; (b) a spacer, wherein the encoding nucleic acid includes or primarily includes the sequence shown in SEQ ID NO:622 or the amino acid sequence shown in SEQ ID NO:649; (c) a transmembrane domain; and (d) an intracellular signal transduction region.

[0015] In some embodiments, after expression of the polynucleotide in cells, the transcribed RNA (optionally messenger RNA (mRNA)) derived from the polynucleotide exhibits at least 70%, 75%, 80%, 85%, 90%, or 95% RNA homogeneity. In some embodiments, after expression in cells, the transcribed RNA (optionally messenger RNA (mRNA)) derived from the polynucleotide exhibits reduced heterogeneity compared to the heterogeneity of mRNA transcribed from a reference polynucleotide encoding the same amino acid sequence as the polynucleotide, wherein the reference polynucleotide differs from the polynucleotide in that it contains one or more splice donor sites and / or one or more splice acceptor sites in the nucleic acid encoding the spacer and / or includes one or more nucleotide modifications compared to the polynucleotide. In some cases, the reduction in RNA heterogeneity is greater than or greater than about 10%, 15%, 20%, 25%, 30%, 40%, 50%, or more than 50%. In some cases, the transcribed RNA (optionally, messenger RNA (mRNA)) from the reference polynucleotide exhibits RNA heterogeneity greater than or greater than about 10%, 15%, 20%, 25%, 30%, 40%, 50%, or more than 50%. In some of any such embodiments, RNA homogeneity and / or heterogeneity are determined by agarose gel electrophoresis, chip-based capillary electrophoresis, analytical ultracentrifugation, field flow fractionation, or liquid chromatography. In some of any such embodiments, the polynucleotide is codon-optimized.

[0016] In some embodiments of any of the polynucleotides described herein, the antigen is associated with a disease or symptom or is expressed in cells within the environment of a lesion associated with the disease or symptom. In some cases, the disease or symptom is cancer. In some instances, the disease or symptom is myeloma, leukemia, or lymphoma. In some implementations, the antigens are ROR1, B cell maturation antigen (BCMA), carbonic anhydrase 9 (CAIX), tEGFR, Her2 / neu (receptor tyrosine kinase erbB2), L1-CAM, CD19, CD20, CD22, mesothelin, CEA and hepatitis B surface antigen, antifolate receptor, CD23, CD24, CD30, CD33, CD38, CD44, EGFR, epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), EPHa2, erb-B2, erb-B3, erb-B4, erbB dimer, EGFR vIII, folate-binding protein (FBP), FCRL5, FCRH5, fetal acetylcholine receptor, GD2, GD3, HMW-MAA, IL-22R-α, IL-13R-α2, kinase insertion domain receptor (kdr), κ light chain, Lewis Y, L1 cell adhesion molecule (L1-CAM), melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, preferentially expressed melanoma antigen (PRAME), susceptin, TAG72, B7-H6, IL-13 receptor α2 (IL-13Ra2), CA9, GD3, HMW-MAA, CD171, G250 / CAIX, HLA-A1, MAGE A1, HLA-A2 NY-ESO-1, PSCA, folate receptor-a, CD44v6, CD44v7 / 8, avb6 integrin, 8H9, NCAM, VEGF receptor, 5T4, fetal AchR, NKG2D ligand, CD44v6, dual antigen, testicular cancer antigen, mesothelin, murine CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, carcinoembryonic antigen, ROR1, TAG72, VEGF-R2, carcinoembryonic antigen (CEA), Her2 / neu, estrogen receptor, progesterone receptor, liver ligand B2, CD123, c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms tumor 1 (WT-1), cyclin, cyclin A2, CCL-1, CD138, pathogen-specific antigen. In some cases, the antigen is B cell maturation antigen (BCMA).

[0017] In some of any such embodiments, the antigen-binding domain is a variable heavy chain (V H ) and variable light chains (V LAntibody fragments in the V region. In some respects, V H The region is or includes the V shown in any of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774, or 814-832. H The amino acid sequence of the region has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity; and / or V L The region is or includes the V shown in any of SEQ ID NO: 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777 or 833-849. L The amino acid sequence of the region has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity. In some cases, V H The region is or includes the V shown in any of SEQ ID NO: 110, 111, 112, 113, 115, 248, 252, 253, 254, 255, 256, 324, 325, 518, 519, 520, 521, 522, 609, 617, 772-774, or 814-832. H The amino acid sequence of the region has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity; and / or V L The region is or includes the V shown in any of the following: 116, 117, 118, 120, 121, 124, 125, 258, 262, 263, 264, 265, 266, 267, 326, 327, 534, 535, 536, 537, 538, 610, 618, 775-777, or 833-849. L The amino acid sequence of the region has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity.

[0018] In some implementations of any of the polynucleotides described herein, V H The region is or contains a V selected from any one of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774 or 814-832. H The region contains CDR-H1, CDR-H2, and CDR-H3 within its amino acid sequence; and / or VL The region is or includes V selected from any one of SEQ ID NO: 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777 or 833-849. L The region contains CDR-L1, CDR-L2, and CDR-L3 within its amino acid sequence. In some embodiments, V H The region is or contains a V selected from any one of SEQ ID NO: 110, 111, 112, 113, 115, 248, 252, 253, 254, 255, 256, 324, 325, 518, 519, 520, 521, 522, 609, 617, 772-774, or 814-832. H The region contains CDR-H1, CDR-H2, and CDR-H3 within its amino acid sequence; and / or V L The region is or includes V selected from any one of SEQ ID NO: 116, 117, 118, 120, 121, 124, 125, 258, 262, 263, 264, 265, 266, 267, 326, 327, 534, 535, 536, 537, 538, 610, 618, 775-777, or 833-849. L The region contains CDR-L1, CDR-L2, and CDR-L3 within its amino acid sequence. In some embodiments, V H The region is or includes (a) a heavy chain complementarity-determining region 1 (CDR-H1) containing an amino acid sequence selected from any of SEQ ID NO: 1-3, 140-144, 288, 289, 294, 295, 507, 532, 593, 596, 604, 611; and / or (b) a heavy chain complementarity-determining region 2 (CDR-H2) containing an amino acid sequence selected from any of SEQ ID NO: 4-6, 145-148, 290, 291, 296, 297, 372-374, 513, 551, 594, 597, 605, or 612; and (c) a region containing an amino acid sequence selected from SEQ ID NO: 1-3, 140-144, 288, 289, 294, 295, 507, 532, 593, 596, 604, 611. The heavy chain complementarity-determining region 3 (CDR-H3) of the amino acid sequences of any one of NO: 7-11, 149-157, 279-287, 292, 293, 376-378, 517, 595, 606, 613; and / or V LThe region is or includes (a) a light chain complementarity-determining region 1 (CDR-L1) containing an amino acid sequence selected from any of SEQ ID NO: 26-36, 174-178, 302, 303, 380-392, 394-398, 589, 601, 607 or 614; (b) a light chain complementarity-determining region 2 (CDR-L2) containing an amino acid sequence selected from any of SEQ ID NO: 37-46, 179-183, 304, 305, 399-409, 411-414, 590, 602, 608 or 615; and (c) a light chain complementarity-determining region 3 (CDR-L3) containing an amino acid sequence selected from any of SEQ ID NO: 47-58, 184-194, 306, 307, 415-427, 429-433, 591 or 603.

[0019] In some implementations of any of the polynucleotides described herein, V H The region is or contains (a) a heavy chain complementarity-determining region 1 (CDR-H1) containing an amino acid sequence selected from any of SEQ ID NO: 1, 2, 3, 141, 143, 144, 288, 289, 507, 593, 604, 611; and / or (b) a heavy chain complementarity-determining region 2 (CDR-H2) containing an amino acid sequence selected from any of SEQ ID NO: 4, 5, 6, 145, 147, 148, 290, 291, 372, 513, 594, 605, or 612; and (c) a heavy chain complementarity-determining region 3 (CDR-H3) containing an amino acid sequence selected from any of SEQ ID NO: 7, 8, 9, 10, 149, 153, 154, 155, 156, 157, 292, 293, 376, 517, 595, 606, or 613; and / or V LThe region is or contains (a) a light chain complementarity-determining region 1 (CDR-L1) containing an amino acid sequence selected from any of SEQ ID NO: 26, 27, 28, 30, 31, 33, 34, 174, 176, 177, 178, 302, 303, 380, 381, 382, ​​589, 601, 607, or 614; (b) contains a region selected from SEQ ID NO: 26, 27, 28, 30, 31, 33, 34, 174, 176, 177, 178, 302, 303, 380, 381, 382, ​​589, 601, 607, or 614; NO: Light chain complementarity-determining region 2 (CDR-L2) containing amino acid sequences selected from any of the following: 37, 38, 39, 41, 43, 44, 179, 181, 182, 183, 304, 305, 399, 400, 401, 402, 590, 602, 608, or 615; and (c) Light chain complementarity-determining region 3 (CDR-L3) containing amino acid sequences selected from any of the following: 47, 48, 49, 51, 52, 55, 56, 185, 189, 190, 191, 192, 193, 194, 306, 307, 415, 417, 418, 421, 591, or 603.

[0020] In some implementations of any of the polynucleotides described herein, V HThe region contains CDR-H1, CDR-H2, and CDR-H3 selected from the following: CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:1, 4, and 7, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 5, and 8, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 5, and 9, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 5, and 10, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 6, and 11, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:140, 145, and 149, respectively; and CDR-H3 containing the amino acid sequences of SEQ ID NO:1, 4, and 7, respectively. CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:141, 145, and 149; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:141, 145, and 150; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:142, 146, and 151; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 5, and 152; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:143, 147, and 153; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:144, 148, and 154; and CDR-H3 containing the amino acid sequences of SEQ ID NO:141, 145, and 154. CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 6, and 155; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 5, and 156; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 5, and 157; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 6, and 376; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 6, and 155; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 372, and 376; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 6, and 376;CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 6, and 377, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 373, and 152, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 5, and 378, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 374, and 9, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:593, 594, and 595, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:611, 612, and 613, respectively; and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 6, and 377, respectively. CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 507, 513, and 517; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 604, 605, and 606; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 288, 290, and 292; or CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 289, 291, and 293.

[0021] In some implementations of any of the polynucleotides described herein, V HThe region contains CDR-H1, CDR-H2, and CDR-H3 selected from the following: CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 1, 4, and 7, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 2, 5, and 8, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 2, 5, and 9, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 2, 5, and 10, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 141, 145, and 149, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 143, 147, and 153, respectively; and CDR-H3 containing the amino acid sequences of SEQ ID NO: 1, 4, and 7, respectively. CDR-H1, CDR-H2, and CDR-H3 containing amino acid sequences of SEQ ID NO: 144, 148, and 154; CDR-H1, CDR-H2, and CDR-H3 containing amino acid sequences of SEQ ID NO: 3, 6, and 155; CDR-H1, CDR-H2, and CDR-H3 containing amino acid sequences of SEQ ID NO: 2, 5, and 156; CDR-H1, CDR-H2, and CDR-H3 containing amino acid sequences of SEQ ID NO: 2, 5, and 157; CDR-H1, CDR-H2, and CDR-H3 containing amino acid sequences of SEQ ID NO: 2, 6, and 376; CDR-H1, CDR-H2, and CDR-H3 containing amino acid sequences of SEQ ID NO: 3, 6, and 155; and CDR-H3 containing amino acid sequences of SEQ ID NO: 144, 148, and 154; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 372, and 376; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 6, and 376; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:593, 594, and 595; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:611, 612, and 613; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:507, 513, and 517; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:604, 605, and 606; and CDR-H3 containing the amino acid sequences of SEQ ID NO:604, 605, and 606. CDR-H1, CDR-H2, and CDR-H3 of amino acid sequences NO:288, 290, and 292;Or CDR-H1, CDR-H2, and CDR-H3, respectively, containing the amino acid sequences of SEQ ID NO:289, 291, and 293.

[0022] In some implementations of any of the polynucleotides described herein, V H The region is or includes the amino acid sequence shown in any of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774, or 814-832. In some aspects, V H The region is or includes the amino acid sequence shown in any of SEQ ID NO: 110, 111, 112, 113, 115, 248, 252, 253, 254, 255, 256, 324, 325, 518, 519, 520, 521, 522, 609, or 617. In some embodiments, V H The region contains CDR-H1, CDR-H2, and CDR-H3, respectively, containing the amino acid sequences SEQ ID NO: 593, 594, and 595; or V H The region includes CDR-H1, CDR-H2, and CDR-H3, respectively, containing the amino acid sequences of SEQ ID NO: 611, 612, and 613. In some embodiments, V H The region is or includes the amino acid sequence shown in SEQ ID NO:617.

[0023] In some implementations of any of the polynucleotides described herein, V LThe region includes CDR-L1, CDR-L2, and CDR-L3 selected from the following: CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:26, 37, and 47, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:27, 38, and 48, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:28, 39, and 49, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:29, 40, and 50, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:30, 39, and 51, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:31, 41, and 52, respectively; and CDR-L3 containing the amino acid sequences of SEQ ID NO:26, 37, and 47, respectively. CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO:32, 42, and 53; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO:30, 39, and 54; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO:33, 43, and 55; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO:34, 44, and 56; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO:35, 45, and 57; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO:36, 46, and 58; and CDR-L3 containing amino acid sequences of SEQ ID NO:30, 39, and 54. CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:174, 179, and 184; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:174, 179, and 185; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:174, 179, and 186; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:174, 179, and 187; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:175, 180, and 188; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:174, 179, and 189; and CDR-L3 containing the amino acid sequences of SEQ ID NO:174, 179, and 189. CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences NO:176, 181, and 190;CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 177, 182, and 191, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 174, 179, and 192, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 178, 183, and 193, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 178, 183, and 194, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 30, 399, and 415, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 380, 400, and 416, respectively; and CDR-L3 containing the amino acid sequences of SEQ ID NO: 177, 182, and 191, respectively. CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:33, 43, and 421; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:381, 401, and 417; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:382, 402, and 418; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:383, 403, and 419; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:384, 39, and 54; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:385, 180, and 58; and CDR-L3 containing the amino acid sequences of SEQ ID NO:385, 180, and 58. CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 175, 180, and 188; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 386, 404, and 420; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 387, 405, and 422; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 388, 406, and 423; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 388, 407, and 424; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 389, 408, and 425; and CDR-L3 containing the amino acid sequences of SEQ ID NO: 175, 180, and 188, respectively. CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences NO:390, 183, and 193;CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:391, 409, and 426, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:392, 40, and 427, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:394, 39, and 429, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:395, 411, and 430, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:396, 412, and 431, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:396, 412, and 58, respectively; and CDR-L3 containing the amino acid sequences of SEQ ID NO:394, 39, and 429, respectively. CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:397, 413, and 432; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:398, 414, and 433; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:601, 602, and 603; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:614, 615, and 603; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:589, 590, and 591; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:607, 608, and 591; and CDR-L3 containing the amino acid sequences of SEQ ID NO:607, 608, and 591. CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 302, 304, and 306; or CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 303, 305, and 307, respectively.

[0024] In some implementations of any of the polynucleotides described herein, V LThe region includes CDR-L1, CDR-L2, and CDR-L3 selected from the following: CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:26, 37, and 47, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:27, 38, and 48, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:28, 39, and 49, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:30, 39, and 51, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:31, 41, and 52, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:33, 43, and 55, respectively; and CDR-L3 containing the amino acid sequences of SEQ ID NO:26, 37, and 47, respectively. CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO:34, 44, and 56; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO:174, 179, and 185; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO:174, 179, and 189; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO:176, 181, and 190; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO:177, 182, and 191; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO:174, 179, and 192; and CDR-L3 containing amino acid sequences of SEQ ID NO:34, 44, and 56, respectively. CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 178, 183, and 193; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 178, 183, and 194; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 30, 399, and 415; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 380, 400, and 416; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 33, 43, and 421; and CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 381, 401, and 417.CDR-L1, CDR-L2, and CDR-L3 respectively containing the amino acid sequences of SEQ ID NO:382, 402, and 418; CDR-L1, CDR-L2, and CDR-L3 respectively containing the amino acid sequences of SEQ ID NO:601, 602, and 603; CDR-L1, CDR-L2, and CDR-L3 respectively containing the amino acid sequences of SEQ ID NO:614, 615, and 603; CDR-L1, CDR-L2, and CDR-L3 respectively containing the amino acid sequences of SEQ ID NO:589, 590, and 591; CDR-L1, CDR-L2, and CDR-L3 respectively containing the amino acid sequences of SEQ ID NO:607, 608, and 591; CDR-L1, CDR-L2, and CDR-L3 respectively containing the amino acid sequences of SEQ ID NO:302, 304, and 306; or CDR-L1, CDR-L2, and CDR-L3 respectively containing the amino acid sequences of SEQ ID NO:382, 402, and 418; or CDR-L3 respectively containing the amino acid sequences of SEQ ID NO:302, 304, and 306; CDR-L1, CDR-L2, and CDR-L3 of the amino acid sequences of NO:303, 305, and 307.

[0025] In some of any such implementations, V L The region is or includes the amino acid sequence shown in any of SEQ ID NO: 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777, or 833-849. In some aspects, V L The region is or contains the amino acid sequence shown in any of SEQ ID NO: 116, 117, 118, 120, 121, 124, 125, 258, 262, 263, 264, 265, 266, 267, 326, 327, 534, 535, 536, 537, 538, 610, 618, 775-777, or 833-849.

[0026] In some implementations of any of the polynucleotides described herein, V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, comprising the amino acid sequences of SEQ ID NO: 601, 602, and 603; or V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, comprising the amino acid sequences of SEQ ID NO: 614, 615, and 603. In some cases, V L The region is or includes the amino acid sequence shown in SEQ ID NO:618.

[0027] In some of any implementation schemes, V HThe region is or contains a V that is any one of SEQ ID NO: 617, 110-115, 247-256, 324, 325, 518-531, 533, 609, 772-774 or 814-832. H The region sequence has an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity; and V L The region is or contains a V that is any one of SEQ ID NO: 618, 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 775-777 or 833-849. L The region sequence has an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity.

[0028] In some of any implementation schemes, V H The region is or contains V selected from any one of SEQ ID NO: 617, 110-115, 247-256, 324, 325, 518-531, 533, 609, 772-774 or 814-832. H The region contains CDR-H1, CDR-H2, and CDR-H3 amino acid sequences; and V L The region is or contains V selected from any one of SEQ ID NO: 618, 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 775-777 or 833-849. L The CDR-L1, CDR-L2 and CDR-L3 contained in the amino acid sequence of the region

[0029] In some of any implementation schemes, V H The region is or includes (a) a CDR-H1 containing a sequence selected from any one of SEQ ID NO: 593, 611, 1-3, 140-144, 288, 289, 294, 295, 507, 532, 596, or 604; (b) a CDR-H2 containing a sequence selected from any one of SEQ ID NO: 594, 612, 4-6, 145-148, 290, 291, 296, 297, 372-374, 513, 551, 597, or 605; and (c) a CDR-H3 containing a sequence selected from any one of SEQ ID NO: 595, 613, 7-11, 149-157, 279-287, 292, 293, 376-378, 517, or 606; and V LThe region is or includes (a) a CDR-L1 containing a sequence selected from any one of SEQ ID NO: 601, 614, 26-36, 174-178, 302, 303, 380-392, 394-398, 589 or 607; (b) a CDR-L2 containing a sequence selected from any one of SEQ ID NO: 602, 615, 37-46, 179-183, 304, 305, 399-409, 411-414, 590 or 608; and (c) a CDR-L3 containing a sequence selected from any one of SEQ ID NO: 603, 47-58, 184-194, 306, 307, 415-427, 429-433 or 591.

[0030] In some of any such implementations, V H District and V L The region includes the amino acid sequences shown in SEQ ID NO:110 and 116, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 116, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:111 and 117, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:111 and 117, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:110 and 118, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 118, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:110 and 119, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 119, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:110 and 120, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 120, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO: 110 and 121, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO: 110 and 121, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:110 and 122, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 122, respectively; V HDistrict and V L The region contains the amino acid sequences shown in SEQ ID NO:110 and 123, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 123, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:112 and 124, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:112 and 124, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:113 and 125, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:113 and 125, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:114 and 126, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:114 and 126, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:115 and 127, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:115 and 127, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:247 and 257, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:247 and 257, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:248 and 258, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:248 and 258, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:249 and 259, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:249 and 259, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:250 and 260, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:250 and 260, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:251 and 261, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:251 and 261, respectively; V H District and VL The region contains the amino acid sequences shown in SEQ ID NO:252 and 262, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:252 and 262, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:253 and 263, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:253 and 263, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:254 and 264, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:254 and 264, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:255 and 265, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:255 and 265, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:256 and 266, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:256 and 266, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:256 and 267, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:256 and 267, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:518 and 534, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:518 and 534, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:519 and 535, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:519 and 535, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:115 and 536, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:115 and 536, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:520 and 264, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:520 and 264, respectively; V H District and V LThe region contains the amino acid sequences shown in SEQ ID NO:521 and 537, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:521 and 537, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:522 and 538, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:522 and 538, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:523 and 539, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:523 and 539, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:519 and 540, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:519 and 540, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:524 and 541, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:524 and 541, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:525 and 261, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:525 and 261, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:526 and 542, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:526 and 542, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:527 and 543, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:527 and 543, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:528 and 544, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:528 and 544, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:529 and 545, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:529 and 545, respectively; V H District and V LThe region contains the amino acid sequences shown in SEQ ID NO:528 and 546, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:528 and 546, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:522 and 547, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:522 and 547, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:256 and 548, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:256 and 548, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:530 and 549, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:530 and 549, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:531 and 550, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:531 and 550, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:519 and 552, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:519 and 552, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:110 and 553, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 553, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:110 and 118, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 118, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:533 and 554, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:533 and 554, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:115 and 555, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:115 and 555, respectively; V H District and V LThe region contains the amino acid sequences shown in SEQ ID NO:524 and 556, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:524 and 556, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:519 and 557, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:519 and 557, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:609 and 610, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:609 and 610, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:617 and 618, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:617 and 618, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:324 and 326, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:324 and 326, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:325 and 327, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:325 and 327, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:772 and 775, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:772 and 775, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:773 and 776, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:773 and 776, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:774 and 777, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:774 and 777, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:815 and 833, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:815 and 833, respectively; or V H District and V LThe region contains the amino acid sequences shown in SEQ ID NO:816 and 834, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:816 and 834, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:817 and 835, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:817 and 835, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:818 and 836, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:818 and 836, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:819 and 837, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:819 and 837, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:820 and 838, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:820 and 838, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:821 and 839, respectively, or amino acid sequences that are at least 90% identical to those in SEQ ID NO:821 and 839, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO: 822 and 840, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO: 822 and 840, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:823 and 841, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:823 and 841, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:824 and 842, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:824 and 842, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:825 and 843, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:825 and 843, respectively; or V H District and V LThe region contains the amino acid sequences shown in SEQ ID NO:826 and 844, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:826 and 844, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:827 and 845, respectively, or amino acid sequences that are at least 90% identical to those in SEQ ID NO:827 and 845, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:828 and 846, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:828 and 846, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:829 and 847, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:829 and 847, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:830 and 847, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:830 and 847, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:831 and 848, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:831 and 848, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:832 and 849, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:832 and 849, respectively.

[0031] In some embodiments of any of the polynucleotides described herein, V is encoded by the polynucleotide. H District and V L The region includes the amino acid sequences shown in SEQ ID NO:110 and 116, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 116, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:111 and 117, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:111 and 117, respectively; V H District and V LThe region contains the amino acid sequences shown in SEQ ID NO:110 and 118, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 118, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:110 and 120, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 120, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:110 and 121, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 121, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:112 and 124, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:112 and 124, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:113 and 125, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:113 and 125, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:248 and 258, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:248 and 258, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:252 and 262, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:252 and 262, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:253 and 263, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:253 and 263, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:254 and 264, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:254 and 264, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:255 and 265, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:255 and 265, respectively; V H District and V LThe region contains the amino acid sequences shown in SEQ ID NO:256 and 266, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:256 and 266, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:256 and 267, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:256 and 267, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:518 and 534, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:518 and 534, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:519 and 535, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:519 and 535, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:115 and 536, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:115 and 536, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:520 and 264, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:520 and 264, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:521 and 537, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:521 and 537, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:522 and 538, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:522 and 538, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:609 and 610, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:609 and 610, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:617 and 618, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:617 and 618, respectively; V H District and V LThe region contains the amino acid sequences shown in SEQ ID NO:324 and 326, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:324 and 326, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:325 and 327, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:325 and 327, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:772 and 775, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:772 and 775, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:773 and 776, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:773 and 776, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:774 and 777, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:774 and 777, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:815 and 833, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:815 and 833, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:816 and 834, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:816 and 834, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:817 and 835, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:817 and 835, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:818 and 836, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:818 and 836, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:819 and 837, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:819 and 837, respectively; or V H District and V LThe region contains the amino acid sequences shown in SEQ ID NO:820 and 838, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:820 and 838, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:821 and 839, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:821 and 839, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:822 and 840, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:822 and 840, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO: 823 and 841, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO: 823 and 841, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:824 and 842, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:824 and 842, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:825 and 843, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:825 and 843, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:826 and 844, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:826 and 844, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:827 and 845, respectively, or amino acid sequences that are at least 90% identical to those in SEQ ID NO:827 and 845, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:828 and 846, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:828 and 846, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:829 and 847, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:829 and 847, respectively; or V H District and V LThe region contains the amino acid sequences shown in SEQ ID NO:830 and 847, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:830 and 847, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:831 and 848, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:831 and 848, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:832 and 849, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:832 and 849, respectively.

[0032] In some of any implementation schemes, V H The region is or contains a sequence of any one of SEQ ID NO: 617, 110-115, 247-256, 324, 325, 518-531, 533, 609, 772-774, or 814-832; and V L The region is a sequence that is or contains any of SEQ ID NO: 618, 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 775-777 or 833-849.

[0033] In some embodiments of any of the polynucleotides described herein, the fragment includes scFv. In some embodiments, V H District and V L The regions are connected by flexible joints. In some embodiments, scFv includes a joint containing the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO:361). In some embodiments, V H The area is located in V L The amino terminus of the region.

[0034] In some embodiments of any polynucleotide described herein, the antigen-binding domain comprises an amino acid sequence selected from any of SEQ ID NO: 128-139, 268-278, 329, 442, 478, 558-576, 578-583, 585, or 769-771, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence selected from any of SEQ ID NO: 128-139, 268-278, 329, 442, 478, 558-576, 578-583, 585, or 769-771. In some embodiments, the antigen-binding domain comprises an amino acid sequence selected from any of SEQ ID NO:128-130, 132, 133, 136, 137, 269, 273-278, 329, 442, 478, 558-563, or 585, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence selected from any of SEQ ID NO:128-130, 132, 133, 136, 137, 269, 273-278, 329, 442, 478, 558-563, or 585.

[0035] In some embodiments of any of the polynucleotides described herein, the nucleic acid encoding the antigen-binding domain comprises (a) the nucleotide sequence shown in any of SEQ ID NO:330-352, 647, 648, 716, or 718; (b) a nucleotide sequence having at least 90% sequence identity with any of SEQ ID NO:330-352, 647, 648, 716, or 718; or (c) a degenerate sequence of (a) or (b). In some embodiments, the nucleic acid encoding the antigen-binding domain comprises (a) the nucleotide sequence shown in any of SEQ ID NO:352, 647, 648, 716, or 718; (b) a nucleotide sequence having at least 90% sequence identity with any of SEQ ID NO:352, 647, 648, 716, or 718; or (c) a degenerate sequence of (a) or (b). In some embodiments, the nucleic acid encoding the antigen-binding domain is codon-optimized. In some embodiments, the nucleic acid encoding the antigen-binding domain comprises the nucleotide sequence shown in any one of SEQ ID NO: 440, 460, 715, 717, or 719. In some embodiments, the nucleic acid encoding the antigen-binding domain comprises the nucleotide sequence shown in SEQ ID NO: 460.

[0036] In some implementations of any of the polynucleotides described herein, VH The area is located in V L The carboxyl terminus of the region. In some embodiments, scFv includes the amino acid sequence shown in SEQ ID NO:328 or 586 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence shown in SEQ ID NO:328 or 586.

[0037] Provides a chimeric antigen receptor comprising: (1) an extracellular antigen-binding domain that specifically binds to human B cell maturation antigen (BCMA), wherein the extracellular antigen-binding domain comprises: (i) a V-shaped structure as defined in SEQ ID NO:617. H Variable heavy chains (VLCCs) whose amino acid sequences have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity. H (ii) includes any of the V in SEQ ID NO:618; L A variable light chain (V) whose amino acid sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity. L (1) a region; (2) a spacer as shown in SEQ ID NO:649 or wherein the nucleic acid encoding the spacer is or comprises the sequence shown in SEQ ID NO:622; (3) a transmembrane domain, optionally, a transmembrane domain derived from human CD28; and (4) an intracellular signaling region comprising a cytoplasmic signaling domain of a CD3-ζ (CD3ζ) chain and an intracellular signaling domain of a T cell costimulatory molecule. Polynucleotides encoding such chimeric antigen receptors are also provided. In some of any embodiments, V H The region contains V of SEQ ID NO:617 H The region sequence contains CDR-H1, CDR-H2, and CDR-H3; and V L The region contains V of SEQ ID NO:618 L The CDR-L1, CDR-L2, and CDR-L3 contained within the region sequence; or V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 593, 594, and 595, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 601, 602, and 603; V HThe region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 596, 597, and 595, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 601, 602, and 603; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 598, 599, and 595, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 601, 602, and 603; or V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 611, 612, and 613, and V L The region contains CDR-L1, CDR-L2 and CDR-L3, which respectively contain sequences of SEQ ID NO:614, 615 and 603.

[0038] Provides a chimeric antigen receptor comprising: (1) an extracellular antigen-binding domain that specifically binds to human B cell maturation antigen (BCMA), wherein the extracellular antigen-binding domain comprises: V comprising SEQ ID NO:617 H The variable heavy chains (V) of CDR-H1, CDR-H2 and CDR-H3 contained in the region sequence H ) area; and V containing SEQ ID NO:618 L The variable light chains (V) of CDR-L1, CDR-L2 and CDR-L3 contained in the region sequence L ) area; or V H The region contains V of SEQ ID NO:617 H The region sequence contains CDR-H1, CDR-H2, and CDR-H3; and V L The region contains V of SEQ ID NO:618 L The CDR-L1, CDR-L2, and CDR-L3 contained within the region sequence; or V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 593, 594, and 595, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 601, 602, and 603; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 596, 597, and 595, and VL The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 601, 602, and 603; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 598, 599, and 595, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 601, 602, and 603; or V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 611, 612, and 613, and V L The region comprises CDR-L1, CDR-L2, and CDR-L3, respectively, comprising the sequences of SEQ ID NO:614, 615, and 603; (2) the spacer shown in SEQ ID NO:649, or the nucleic acid encoding the spacer being or comprising the sequence shown in SEQ ID NO:622; (3) a transmembrane domain, optionally, a transmembrane domain derived from human CD28; and (4) an intracellular signaling region comprising a cytoplasmic signaling domain of the human CD3-ζ (CD3ζ) chain and an intracellular signaling domain of human 4-1BB or human CD28. A polynucleotide encoding such a chimeric antigen receptor is also provided. In some of any embodiments, the extracellular antigen-binding domain comprises V of SEQ ID NO:617. H Region sequence and V of SEQ ID NO:618 L Region sequence.

[0039] In some embodiments, the receptor includes any of the antibodies and fragments described herein (including in any of the foregoing embodiments) or an antibody having the provided VH / VL or CDR sequence combination binding to the same or substantially the same epitope on BCMA or competing for binding to the antigen-binding domain of BCMA. In some embodiments, the binding domain recognizes an epitope comprising a portion of one or more amino acid sequences within the BCMA polypeptide. In some aspects, such one or more amino acid sequences are or comprise: MLMAG (SEQ ID NO: 640), YFDSL (SEQ ID NO: 779), and QLRCSSNTPPL (SEQ ID NO: 642). In some aspects, such one or more amino acid sequences are or comprise: MLMAG (SEQ ID NO: 640), YFDSLL (SEQ ID NO: 641), and QLRCSSNTPPL (SEQ ID NO: 642). In some aspects, such one or more amino acid sequences are or include: MLMAG (SEQ ID NO: 640), QNEYFDSLL (SEQ ID NO: 780), and QLRCSSNTPPL (SEQ ID NO: 642). In some aspects, such one or more amino acid sequences are or include: QNEYF (SEQ ID NO: 637), CIPCQL (SEQ ID NO: 638), and CQRYC (SEQ ID NO: 639). In some aspects, such one or more amino acid sequences are or include: CSQNEYF (shown in SEQ ID NO: 410) and LLHACIPCQLR (shown in SEQ ID NO: 428).

[0040] In some embodiments of any of the polynucleotides described herein, the intracellular signaling domain includes an activating cytoplasmic signaling domain. In some embodiments, the activating cytoplasmic signaling domain is capable of inducing a primary activation signal in T cells, is a T cell receptor (TCR) component, and / or includes an immune receptor tyrosine-based activation motif (ITAM). In some embodiments, the activating cytoplasmic signaling domain is or includes a cytoplasmic signaling domain of the ζ chain of the CD3-ζ (CD3ζ) chain, or a functional variant or signaling portion thereof. In some embodiments, the activating cytoplasmic domain is a human or human-derived protein. In some embodiments, the activating cytoplasmic domain is or includes the sequence shown in SEQ ID NO:628 or an amino acid sequence having at least 90% sequence identity with SEQ ID NO:628.

[0041] In some embodiments of any of the polynucleotides described herein, the nucleic acid encoding the activating cytoplasmic domain is or includes the sequence shown in SEQ ID NO:627 or its codon-optimized and / or degenerate sequence. In other embodiments, the nucleic acid encoding the activating cytoplasmic signaling domain is or includes the sequence shown in SEQ ID NO:652.

[0042] In some embodiments of any of the polynucleotides described herein, the intracellular signaling region further includes a co-stimulatory signaling region. In some embodiments, the co-stimulatory signaling region includes an intracellular signaling domain of a T-cell co-stimulatory molecule or a signaling portion thereof. In some embodiments, the co-stimulatory signaling region includes an intracellular signaling domain of CD28, 4-1BB, or ICOS or a signaling portion thereof. In some embodiments, the co-stimulatory signaling region includes an intracellular signaling domain of 4-1BB. In some embodiments, the co-stimulatory signaling region is a human or human-derived protein. In other embodiments, the co-stimulatory signaling region is or includes the sequence shown in SEQ ID NO:626 or an amino acid sequence exhibiting at least 90% sequence identity with the sequence shown in SEQ ID NO:626.

[0043] In some embodiments of any of the polynucleotides described herein, the nucleic acid encoding the co-stimulatory region is or includes the sequence shown in SEQ ID NO:625 or its codon-optimized and / or degenerate sequence. In some embodiments, the nucleic acid encoding the co-stimulatory signal transduction region includes the sequence shown in SEQ ID NO:681. In some embodiments, the co-stimulatory signal transduction region is located between the transmembrane domain and the intracellular signal transduction region. In some embodiments, the transmembrane domain is or includes a transmembrane domain derived from CD4, CD28, or CD8. In some embodiments, the transmembrane domain is or includes a transmembrane domain derived from CD28. In some embodiments, the transmembrane domain is human or derived from human proteins. In other embodiments, the transmembrane domain is or includes the sequence shown in SEQ ID NO:624 or an amino acid sequence exhibiting at least 90% sequence identity with SEQ ID NO:624.

[0044] In some embodiments of any of the polynucleotides described herein, the nucleic acid encoding the transmembrane domain is or includes the sequence shown in SEQ ID NO:623 or its codon-optimized and / or degenerate sequence. In some embodiments, the nucleic acid encoding the transmembrane domain includes the sequence shown in SEQ ID NO:688. In some embodiments of any of the polynucleotides described herein, the encoded chimeric antigen receptor comprises, from its N-terminus to its C-terminus, an antigen-binding domain, a spacer, a transmembrane domain, and an intracellular signal transduction domain.

[0045] In some of any embodiments, the polynucleotide comprises a sequence shown in any of SEQ ID NO:751-756 or a sequence showing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with a sequence shown in any of SEQ ID NO:751-756, and the encoded receptor retains its function of binding to BCMA and retains reduced RNA heterogeneity. In some of any embodiments, the polynucleotide comprises a sequence shown in any of SEQ ID NO: 755 and 756 or a sequence showing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the sequence shown in any of SEQ ID NO: 755, and the encoded receptor retains its BCMA-binding function and retains reduced RNA heterogeneity. In some of any embodiments, the polynucleotide comprises a sequence shown in SEQ ID NO: 755 or a sequence showing at least or at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the sequence shown in SEQ ID NO: 755, and the encoded receptor retains its BCMA-binding function and retains reduced RNA heterogeneity. In some of any embodiments, the polynucleotide comprises the sequence shown in SEQ ID NO:755, and the encoded receptor retains its function of binding to BCMA and retains reduced RNA heterogeneity.

[0046] In some implementations, the polynucleotide further encodes a truncated receptor.

[0047] Vectors comprising any of the polynucleotides described herein are also provided. In some embodiments, the vector is a viral vector. In some embodiments, the viral vector is a retroviral vector. In some embodiments, the viral vector is a lentiviral vector.

[0048] In some aspects, a chimeric antigen receptor encoded by any embodiment described herein is provided. In some embodiments, the chimeric antigen receptor includes: (a) an extracellular antigen-binding domain that specifically recognizes B cell maturation antigen (BCMA); (b) a spacer of at least 125 amino acids in length; (c) a transmembrane domain; and (d) an intracellular signal transduction region.

[0049] In some embodiments of any of the chimeric antigen receptors described herein, the spacer is derived from an immunoglobulin. In some embodiments, the spacer includes a hinge region, C... H 2 and CH The sequence of region 3. In some embodiments of any chimeric antigen receptor described herein, the hinge, C H 2 and C H One or more of the three components are wholly or partially derived from IgG4 or IgG2. In some implementations, the hinge, C... H 2 and C H 3 is derived from IgG4. In some implementations, the hinge, C H 2 and C H One or more of the three sequences are chimeric and include sequences derived from IgG4 and IgG2. In some embodiments, the spacer contains an IgG4 / 2 chimeric hinge and an IgG2 / 4C... H 2 and IgG4 C H Zone 3.

[0050] In some embodiments of any of the chimeric antigen receptors described herein, the spacer is or includes (i) the sequence shown in SEQ ID NO:649; (ii) a functional variant of SEQ ID NO:649 having at least 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO:649; or (iii) a continuous portion of (i) or (ii) of at least 125 amino acids in length. In some embodiments, the encoded spacer is or includes the sequence shown in SEQ ID NO:649.

[0051] In other respects, chimeric antigen receptors are provided, comprising (a) an extracellular antigen-binding domain that specifically recognizes B cell maturation antigen (BCMA); (b) a spacer as shown in SEQ ID NO:649; (c) a transmembrane domain; and (d) an intracellular signaling region. In some embodiments of any chimeric antigen receptor described herein, the antigen-binding domain is containing a variable heavy chain (V... H ) and variable light chains (V L Antibody fragments in the region )

[0052] In some embodiments of any chimeric antigen receptor described herein, V H The region is or includes the V shown in any of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774, or 814-832. H The amino acid sequence of the region has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity; and / or V LThe region is or includes the V shown in any of SEQ ID NO: 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777 or 833-849. L The amino acid sequence of the region has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity.

[0053] In some embodiments of any chimeric antigen receptor described herein, V H The region is or includes the V shown in any of SEQ ID NO: 110, 111, 112, 113, 115, 248, 252, 253, 254, 255, 256, 324, 325, 518, 519, 520, 521, 522, 609, 617, 772-774, or 814-832. H The amino acid sequence of the region has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity; and / or V L The region is or includes the V shown in any of SEQ ID NO: 116, 117, 118, 120, 121, 124, 125, 258, 262, 263, 264, 265, 266, 267, 326, 327, 534, 535, 536, 537, 538, 610, 618, 775-777, or 833-849. L The amino acid sequence of the region has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity.

[0054] In some embodiments of any chimeric antigen receptor described herein, V H The region is or includes V selected from any one of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774 or 814-832. H The region contains CDR-H1, CDR-H2, and CDR-H3 within its amino acid sequence; and / or V L The region is or includes V selected from any one of SEQ ID NO: 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777 or 833-849. L The amino acid sequence of the region contains CDR-L1, CDR-L2 and CDR-L3.

[0055] In some embodiments of any chimeric antigen receptor described herein, V H The region is or includes V selected from any one of SEQ ID NO: 110, 111, 112, 113, 115, 248, 252, 253, 254, 255, 256, 324, 325, 518, 519, 520, 521, 522, 609, 617, 772-774, or 814-832. H The region contains CDR-H1, CDR-H2, and CDR-H3 within its amino acid sequence; and / or V L The region is or includes V selected from any one of SEQ ID NO: 116, 117, 118, 120, 121, 124, 125, 258, 262, 263, 264, 265, 266, 267, 326, 327, 534, 535, 536, 537, 538, 610, 618, 775-777, or 833-849. L The amino acid sequence of the region contains CDR-L1, CDR-L2 and CDR-L3.

[0056] In some embodiments of any chimeric antigen receptor described herein, V H The region is or includes (a) a heavy chain complementarity-determining region 1 (CDR-H1) containing an amino acid sequence selected from any of SEQ ID NO: 1-3, 140-144, 288, 289, 294, 295, 507, 532, 593, 596, 604, 611; and / or (b) a heavy chain complementarity-determining region 2 (CDR-H2) containing an amino acid sequence selected from any of SEQ ID NO: 4-6, 145-148, 290, 291, 296, 297, 372-374, 513, 551, 594, 597, 605, 612; and (c) a region containing an amino acid sequence selected from SEQ ID NO: 1-3, 140-144, 288, 289, 294, 295, 507, 532, 593, 596, 604, 611. The heavy chain complementarity-determining region 3 (CDR-H3) of the amino acid sequences of any one of NO: 7-11, 149-157, 279-287, 292, 293, 376-378, 517, 595, 606, 613; and / or V LThe region is or includes (a) a light chain complementarity-determining region 1 (CDR-L1) containing an amino acid sequence selected from any of SEQ ID NO: 26-36, 174-178, 302, 303, 380-392, 394-398, 589, 601, 607 or 614; (b) a light chain complementarity-determining region 2 (CDR-L2) containing an amino acid sequence selected from any of SEQ ID NO: 37-46, 179-183, 304, 305, 399-409, 411-414, 590, 602, 608 or 615; and (c) a light chain complementarity-determining region 3 (CDR-L3) containing an amino acid sequence selected from any of SEQ ID NO: 47-58, 184-194, 306, 307, 415-427, 429-433, 591 or 603.

[0057] In some embodiments of any chimeric antigen receptor described herein, V H The region is or includes (a) a heavy chain complementarity-determining region 1 (CDR-H1) containing an amino acid sequence selected from any of SEQ ID NO: 1, 2, 3, 141, 143, 144, 288, 289, 507, 593, 604, 611; and / or (b) a heavy chain complementarity-determining region 2 (CDR-H2) containing an amino acid sequence selected from any of SEQ ID NO: 4, 5, 6, 145, 147, 148, 290, 291, 372, 513, 594, 605, or 612; and (c) a heavy chain complementarity-determining region 3 (CDR-H3) containing an amino acid sequence selected from any of SEQ ID NO: 7, 8, 9, 10, 149, 153, 154, 155, 156, 157, 292, 293, 376, 517, 595, 606, or 613; and / or V LThe region is or includes (a) a light chain complementarity-determining region 1 (CDR-L1) containing an amino acid sequence selected from any of SEQ ID NO: 26, 27, 28, 30, 31, 33, 34, 174, 176, 177, 178, 302, 303, 380, 381, 382, ​​589, 601, 607, or 614; (b) a light chain complementarity-determining region 2 (CDR-L2) containing an amino acid sequence selected from any of SEQ ID NO: 37, 38, 39, 41, 43, 44, 179, 181, 182, 183, 304, 305, 399, 400, 401, 402, 590, 602, 608, or 615; and (c) a region containing an amino acid sequence selected from SEQ ID NO: 26, 27, 28, 30, 31, 33, 34, 174, 176, 177, 178, 302, 303, 380, 381, 382, ​​589, 602, 608, or 615. The light chain complementarity-determining region 3 (CDR-L3) of any of the amino acid sequences of NO: 47, 48, 49, 51, 52, 55, 56, 185, 189, 190, 191, 192, 193, 194, 306, 307, 415, 417, 418, 421, 591, or 603. In some embodiments of any chimeric antigen receptor described herein, V HThe region includes CDR-H1, CDR-H2, and CDR-H3 selected from the following: CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:1, 4, and 7, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 5, and 8, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 5, and 9, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 5, and 10, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 6, and 11, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:140, 145, and 149, respectively; and CDR-H3 containing the amino acid sequences of SEQ ID NO:1, 4, and 7, respectively. CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:141, 145, and 149; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:141, 145, and 150; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:142, 146, and 151; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 5, and 152; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:143, 147, and 153; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:144, 148, and 154; and CDR-H3 containing the amino acid sequences of SEQ ID NO:141, 145, and 154. CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 6, and 155; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 5, and 156; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 5, and 157; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 6, and 376; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 6, and 155; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 372, and 376; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 6, and 376;CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 6, and 377, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 373, and 152, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 5, and 378, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 374, and 9, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:593, 594, and 595, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:611, 612, and 613, respectively; and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 6, and 377, respectively. CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 507, 513, and 517; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 604, 605, and 606; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 288, 290, and 292; or CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 289, 291, and 293.

[0058] In some embodiments of any chimeric antigen receptor described herein, V HThe region includes CDR-H1, CDR-H2, and CDR-H3 selected from the following: CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 1, 4, and 7 respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 2, 5, and 8 respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 2, 5, and 9 respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 2, 5, and 10 respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 141, 145, and 149 respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO: 143, 147, and 153 respectively; and CDR-H3 containing the amino acid sequences of SEQ ID NO: 1, 4, and 7 respectively. CDR-H1, CDR-H2, and CDR-H3 containing amino acid sequences of SEQ ID NO: 144, 148, and 154; CDR-H1, CDR-H2, and CDR-H3 containing amino acid sequences of SEQ ID NO: 3, 6, and 155; CDR-H1, CDR-H2, and CDR-H3 containing amino acid sequences of SEQ ID NO: 2, 5, and 156; CDR-H1, CDR-H2, and CDR-H3 containing amino acid sequences of SEQ ID NO: 2, 5, and 157; CDR-H1, CDR-H2, and CDR-H3 containing amino acid sequences of SEQ ID NO: 2, 6, and 376; CDR-H1, CDR-H2, and CDR-H3 containing amino acid sequences of SEQ ID NO: 3, 6, and 155; and CDR-H3 containing amino acid sequences of SEQ ID NO: 144, 148, and 154, respectively. CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 372, and 376; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 6, and 376; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:593, 594, and 595; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:611, 612, and 613; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:507, 513, and 517; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:604, 605, and 606; and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 6, and 376, respectively. CDR-H1, CDR-H2, and CDR-H3 of amino acid sequences NO:288, 290, and 292;Or CDR-H1, CDR-H2, and CDR-H3, respectively, containing the amino acid sequences of SEQ ID NO:289, 291, and 293.

[0059] In some embodiments of any chimeric antigen receptor described herein, V H The region is or includes the amino acid sequence shown in any of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774, or 814-832. In some embodiments of any chimeric antigen receptor described herein, V H The region is or includes the amino acid sequence shown in any of SEQ ID NO: 110, 111, 112, 113, 115, 248, 252, 253, 254, 255, 256, 324, 325, 518, 519, 520, 521, 522, 609, 617, 772-774, or 814-832. In some embodiments, V H The region includes CDR-H1, CDR-H2, and CDR-H3, respectively, containing the amino acid sequences of SEQ ID NO: 593, 594, and 595; or V H The region includes CDR-H1, CDR-H2, and CDR-H3, respectively, containing the amino acid sequences of SEQ ID NO: 611, 612, and 613. In some embodiments, V H The region is or includes the amino acid sequence shown in SEQ ID NO:617.

[0060] In some embodiments of any chimeric antigen receptor described herein, V LThe region includes CDR-L1, CDR-L2, and CDR-L3 selected from the following: CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:26, 37, and 47, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:27, 38, and 48, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:28, 39, and 49, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:29, 40, and 50, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:30, 39, and 51, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:31, 41, and 52, respectively; and CDR-L3 containing the amino acid sequences of SEQ ID NO:26, 37, and 47, respectively. CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO:32, 42, and 53; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO:30, 39, and 54; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO:33, 43, and 55; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO:34, 44, and 56; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO:35, 45, and 57; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO:36, 46, and 58; and CDR-L3 containing amino acid sequences of SEQ ID NO:30, 39, and 54. CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:174, 179, and 184; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:174, 179, and 185; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:174, 179, and 186; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:174, 179, and 187; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:175, 180, and 188; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:174, 179, and 189; and CDR-L3 containing the amino acid sequences of SEQ ID NO:174, 179, and 189. CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences NO:176, 181, and 190;CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 177, 182, and 191, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 174, 179, and 192, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 178, 183, and 193, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 178, 183, and 194, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 30, 399, and 415, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 380, 400, and 416, respectively; and CDR-L3 containing the amino acid sequences of SEQ ID NO: 177, 182, and 191, respectively. CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:33, 43, and 421; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:381, 401, and 417; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:382, 402, and 418; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:383, 403, and 419; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:384, 39, and 54; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:385, 180, and 58; and CDR-L3 containing the amino acid sequences of SEQ ID NO:385, 180, and 58. CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO: 175, 180, and 188; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO: 386, 404, and 420; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO: 387, 405, and 422; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO: 388, 406, and 423; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO: 388, 407, and 424; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO: 389, 408, and 425; and CDR-L3 containing amino acid sequences of SEQ ID NO: 175, 180, and 188, respectively. CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences NO:390, 183, and 193;CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:391, 409, and 426, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:392, 40, and 427, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:394, 39, and 429, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:395, 411, and 430, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:396, 412, and 431, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:396, 412, and 58, respectively; and CDR-L3 containing the amino acid sequences of SEQ ID NO:394, 39, and 429, respectively. CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:397, 413, and 432; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:398, 414, and 433; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:601, 602, and 603; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:614, 615, and 603; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:589, 590, and 591; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:607, 608, and 591; and CDR-L3 containing the amino acid sequences of SEQ ID NO:607, 608, and 591. CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences NO:302, 304, and 306; or CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO:303, 305, and 307, respectively.

[0061] In some embodiments of any chimeric antigen receptor described herein, V LThe region includes CDR-L1, CDR-L2, and CDR-L3 selected from the following: CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:26, 37, and 47, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:27, 38, and 48, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:28, 39, and 49, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:30, 39, and 51, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:31, 41, and 52, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO:33, 43, and 55, respectively; and CDR-L3 containing the amino acid sequences of SEQ ID NO:26, 37, and 47, respectively. CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO: 34, 44, and 56; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO: 174, 179, and 185; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO: 174, 179, and 189; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO: 176, 181, and 190; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO: 177, 182, and 191; CDR-L1, CDR-L2, and CDR-L3 containing amino acid sequences of SEQ ID NO: 174, 179, and 192; and CDR-L3 containing amino acid sequences of SEQ ID NO: 34, 44, and 56, respectively. CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 178, 183, and 193; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 178, 183, and 194; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 30, 399, and 415; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 380, 400, and 416; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 33, 43, and 421; and CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 381, 401, and 417.CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 382, ​​402, and 418, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 601, 602, and 603, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 614, 615, and 603, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 589, 590, and 591, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 607, 608, and 591, respectively; CDR-L1, CDR-L2, and CDR-L3 containing the amino acid sequences of SEQ ID NO: 302, 304, and 306, respectively; or containing the amino acid sequences of SEQ ID NO: 382, ​​402, and 418, respectively. CDR-L1, CDR-L2, and CDR-L3 of the amino acid sequences of NO:303, 305, and 307.

[0062] In some embodiments of any chimeric antigen receptor described herein, V L The region is or includes the amino acid sequence shown in any of SEQ ID NO: 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777, or 833-849. In some embodiments of any chimeric antigen receptor described herein, V L The region is or includes the amino acid sequence shown in any of SEQ ID NO: 116, 117, 118, 120, 121, 124, 125, 258, 262, 263, 264, 265, 266, 267, 326, 327, 534, 535, 536, 537, 538, 610, 618, 775-777, or 833-849.

[0063] In some embodiments of any chimeric antigen receptor described herein, V L The region includes CDR-L1, CDR-L2, and CDR-L3, respectively, containing the amino acid sequences of SEQ ID NO: 601, 602, and 603; or V L The region includes CDR-L1, CDR-L2 and CDR-L3, which respectively contain the amino acid sequences of SEQ ID NO: 614, 615 and 603.

[0064] In some embodiments of any chimeric antigen receptor described herein, V LThe region is or includes the amino acid sequence shown in SEQ ID NO:618. In some embodiments of any of the chimeric antigen receptors described herein, V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:110 and 116, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 116, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:111 and 117, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:111 and 117, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:110 and 118, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 118, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:110 and 119, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 119, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:110 and 120, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 120, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:110 and 121, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 121, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:110 and 122, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 122, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:110 and 123, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 123, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:112 and 124, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:112 and 124, respectively; V H District and V LThe region contains the amino acid sequences shown in SEQ ID NO: 113 and 125, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO: 113 and 125, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:114 and 126, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:114 and 126, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO: 115 and 127, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO: 115 and 127, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:247 and 257, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:247 and 257, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:248 and 258, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:248 and 258, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:249 and 259, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:249 and 259, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:250 and 260, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:250 and 260, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:251 and 261, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:251 and 261, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:252 and 262, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:252 and 262, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:253 and 263, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:253 and 263, respectively; V H District and V LThe region contains the amino acid sequences shown in SEQ ID NO:254 and 264, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:254 and 264, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:255 and 265, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:255 and 265, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:256 and 266, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:256 and 266, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:256 and 267, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:256 and 267, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:518 and 534, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:518 and 534, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:519 and 535, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:519 and 535, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:115 and 536, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:115 and 536, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:520 and 264, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:520 and 264, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:521 and 537, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:521 and 537, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:522 and 538, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:522 and 538, respectively; V H District and V LThe region contains the amino acid sequences shown in SEQ ID NO:523 and 539, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:523 and 539, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:519 and 540, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:519 and 540, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:524 and 541, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:524 and 541, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:525 and 261, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:525 and 261, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:526 and 542, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:526 and 542, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:527 and 543, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:527 and 543, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:528 and 544, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:528 and 544, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:529 and 545, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:529 and 545, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:528 and 546, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:528 and 546, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:522 and 547, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:522 and 547, respectively; V H District and V LThe region contains the amino acid sequences shown in SEQ ID NO:256 and 548, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:256 and 548, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:530 and 549, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:530 and 549, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:531 and 550, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:531 and 550, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:519 and 552, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:519 and 552, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:110 and 553, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 553, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:110 and 118, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:110 and 118, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:533 and 554, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:533 and 554, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:115 and 555, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:115 and 555, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:524 and 556, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:524 and 556, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:519 and 557, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:519 and 557, respectively; V H District and V LThe region contains the amino acid sequences shown in SEQ ID NO:609 and 610, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:609 and 610, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:617 and 618, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:617 and 618, respectively; V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:324 and 326, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:324 and 326, respectively; or V H District and V L The region contains the amino acid sequences shown in SEQ ID NO:325 and 327, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO:325 and 327, respectively.

[0065] In some embodiments of any chimeric antigen receptor described herein, the VH and VL regions contain the amino acid sequences shown in SEQ ID NO: 110 and 116, respectively, or amino acid sequences having at least 90% identity with SEQ ID NO: 110 and 116, respectively; the VH and VL regions contain the amino acid sequences shown in SEQ ID NO: 111 and 117, respectively, or amino acid sequences having at least 90% identity with SEQ ID NO: 111 and 117, respectively; the VH and VL regions contain the amino acid sequences shown in SEQ ID NO: 110 and 118, respectively, or amino acid sequences having at least 90% identity with SEQ ID NO: 110 and 118, respectively; the VH and VL regions contain the amino acid sequences shown in SEQ ID NO: 110 and 120, respectively, or amino acid sequences having at least 90% identity with SEQ ID NO: 110 and 120, respectively; the VH and VL regions contain the amino acid sequences shown in SEQ ID NO: 110 and 121, respectively, or amino acid sequences having at least 90% identity with SEQ ID NO: 110 and 121, respectively. The amino acid sequences NO:110 and 121 have at least 90% identity; the VH and VL regions contain the amino acid sequences shown in SEQ ID NO:112 and 124 respectively, or amino acid sequences with at least 90% identity to SEQ ID NO:112 and 124 respectively; the VH and VL regions contain the amino acid sequences shown in SEQ ID NO:113 and 125 respectively, or amino acid sequences with at least 90% identity to SEQ ID NO:113 and 125 respectively; the VH and VL regions contain the amino acid sequences shown in SEQ ID NO:248 and 258 respectively, or amino acid sequences with at least 90% identity to SEQ ID NO:248 and 258 respectively; the VH and VL regions contain the amino acid sequences shown in SEQ ID NO:252 and 262 respectively, or amino acid sequences with at least 90% identity to SEQ ID NO:252 and 262 respectively; the VH and VL regions contain the amino acid sequences shown in SEQ ID NO:253 and 263 respectively, or amino acid sequences with at least 90% identity to SEQ ID NO:252 and 262 respectively; NO:253 and 263 have amino acid sequences with at least 90% identity; the VH and VL regions contain amino acid sequences shown in SEQ ID NO:254 and 264 respectively, or amino acid sequences with at least 90% identity with SEQ ID NO:254 and 264 respectively; the VH and VL regions contain amino acid sequences shown in SEQ ID NO:255 and 265 respectively, or amino acid sequences with at least 90% identity with SEQ ID NO:255 and 265 respectively; the VH and VL regions contain amino acid sequences shown in SEQ ID NO:256 and 266 respectively, or amino acid sequences with at least 90% identity with SEQ ID NO:256 and 266 respectively;The VH and VL regions contain the amino acid sequences shown in SEQ ID NO: 256 and 267, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO: 256 and 267, respectively; the VH and VL regions contain the amino acid sequences shown in SEQ ID NO: 518 and 534, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO: 518 and 534, respectively; the VH and VL regions contain the amino acid sequences shown in SEQ ID NO: 519 and 535, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO: 519 and 535, respectively; the VH and VL regions contain the amino acid sequences shown in SEQ ID NO: 115 and 536, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO: 115 and 536, respectively; the VH and VL regions contain the amino acid sequences shown in SEQ ID NO: 520 and 264, respectively, or amino acid sequences that are at least 90% identical to SEQ ID NO: 256 and 267, respectively. The amino acid sequences NO:520 and 264 have at least 90% identity; the VH and VL regions contain the amino acid sequences shown in SEQ ID NO:521 and 537 respectively, or amino acid sequences with at least 90% identity to SEQ ID NO:521 and 537 respectively; the VH and VL regions contain the amino acid sequences shown in SEQ ID NO:522 and 538 respectively, or amino acid sequences with at least 90% identity to SEQ ID NO:522 and 538 respectively; the VH and VL regions contain the amino acid sequences shown in SEQ ID NO:609 and 610 respectively, or amino acid sequences with at least 90% identity to SEQ ID NO:609 and 610 respectively; the VH and VL regions contain the amino acid sequences shown in SEQ ID NO:617 and 618 respectively, or amino acid sequences with at least 90% identity to SEQ ID NO:617 and 618 respectively; the VH and VL regions contain the amino acid sequences shown in SEQ ID NO:324 and 326 respectively, or amino acid sequences with at least 90% identity to SEQ ID NO:617 and 618 respectively; SEQ ID NO:324 and 326 have amino acid sequences with at least 90% identity; or the VH and VL regions contain the amino acid sequences shown in SEQ ID NO:325 and 327, respectively, or amino acid sequences with at least 90% identity to SEQ ID NO:325 and 327, respectively.

[0066] In some embodiments of any chimeric antigen receptor described herein, the fragment includes scFv. In some embodiments, V H District and V L The regions are connected by flexible joints. In some embodiments, scFv includes a joint containing the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO:361). In some embodiments, VH The area is located in V L The amino terminus of the region.

[0067] In some embodiments of any chimeric antigen receptor described herein, the antigen-binding domain comprises an amino acid sequence selected from any of SEQ ID NO:128-139, 268-278, 329, 442, 478, 558-576, 578-583, 585, or 769-771, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence selected from any of SEQ ID NO:128-139, 268-278, 329, 442, 478, 558-576, 578-583, 585, or 769-771. In some embodiments, the antigen-binding domain comprises an amino acid sequence selected from any of SEQ ID NO: 128-130, 132, 133, 136, 137, 269, 273-278, 329, 442, 478, 558-563, or 585, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence selected from any of SEQ ID NO: 128-130, 132, 133, 136, 137, 269, 273-278, 329, 442, 478, 558-563, or 585.

[0068] In some embodiments of any of the chimeric antigen receptors described herein, the VH region is located at the carboxyl terminus of the VL region. In some embodiments, the scFv comprises the amino acid sequence shown in SEQ ID NO:328 or 586, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence shown in SEQ ID NO:328 or 586.

[0069] In some embodiments of any chimeric antigen receptor described herein, the intracellular signaling domain includes an activating cytoplasmic signaling domain. In some embodiments of any chimeric antigen receptor described herein, the activating cytoplasmic signaling domain is capable of inducing primary activation signals in T cells, is a T cell receptor (TCR) component, and / or includes an immune receptor tyrosine-based activation motif (ITAM). In some embodiments, the activating cytoplasmic signaling domain is or includes a cytoplasmic signaling domain of the ζ chain of the CD3-ζ (CD3ζ) chain, or a functional variant or signaling portion thereof. In some embodiments, the activating cytoplasmic domain is a human or human-derived protein. In some embodiments, the activating cytoplasmic domain is or includes the sequence shown in SEQ ID NO:628 or an amino acid sequence having at least 90% sequence identity with SEQ ID NO:628.

[0070] In some embodiments of any of the chimeric antigen receptors described herein, the intracellular signaling region further includes a co-stimulatory signaling region. In some embodiments, the co-stimulatory signaling region includes an intracellular signaling domain of a T-cell co-stimulatory molecule or a signaling portion thereof. In some embodiments, the co-stimulatory signaling region includes an intracellular signaling domain of CD28, 4-1BB, or ICOS or a signaling portion thereof. In some embodiments, the co-stimulatory signaling region includes an intracellular signaling domain of 4-1BB. In some embodiments, the co-stimulatory signaling region is human or derived from a human protein. In some embodiments, the co-stimulatory signaling region is or includes the sequence shown in SEQ ID NO:626 or an amino acid sequence exhibiting at least 90% sequence identity with the sequence shown in SEQ ID NO:626. In some embodiments, the co-stimulatory signaling region is located between a transmembrane domain and an intracellular signaling region. In some embodiments, the transmembrane domain is or includes a transmembrane domain derived from CD4, CD28, or CD8. In some embodiments, the transmembrane domain is or includes a transmembrane domain derived from CD28. In some embodiments, the transmembrane domain is human or derived from a human protein. In some embodiments of any chimeric antigen receptor described herein, the transmembrane domain is or includes the sequence shown in SEQ ID NO:624 or an amino acid sequence exhibiting at least 90% sequence identity with SEQ ID NO:624.

[0071] In some embodiments of any chimeric antigen receptor described herein, the encoded chimeric antigen receptor comprises, from its N-terminus to its C-terminus, an antigen-binding domain, a spacer, a transmembrane domain, and an intracellular signal transduction domain.

[0072] In some of any embodiments, the chimeric antigen receptor is encoded by a polynucleotide sequence comprising a sequence shown in any of SEQ ID NO:751-756 or a sequence showing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with any of the sequences shown in any of SEQ ID NO:755-756. In some of any embodiments, the chimeric antigen receptor is encoded by a polynucleotide sequence comprising a sequence shown in any of SEQ ID NO:755 and 756 or a sequence showing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with any of the sequences shown in any of SEQ ID NO:755 and 756. In some of any embodiments, the chimeric antigen receptor is encoded by a polynucleotide sequence comprising the sequence shown in SEQ ID NO:755 or a sequence exhibiting at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with it. In some of any embodiments, the chimeric antigen receptor is encoded by a polynucleotide sequence comprising the sequence shown in SEQ ID NO:755.

[0073] In some embodiments, engineered cells are provided that contain the polynucleotides of any of the embodiments described herein. In some embodiments of any of the engineered cells described herein, the engineered cells contain the chimeric antigen receptor of any of the embodiments described herein.

[0074] In some embodiments of any of the engineered cells described herein, the cell is an immune cell. In some embodiments, the immune cell is a primary cell derived from an individual. In some embodiments, the immune cell is an NK cell or a T cell. In some embodiments, the immune cell is a T cell, and the T cell is a CD4+ and / or CD8+ T cell.

[0075] In some embodiments of any of the engineered cells described herein, the cells contain transtranscribed RNA (optionally, messenger RNA (mRNA)) encoding a chimeric antigen receptor, which exhibits at least 70%, 75%, 80%, 85%, 90%, or 95% RNA homogeneity. In some embodiments, the cells contain transtranscribed RNA (optionally, messenger RNA (mRNA)) encoding a chimeric antigen receptor, which exhibits reduced heterogeneity compared to transtranscribed mRNA in cells encoding a reference chimeric antigen receptor containing the same amino acid sequence as the chimeric antigen receptor, but encoded by a different polynucleotide sequence containing one or more nucleotide differences in the polynucleotide encoding such a CAR, and / or wherein the reference chimeric antigen receptor is encoded by a polynucleotide containing one or more splice donor sites and / or one or more splice acceptor sites in the nucleic acid encoding a spacer. In some embodiments, RNA heterogeneity is reduced by more than or equal to about 10%, 15%, 20%, 25%, 30%, 40%, 50%, or more than 50%. In some embodiments, the cell encoding the reference CAR includes a transcribed RNA (optionally, messenger RNA (mRNA)) encoding the reference CAR, which exhibits RNA heterogeneity of more than or equal to about 10%, 15%, 20%, 25%, 30%, 40%, 50%, or more than 50%. In some embodiments, RNA homogeneity and / or heterogeneity are determined by agarose gel electrophoresis, chip-based capillary electrophoresis, analytical ultracentrifugation, field flow fractionation, or liquid chromatography.

[0076] In some embodiments of any of the engineered cells described herein, less than or less than about 10%, 9%, 8%, 7%, 5%, 4%, 3%, 2%, or 1% of the engineered cells contain chimeric antigen receptors exhibiting tonic signaling and / or antigen-independent activity or signaling.

[0077] Compositions comprising any of the engineered cells provided herein are also provided. In some of any such embodiments, the composition comprises CD4+ and CD8+ T cells, and the ratio of CD4+ to CD8+ T cells is from about 1:3 to 3:1.

[0078] This document also provides compositions comprising a polynucleotide of any embodiment described herein, a chimeric antigen receptor of any embodiment described herein, or an engineered cell of any embodiment described herein. In some embodiments, the composition further comprises a pharmaceutically acceptable excipient. In some of any such embodiments, the composition is sterile.

[0079] In other respects, treatment methods are provided that involve administering to an individual suffering from a disease or condition an engineered cell of any of the embodiments described herein or a composition of any of the embodiments described herein. In some of any embodiments, the method includes administering a dose of engineered cells or a composition containing a dose of engineered cells.

[0080] Use of any of the engineered cells or compositions described herein in the preparation of a medicament for treating a disease or condition is also provided. Use of any of the engineered cells or compositions described herein in the treatment of a disease or condition is also provided. In some of any such embodiments, the engineered cells or compositions are used in a treatment regimen in which the treatment regimen includes the administration of a dose of engineered cells or a composition containing a dose of engineered cells.

[0081] In some embodiments of any of the methods described herein, the disease or condition is associated with the expression of B-cell maturation antigen (BCMA). In some embodiments, the disease or condition associated with BCMA is a B-cell-related condition. In some embodiments, the disease or condition associated with BCMA is an autoimmune disease or condition. In some implementations, autoimmune diseases or conditions include systemic lupus erythematosus (SLE), lupus nephritis, inflammatory bowel disease, rheumatoid arthritis, ANCA-associated vasculitis, idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune thrombocytopenia, Chagas' disease, Grave's disease, Wegener's granulomatosis, polyarteritis nodosa, Sjögren's syndrome, pemphigus vulgaris, scleroderma, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathy, vasculitis, diabetes mellitus, Reynaud's syndrome, antiphospholipid syndrome, Goodpasture disease, Kawasaki disease, autoimmune hemolytic anemia, myasthenia gravis, or progressive glomerulonephritis.

[0082] In some embodiments of any of the methods described herein, the disease or condition associated with BCMA is cancer. In some embodiments, the cancer is cancer that expresses BCMA. In some embodiments, the cancer is a B-cell malignancy. In some embodiments, the cancer is lymphoma, leukemia, or plasma cell malignancy. In some implementations, the cancer is lymphoma, specifically Burkitt's lymphoma, non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma, Waldenstrom macroglobulinemia, follicular lymphoma, small non-cleaved cell lymphoma, mucosa-associated lymphoid tissue lymphoma (MALT), marginal zone lymphoma, splenic lymphoma, nodular monocytic B-cell lymphoma, immunoblastic lymphoma, large cell lymphoma, diffuse mixed cell lymphoma, pulmonary B-cell angiogenic lymphoma, small lymphocytic lymphoma, primary mediastinal B-cell lymphoma, lymphoplasmacytic lymphoma (LPL), or mantle cell lymphoma (MCL). In some embodiments, the cancer is leukemia, specifically chronic lymphocytic leukemia (CLL), plasma cell leukemia, or acute lymphoblastic leukemia (ALL). In some embodiments, the cancer is a plasma cell malignancy, specifically multiple myeloma (MM) or plasmacytoma. In some embodiments, the cancer is multiple myeloma (MM).

[0083] In some of any embodiments, the dose of engineered T cells comprises between or between about 1 x 10⁻⁶ cells. 7 CAR-expressing T cells with 2 x 10 9 Between CAR-expressing T cells. In some of any embodiments, the dose of engineered T cells comprises between or between about 2.5 x 10⁻⁶ CAR-expressing T cells. 7 One CAR-expressing T cell and 1.2 x 10 9 Between CAR-expressing T cells, between or between approximately 5.0 x 10⁻⁶ 7 CAR-expressing T cells and 4.5 x 10 8 Between CAR-expressing T cells, between or between approximately 1.5 x 10^6 cells. 8 CAR-expressing T cells and 3.0 x 10 8 Between CAR-expressing T cells. In some of any embodiments, the dose of engineered T cells comprises or contains approximately 2.5 x 10⁻⁶ CAR-expressing T cells. 7 Contains or contains approximately 5.0 x 10 7 Contains or contains approximately 1.5 x 108 Contains or contains approximately 3.0 x 10 8 Contains or contains approximately 4.5 x 10 8 Contains or contains approximately 8.0 x 10 8 or contains or includes approximately 1.2 x 10 9 CAR-expressing T cells. In some embodiments, the dose of engineered T cells comprises or contains approximately 5.0 x 10⁻⁶ CAR-expressing T cells. 7 Contains or contains approximately 1.5 x 10 8 Contains or contains approximately 3.0 x 10 8 or contains or includes approximately 4.5 x 10 8 One dose of CAR-expressing T cells. In some of any embodiments, the dose of engineered T cells comprises a combination of CD4+ T cells and CD8+ T cells, wherein a defined ratio of CD4+ CAR-expressing T cells to CD8+ CAR-expressing T cells and / or a defined ratio of CD4+ T cells to CD8+ T cells is or approximately 1:1, or between approximately 1:3 and approximately 3:1.

[0084] In some of any embodiments, less than about 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the engineered T cells expressed at the stated dose express an apoptosis marker, optionally annexin V or active caspase 3. In some of any embodiments, less than 5%, 4%, 3%, 2%, or 1% of the engineered T cells expressed at the stated dose express annexin V or active caspase 3.

[0085] In some of the implementation methods, prior to administration, the subject had received lymphodepleting therapy, which included daily administration at or around 20-40 mg / m². 2 (optionally at or at about 30 mg / m²) 2 Subjects were given topical fludarabine for 2-4 days, and / or daily at approximately 200-400 mg / m². 2 (Optionally at or around 300 mg / m 2 Cyclophosphamide was applied to the surface of the subjects' bodies for 2-4 days.

[0086] In some of the implementation schemes, the subject has received lymphocyte clearance therapy, which includes daily administration of approximately 30 mg / m². 2 Subjects were given topical fludarabine and daily at approximately 300 mg / m². 2Cyclophosphamide was applied to the body surface for 3 consecutive days.

[0087] In some of any implementation schemes, the subject has received three or more therapies selected from the following when or before the administration of the dose of cells: autologous stem cell transplantation (ASCT); immunomodulators; proteasome inhibitors; and anti-CD38 antibodies.

[0088] In some of any embodiments, the immunomodulator is selected from thalidomide, lenalidomide, or pomalidomide. In some of any embodiments, the proteasome inhibitor is selected from bortezomib, carfilzomib, or ixazomib. In some of any embodiments, the anti-CD38 antibody is or comprises daratumumab.

[0089] In some of any implementations, the subject did not have active or historical plasma cell leukemia (PCL) at the time the dose of cells was administered.

[0090] In some of the embodiments, when administered to a subject, the dose or composition is capable of achieving an objective response in at least 50%, 60%, 70%, 80%, 90%, or 95% of the administered subjects. In some of the embodiments, OR includes subjects achieving a strict complete response (sCR), a complete response (CR), a very good partial response (VGPR), a partial response (PR), and a minimum response (MR). In some of the embodiments, when administered to a subject, the dose or composition is capable of achieving a strict complete response (sCR), a complete response (CR), a very good partial response (VGPR), or a partial response (PR) in at least 50%, 60%, 70%, 80%, or 85% of the administered subjects. In some of the embodiments, when administered to a subject, the dose or composition is capable of achieving a strict complete response (sCR) or a complete response (CR) in at least 20%, 30%, 40%, 50%, 60%, or 70% of the administered subjects.

[0091] In some of any embodiments, the dose of engineered T cells comprises or contains about 5.0 x 10⁻⁶ cells. 7 Contains or contains approximately 1.5 x 10 8 Contains or contains approximately 3.0 x 10 8 or contains or includes approximately 4.5 x 10 8 CAR-expressing T cells. In some embodiments, the dose of engineered T cells comprises or contains approximately 5.0 x 10⁶ CAR-expressing T cells. 7 One T cell expressing CAR.

[0092] This article also provides a method for determining the heterogeneity of transgenic transcribed nucleic acids, the method comprising: a) amplifying the transgenic nucleic acid using at least one 5' and 3' primer pair, wherein at least one pair comprises a 5' primer complementary to a nucleic acid sequence in the 5' untranslated region (5'UTR) of the transgenic nucleic acid and a 3' primer complementary to a nucleic acid sequence in the 3' untranslated region (3'UTR) of the transgenic nucleic acid, to produce one or more amplification products; and b) detecting the amplification products, wherein the presence of two or more amplification products from at least one 5' and 3' primer pair indicates heterogeneity of such amplification products.

[0093] In some embodiments of this method, the difference detected in b) is the difference in length of the amplified transcript. In some embodiments, the difference in b) is the difference in the chromatographic profile of the amplified transcript.

[0094] In some embodiments, the differences in amplified products are determined by agarose gel electrophoresis, chip-based capillary electrophoresis, analytical ultracentrifugation, field flow fractionation, or chromatography. In some embodiments, the 5′ primer is specific to the sequence transcribed from the promoter region of the transtranscribed nucleic acid. In some embodiments, the transtranscribed nucleic acid is amplified using a 3′ primer specific to the amino acid coding sequence of the polynucleotide on the pretranscribed mRNA and / or the 3′ untranslated region. In some embodiments, the 3′ primer is specific to the polyadenylated sequence or enhancer region of the 3′ untranslated region of the pretranscribed mRNA.

[0095] In some implementations, step a) is performed by a single amplification reaction using a single 5' and 3' primer pair, which contains a 5' primer complementary to the nucleic acid sequence in the 5' untranslated region (5'UTR) of the transcribed nucleic acid and a 3' primer complementary to the nucleic acid sequence in the 3' untranslated region (3UTR). In some embodiments, step a) is performed by parallel or subsequent amplification reactions using a first 5' and 3' primer pair, a second 5' and 3' primer pair, and optionally additional 5' and 3' primer pairs, wherein: the first 5' and 3' primer pair contains a 5' primer complementary to a nucleic acid sequence within the 5' UTR of the transcribed nucleic acid and a 3' primer complementary to a nucleic acid sequence within the 3' UTR of the transcribed nucleic acid; the second 5' and 3' primer pair contains a 5' primer whose sequence is complementary to a portion of the translated sequence of the nucleic acid transcript and a 3' primer whose sequence is complementary to a nucleic acid sequence within the 3' UTR of the transcript; and each of the optionally additional 5' and 3' primer pairs contains a sequence complementary to a sequence within the translated region of the transcript. In some embodiments, parallel or subsequent amplification reactions amplify overlapping portions of the transcript.

[0096] In some implementations, the length of the amplified product is predicted to be approximately 1.5 kilobases, 2 kilobases, 2.5 kilobases, 3 kilobases, 3.5 kilobases, 4 kilobases, 4.5 kilobases, 5 kilobases, 5.5 kilobases, 6 kilobases, 7 kilobases, or 8 kilobases.

[0097] In some of any embodiments, the transtranscribed nucleic acids detected as heterogeneous are identified as transgenic candidates for the removal of one or more splice sites. In some of any embodiments, the transtranscribed nucleic acids of the transgenic candidates exhibit at least or at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or more than 75% heterogeneity after expression in cells.

[0098] Methods for reducing the heterogeneity of expressed transgenic transcripts are also provided, comprising: a) identifying transgenic candidates for splice site removal according to any of the methods provided herein for determining the heterogeneity of transcribed nucleic acids; b) identifying one or more potential splice donor and / or splice acceptor sites; and c) modifying the nucleic acid sequence at or near the one or more potential splice donor and / or splice acceptor sites identified in b) to produce modified polynucleotides.

[0099] In some of any such embodiments, the method further involves d) evaluating the transgene candidate for splice site removal, as in step a). In some of any such embodiments, the method further involves e) repeating steps b)-d) until the transcript heterogeneity in step d) is reduced compared to the transcript heterogeneity as determined in step a).

[0100] In some of any such embodiments, one or more potential splice donor and / or splice acceptor sites exhibit a splicing event score of about or at least about 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, or 1.0, and / or the probability of the one or more sites being involved in a splicing event is predicted to be at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%.

[0101] In some of these embodiments, splice donor sites and splice acceptor sites are identified independently. In some of these embodiments, the one or more splice acceptor and / or donor sites are typical, atypical, and / or occult splice acceptor and / or donor sites.

[0102] In some of these embodiments, the transgene is a chimeric antigen receptor or part of a chimeric antigen receptor. In some of these embodiments, the CAR peptide comprises an antigen-binding domain, a spacer (e.g., a spacer region located between the ligand-binding domain and the transmembrane domain of the recombinant receptor), a transmembrane region, and an intracellular signaling domain, the antigen-binding domain comprising a variable heavy chain (V... H ) and variable light chains (V L Antibody fragments, optionally, single-chain antibody fragments (scFv).

[0103] In some of these embodiments, the modified polynucleotide is not modified within the coding sequence of the antigen-binding domain of the encoded CAR polypeptide. In some of these embodiments, the amino acid sequence encoded by the transgene remains unchanged after the polynucleotide modification. In some of these embodiments, the RNA transcribed from the modified polynucleotide exhibits at least or at least about 70%, 75%, 80%, 85%, 90%, or 95% homogeneity after expression in unmodified polynucleotide cells.

[0104] In some of these embodiments, the cells are human cells. In some of these embodiments, the cells are T cells.

[0105] In some of any such implementations, the method is a computer-implemented method, and one or more steps a)-c) are performed at an electronic device containing one or more processors and memory.

[0106] A computer system including a processor and memory is also provided, the memory containing instructions operable to cause the processor to perform any one or more steps of a method for reducing the heterogeneity of the expressed transgenic transcripts. Attached Figure Description

[0107] Figure 1A and Figure 1B The results of the analysis assessing RNA heterogeneity, as determined by agarose gel electrophoresis, are described. Figure 1A The RNA heterogeneity of several anti-BCMA-CARs, which contain long spacer (LS) regions or shorter CD28 spacer regions, was described. Figure 1B This study depicts RNA heterogeneity in three different sequences containing long spacer (LS) regions that encode anti-BCMACAR before and after sequence optimization and splice site elimination (O / SSE).

[0108] Figure 2 The results of an analysis assessing the expression levels of BCMA-LS CAR on the surface of transduced T cells before (non-SSE) and after (O / SSE) coding sequence optimization and splice site elimination.

[0109] Figure 3 This study compares the transduction efficiency of lentiviral vectors encoding the BMCA-LS CAR construct with those encoding a BCMA-LS CAR construct that has been codon-optimized and modified to eliminate the predicted splice site (O / SSE).

[0110] Figure 4A The results of an analysis depicting the cytolytic activity of BMCA-LS CAR-expressing T cells against cell lines expressing high (K562 / BCMA) or low (RPMI 8226) levels of BCMA at several effector cell:target cell (E:T) ratios. Figure 4B The cytolytic activity of several BMCA-LS CAR-expressing T cells against RPMI-8226 cells was depicted at an E:T ratio of 3:1. Figure 4C and Figure 4D To characterize the cytolytic activity of unoptimized BCMA-LS CAR-expressing T cells and optimized (O / SSE) BCMA-LS CAR-expressing T cells against various BCMA-expressing cell lines.

[0111] Figure 5A The results depict the analysis of the release of IFNγ, IL-2, and TNFα cytokines by BMCA-LS CAR-expressing T cells in response to incubation with cell lines expressing either higher (K562 / BCMA) or lower (RPMI 8226) levels of BCMA at several effector cell:target cell (E:T) ratios (in the figure, 5:1, 2.5:1, 1.25:1, and 0.6:1 are represented as a, b, c, and d, respectively). Figure 5B The figures depict the release of IFNγ, IL-2, and TNFα cytokines by unoptimized BMCA-LS CAR-expressing T cells and optimized (O / SSE) BCMA-LS CAR-expressing T cells in response to co-incubation with BCMA-expressing K562 / BCMA and RPMI 8226 cells at different E:T ratios (a, b, c, and d, respectively).

[0112] Figure 6 The results of the analysis describe the cytolytic activity of BCMA-55-LS-O / SSE CAR-expressing T cells from two donors after co-incubation with BCMA-expressing cells expressing different levels of BCMA.

[0113] Figure 7The results of an analysis describing the release of IFNγ after incubating BCMA-55-LS CAR O / SSE-expressing T cells from two donors with BCMA-expressing cells expressing different levels of BCMA were described.

[0114] Figure 8 The results of an analysis describing the cytolytic activity of anti-BCMA-expressing CAR T cells containing different spacer regions against OPM2 target cells were described.

[0115] Figure 9A and Figure 9B The results describe the analysis of the cytolytic activity of anti-BCMACAR-expressing T cells after incubation with OPM2 target cells in the presence of soluble BCMA-Fc.

[0116] Figure 10A The results of an analysis assessing the cytolytic activity of optimized (O / SSE) anti-BCMACAR-expressing T cells in the presence of supernatant from the H929 multiple myeloma cell line were described. Figure 10B The results of an analysis depicting the cytolytic activity of optimized (O / SSE) anti-BCMACAR-expressing T cells in the presence of recombinant B cell activating factor (BAFF).

[0117] Figure 11A and Figure 11B The figure depicts and evaluates the effects of different concentrations (in the figure, 0 ng / mL, 111 ng / mL, 333 ng / mL and 1000 ng / mL are represented as a, b, c and d, respectively) of soluble BCMA-Fc (anti-BCMACAR-expressing T cells and OPM2 target cells) on the expression of anti-BCMACAR-expressing T cells and OPM2 target cells. Figure 11A ) or supernatant from the multiple myeloma cell line H929 ( Figure 11B The results of analysis on the release of IFNγ, IL-2 and TNFα cytokines after incubation in the presence of these substances.

[0118] Figure 12A The results of an analysis describing and evaluating tumor growth in an OPM2 human multiple myeloma xenograft mouse model following a single intravenous injection of CART cells expressing optimized (O / SSE) anti-BCMACAR. Figure 12B The results of an analysis of the survival rate of OPM2 human multiple myeloma xenograft mouse model following a single intravenous injection of CAR-T cells expressing optimized (O / SSE) anti-BCMA CAR.

[0119] Figure 13AThe results of an analysis describing and evaluating tumor growth in the RPMI-8226 (subcutaneous) xenograft mouse model following a single intravenous injection of CART cells expressing optimized (O / SSE) anti-BCMACAR. Figure 13B To depict the survival rate of RPMI-8226 (subcutaneous) xenograft mouse model after a single intravenous injection of CAR T cells expressing optimized (O / SSE) anti-BCMA CAR.

[0120] Figure 14A and Figure 14B The characterization and evaluation of CD4+ levels in the blood of RPMI-8226 (subcutaneous) xenograft mice treated with optimized (O / SSE) anti-BCMACAR T cells derived from a single donor (donor 2) was performed. Figure 14A ) and CD8+ Figure 14B The results of the analysis of the number of CAR-positive T cells.

[0121] Figure 15A and Figure 15B The characterization and evaluation of CD4+ levels in the blood of RPMI-8226 (subcutaneous) xenograft mice treated with optimized (O / SSE) anti-BCMACAR T cells derived from a single donor (donor 1) was performed. Figure 15A ) and CD8+ Figure 15B The results of the analysis of the number of CAR-positive T cells.

[0122] Figure 16A The results were described in 96-well cell culture dishes containing BCMA-55-LS-O / SSE CAR-expressing cells coated overnight with BCMA-Fc (soluble human BCMA fused to the Fc region of IgG at its C-terminus) fusion peptide (0.008 μg / mL, 0.04 μg / mL, 0.2 μg / mL, 1 μg / mL, and 5 μg / mL) and incubated for 6 hours. The expression levels of tdTomato and the truncated receptor (an alternative marker for CAR expression) were assessed by flow cytometry. The recombinant Fc peptide was used as a control (Fc control).

[0123] Figure 16B The results of an analysis assessing the percentage of tdTomato+ cells among cells expressing truncated receptors were plotted in reporter cells expressing BCMA-55-LS-O / SSE CAR, BCMA-26-LS-O / SSE CAR, BCMA-23-LS-O / SSE CAR, and BCMA-25-LS-O / SSE CAR, incubated with ten (10) 2-fold serial dilutions of BCMA-Fc. Cells expressing CARs specific to different antigens (anti-CD19 CAR) served as controls.

[0124] Figure 17 The percentage of tdTomato+ cells among reporter cells expressing BCMA-55-LS-O / SSE CAR or BCMA-55-SS CAR after co-culturing with human BCMA-expressing K562 target cells (BCMA.K562 target cells) at various E:T ratios is depicted.

[0125] Figure 18 The expression levels of tdTomato and GFP (an alternative marker for CAR expression) as detected by flow cytometry in reporter cells incubated for 3 days without antigen stimulation (to assess the degree of antigen-independent (stressful) signaling) expressing anti-CD19 CAR, BCMA-55-LS-O / SSE CAR, BCMA-26-LS-O / SSE CAR, BCMA-23-LS-O / SSE CAR, or BCMA-52-LS-O / SSE CAR, were described in relation to the expression levels of tdTomato and GFP (alternative markers for CAR expression) in reporter cells, which were incubated for 3 days without antigen stimulation (to assess the degree of antigen-independent (stressful) signaling).

[0126] Figure 19A and Figure 19B The description focuses on the expression levels of anti-CD19 CAR, BCMA-55-LS-O / SSE CAR, BCMA-26-LS-O / SSE CAR, BCMA-23-LS-O / SSE CAR, or BCMA-52-LS-O / SSE CAR (as detected by flow cytometry) and truncated receptors (alternative markers of CAR expression) in reporter cells incubated without antigen stimulation (to assess the degree of antigen-independent (tonic) signaling).

[0127] Figure 20A The percentage of tdTomato+ cells, as detected by flow cytometry, in Nur77-tdTomato reporter cells co-cultured with K562 human myeloid leukemia cells expressing human BCMA (huBCMA), mouse BCMA (muBCMA), or cynomonmomycosis BCMA (cynoBCMA) at an E:T ratio of 2:1 or 5:1, to express the human BCMA-55-LS-O / SSE CAR. Figure 20B and Figure 20CThe percentage of tdTomato+ cells expressed as BCMA-55-LS-O / SSE CAR, as detected by flow cytometry, was plotted among reporter cells incubated with huBCMA and cynoBCMA at increasing concentrations (0, 0.1, 0.25, 1, 2.5, 10, 25, and 100 μg / mL) coated on 96-well flat-bottom culture dishes. Figure 20B ) and average fluorescence intensity (MFI; Figure 20C ).

[0128] Figure 21A Describe exemplary amplification strategies for transcripts and predicted amplification products. Figure 21B Depicts exemplary amplification products generated by the amplification of transcripts with known and unknown (hidden) splicing sites. Figure 21C An illustrative sliding window amplification of transcripts using nested primer pairs is depicted. Invention Details

[0129] The provided embodiments include compositions, articles, compounds, methods, and uses, including those targeting or specific to BCMA and BCMA-expressing cells and diseases. BCMA has been observed to be expressed in certain diseases and conditions (such as malignancies) or their tissues or cells, for example, in malignant plasma cells (such as those from all relapsed or newly diagnosed myeloma patients), for example, heterogeneous expression, while expression in normal tissues is minimal. The provided embodiments include methods suitable for treating such diseases and conditions and / or for targeting such cell types, including nucleic acid molecules encoding BCMA-binding receptors (including chimeric antigen receptors (CARs)), and encoded receptors (such as encoded CARs), and compositions and articles comprising them. Receptors may generally contain antibodies specific to BCMA (including antigen-binding antibody fragments, such as heavy chain variable (V) chains). H The invention provides BCMA-binding receptors, single-domain antibody fragments, and single-chain fragments, including scFv. It also provides cells (such as engineered or recombinant cells) expressing such BCMA-binding receptors (e.g., anti-BCMA receptors) and / or containing nucleic acids encoding such receptors, and compositions, articles, and therapeutic agents containing such cells. Methods are also provided for evaluating, optimizing, manufacturing, and using nucleic acid sequences, such as sequences encoding recombinant BCMA-binding receptors. Methods are also provided for manufacturing and using (such as in the treatment or improvement of BCMA-expressing diseases and symptoms) cells (e.g., engineered cells) expressing or containing recombinant BCMA-binding receptors and polynucleotides encoding recombinant BCMA-binding receptors, or compositions containing such cells.

[0130] Adoptive cell therapy (including those involving the administration of cells expressing chimeric receptors (such as chimeric antigen receptors) and / or other recombinant antigen receptors specific to the disease or symptom of interest, as well as other adoptive immune cell and adoptive T cell therapies) can effectively treat cancer and other diseases and conditions. In some cases, the available approaches to adoptive cell therapy have not been entirely satisfactory. In some aspects, the administered cells recognize and bind to targets (e.g., target antigens such as BCMA), transport, localize, and successfully enter appropriate sites within the subject, tumor, and its environment; become activated, amplify, perform multiple effector functions (including cell killing and secretion of multiple factors such as cytokines), persist (including long-term), differentiate upon clearance and re-exposure to target ligands or antigens, transform, participate in programmed entry into certain phenotypic states to provide an effective and powerful memory response, and have the ability to avoid or reduce exhaustion, allergy, terminal differentiation, and / or differentiation into a repressive state.

[0131] In some cases, the optimal response to treatment may depend on the ability of an engineered recombinant receptor (such as a CAR) to be consistently and reliably expressed on the cell surface and / or to bind to a target antigen. For example, in some cases, the heterogeneity of the transcribed RNA from an introduced transgene (e.g., a transgene encoding a recombinant receptor) can affect the expression and / or activity of the recombinant receptor, in some cases when expressed in cells (such as human T cells) for cell therapy. In some cases, the length and type of spacers in the recombinant receptor (such as a CAR) can affect the receptor's expression, activity, and / or function.

[0132] Furthermore, in some cases, certain recombinant receptors can exhibit antigen-independent activity or signaling (also known as "tense signaling"), which can lead to unwanted effects, such as increased differentiation and / or exhaustion of T cells expressing the recombinant receptor. In some respects, such activity can limit the activity, efficacy, or capacity of T cells. In some cases, during the engineering and in vitro expansion of cells for expressing recombinant receptors, the cells may exhibit exhaustion-indicating phenotypes due to tensile signaling via the recombinant receptor.

[0133] In some cases, the specific binding, recognition, or targeting of a particular target antigen by a recombinant receptor can affect the receptor's activity. In some cases, B-cell maturation antigen (BCMA) is commonly expressed on malignant plasma cells and is an attractive therapeutic target for cell therapy. In some cases, BCMA can be cleaved by gamma-secretases, producing soluble BCMA (sBCMA) or a "shed" form of BCMA, reducing the amount of BCMA expressed on the surface of target cells. In some cases, the activity of BCMA-binding molecules (such as anti-BCMA chimeric antigen receptors) can be blocked or inhibited by the presence of soluble BCMA. Improved strategies are needed to optimally respond to cell therapies, particularly to recombinant receptors that specifically bind, recognize, or target BCMA.

[0134] In some embodiments, the provided implementations are based on the observation that optimization of specific spacers and nucleic acid sequences can lead to consistent and robust expression of the recombinant receptor. The provided BCMA-binding recombinant receptor offers advantages over available methods for cell therapy, particularly BCMA-targeted cell therapy. In some implementations, the provided BCMA-binding recombinant receptor has been observed to exhibit a lack of antigen-independent tonic signaling and inhibitory activity due to reduced soluble BCMA production. In some aspects, the provided BCMA-binding recombinant receptor, the polynucleotide encoding such receptor, the engineered cells, and the cell composition exhibit certain desirable properties that can overcome or counteract certain limitations that can reduce the optimal response to cell therapy, such as cell therapy using engineered cells expressing a BCMA-binding recombinant receptor. In some aspects, compositions containing engineered cells expressing exemplary BCMA-binding recombinant receptors provided herein have been observed to exhibit consistent cell health status of the engineered cells and correlate with clinical response. In some cases, the provided implementation methods (including recombinant receptors, polynucleotides encoding such receptors, engineered cells, and cell compositions) can offer multiple advantages over available BCMA-targeting therapies to enhance the activity of recombinant receptors and the response to BCMA-targeting cell therapies.

[0135] I. Receptors that bind to BCMA and encode polynucleotides

[0136] In some aspects, BCMA binding agents are provided, such as cell surface proteins (e.g., recombinant receptors or chimeric antigen receptors) that bind or recognize BCMA molecules, and polynucleotides encoding cell surface proteins that bind BCMA (e.g., recombinant receptors (e.g., CARs)), and cells expressing such receptors. Cell surface proteins that bind BCMA generally contain antibodies (e.g., antigen-binding antibody fragments) that specifically recognize (e.g., specifically bind) BCMA (e.g., BCMA protein, such as human BCMA protein) and / or other binding peptides. In some aspects, the agent binds the extracellular portion of BCMA.

[0137] In some embodiments, the polynucleotide is optimized, or contains certain features designed for optimization (such as for codon usage), to reduce RNA heterogeneity and / or regulate the expression of the encoded receptor (such as surface expression) (e.g., increasing or conferring higher consistency between individual cell product batches). In some embodiments, the polynucleotide encoding a BCMA-binding cell surface protein is modified compared to a reference polynucleotide to remove cryptic / hidden splicing sites to reduce RNA heterogeneity. In some embodiments, the polynucleotide encoding a BCMA-binding cell surface protein is codon-optimized, such as for expression in mammalian (e.g., human) cells, such as in human T cells. In some aspects, when expressed in cells, the modified polynucleotide causes an increase in the level of expression (e.g., surface expression), such as an increase or more uniform or consistent expression. Such polynucleotides can be utilized in constructs for producing engineered cells that express the encoded BCMA-binding cell surface protein. Therefore, cells expressing recombinant receptors encoded by the polynucleotides provided herein and their use in adoptive cell therapies (such as for treating diseases and conditions associated with BCMA expression) are also provided.

[0138] Among the provided polynucleotides are those encoding recombinant receptors (such as antigen receptors) that specifically recognize (e.g., specifically bind) BCMA. In some aspects, the provided are also those encoded receptors, such as those containing polypeptides that bind BCMA, and compositions, articles thereof, and uses thereof.

[0139] The BCMA-binding polypeptide may be an antibody, such as a single-chain antibody (e.g., an antibody fragment that binds to an antigen), or a portion thereof. In some instances, the recombinant receptor is a chimeric antigen receptor, such as those containing an anti-BCMA antibody or an antigen-binding fragment thereof. In any embodiment, the antibody or antigen-binding fragment in the provided CAR that specifically recognizes an antigen (e.g., BCMA) binds specifically to that antigen. The provided polynucleotide may be incorporated into a construct, such as a deoxyribonucleic acid (DNA) or RNA construct, such as those that may be introduced into cells used to express the encoded recombinant BCMA-binding receptor.

[0140] In some cases, the polynucleotide encoding a BCMA-binding receptor contains a signal sequence encoding a signal peptide. In some cases, this signal sequence is encoded upstream of the nucleic acid sequence encoding the BCMA-binding receptor or attached to the 5' end of the nucleic acid sequence encoding the antigen-binding domain. In some cases, the polynucleotide containing a nucleic acid sequence encoding a BCMA-binding receptor (e.g., a chimeric antigen receptor (CAR)) contains a signal sequence encoding a signal peptide. In some aspects, the signal sequence may encode a signal peptide derived from a natural polypeptide. In other aspects, the signal sequence may encode a heterologous or non-natural signal peptide. In some aspects, non-limiting exemplary signal peptides include an IgGκ chain signal peptide encoded by the nucleotide sequences shown in SEQ ID NO:620 or SEQ ID NO:619 or 682-685; a GMCSFRα chain encoded by the nucleotide sequences shown in SEQ ID NO:851 and SEQ ID NO:850; a CD8α signal peptide shown in SEQ ID NO:852; or a CD33 signal peptide shown in SEQ ID NO:853. In some cases, the polynucleotide encoding the BCMA-binding receptor may contain a nucleic acid sequence encoding an additional molecule (such as an alternative marker or other marker), or may contain additional components such as a promoter, regulatory element, and / or polycistronic element. In some embodiments, the nucleic acid sequence encoding the BCMA-binding receptor is operatively linked to any of the additional components.

[0141] A. Components of the encoded recombinant BCMA-binding receptor

[0142] The provided BCMA-binding receptors generally contain an extracellular binding molecule and an intracellular signaling domain. Among the provided binding molecules are antibody-containing peptides, including single-chain cell surface proteins, such as recombinant receptors containing such antibodies (e.g., chimeric antigen receptors).

[0143] Among the provided binding molecules (e.g., BCMA binding molecules) are single-chain cell surface proteins including one of the provided antibodies or fragments thereof (e.g., BCMA binding fragments), such as recombinant receptors (e.g., antigen receptors). Recombinant receptors include antigen receptors that specifically bind to or specifically recognize BCMA, such as antigen receptors containing the provided anti-BCMA antibody, such as antigen-binding fragments. Among antigen receptors are functional non-TCR antigen receptors, such as chimeric antigen receptors (CARs). Cells expressing recombinant receptors and their use in adoptive cell therapy (e.g., for treating diseases and conditions associated with BCMA expression) are also provided.

[0144] Exemplary antigen receptors (including CARs) and methods for engineering such antigen receptors and introducing them into cells include, for example, International Patent Application Publications Nos. WO200014257, WO2013126726, WO2012 / 129514, WO2014031687, WO2013166321, WO2013071154, and WO2013123061, and U.S. Patent Application Publications Nos. US2002131960, US2013287748, and US2013014933. 7. The contents described in U.S. Patents 6,451,995, 7,446,190, 8,252,592, 8,339,645, 8,398,282, 7,446,179, 6,410,319, 7,070,995, 7,265,209, 7,354,762, 7,446,191, 8,324,353 and 8,479,118, and European Patent Application EP2537416, and / or by Sadelain et al., Cancer Discov. April 2013; 3(4):388-398; Davila et al. (2013) PLoS ONE 8(4):e61338; Turtle et al., Curr. Opin. Immunol., October 2012; 24(5):633-39; Wu et al., Cancer, March 2012 18(2):160-75. In some aspects, antigen receptors include those described in U.S. Patent No. 7,446,190 and International Patent Application Publication No. WO2014055668. Exemplary CARs include those disclosed in any of the aforementioned disclosures (such as WO2014031687, US 8,339,645, US 7,446,179, US2013 / 0149337, US7,446,190, and US 8,389,282), wherein the antigen-binding portion (e.g., scFv) is replaced with an antibody or its antigen-binding fragment as provided herein.

[0145] In some embodiments, the provided CAR has an amino acid sequence selected from SEQ ID NO:757-762, or an amino acid sequence showing at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with any of the amino acid sequences shown in SEQ ID NO:757-762. In some embodiments, the provided CAR is encoded by a polynucleotide, such as a polynucleotide having a nucleic acid sequence shown in any of SEQ ID NO:751-756, or a nucleic acid sequence showing at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with any of the nucleic acid sequences shown in SEQ ID NO:751-756.

[0146] In some embodiments, the provided CAR is encoded by a polynucleotide, such as a polynucleotide having a nucleic acid sequence shown in any of SEQ ID NO:755 and 756 or a sequence showing at least or at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with a nucleic acid sequence shown in any of SEQ ID NO:755 and 756.

[0147] In some embodiments, the provided CAR is encoded by a polynucleotide, such as a polynucleotide having the nucleic acid sequence shown in SEQ ID NO:755 or a sequence exhibiting at least or at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity therewith. In some embodiments, the provided CAR is encoded by a polynucleotide, such as a polynucleotide having the nucleic acid sequence shown in SEQ ID NO:755.

[0148] In some embodiments, the nucleic acid encoding the antigen-binding domain comprises (a) the nucleotide sequence shown in any of SEQ ID NO:648, 330-352, 647, 716 or 718; (b) a nucleotide sequence having at least 90% sequence identity with any of SEQ ID NO:648, 330-352, 647, 716 or 718; or (c) a degenerate sequence of (a) or (b).

[0149] 1. Antigen-binding domain

[0150] Among chimeric receptors is the chimeric antigen receptor (CAR). Chimeric receptors (such as CARs) generally include an extracellular antigen-binding domain that includes, is, or is contained within or contains one of the provided anti-BCMA antibodies. Therefore, chimeric receptors (e.g., CARs) typically include one or more BCMA-binding molecules in their extracellular portion, such as one or more antigen-binding fragments, antigen-binding domains, or antigen-binding moieties, or one or more antibody variable regions and / or antibody molecules, such as those described herein.

[0151] In this article, the term "antibody" is used in the broadest sense and includes both polyclonal and monoclonal antibodies, including complete antibodies and functional (antigen-binding) antibody fragments, including antigen-binding fragments (Fab), F(ab')2 fragments, Fab' fragments, Fv fragments, recombinant IgG (rIgG) fragments, and variable heavy chains (V) capable of specifically binding antigens. H The term "antibody" refers to single-chain antibody fragments, including single-chain variable fragments (scFvs) and single-domain antibody fragments (e.g., sdAbs, sdFvs, nanobodies). It encompasses genetically engineered and / or otherwise modified forms of immunoglobulins, such as intracellular antibodies, peptide bodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugated antibodies, multispecific (e.g., bispecific or trispecific) antibodies, bifunctional antibodies, trifunctional and tetrafunctional antibodies, tandem di-scFvs, and tandem tri-scFvs. Unless otherwise stated, the term "antibody" should be understood to encompass its functional antibody fragment, also referred to herein as an "antigen-binding fragment." The term also encompasses complete or full-length antibodies, including antibodies of any class or subclass, including IgG and its subclasses, IgM, IgE, IgA, and IgD.

[0152] The terms “complementarity-determining region” and “CDR,” synonyms with “hypervariate region” or “HVR,” are known in the art to refer to the non-continuous amino acid sequence within the variable region of an antibody that confers antigen specificity and / or binding affinity. Generally, each heavy chain variable region contains three CDRs (CDR-H1, CDR-H2, CDR-H3), and each light chain variable region contains three CDRs (CDR-L1, CDR-L2, CDR-L3). The terms “frame region” and “FR” are known in the art to refer to the non-CDR portions of the variable regions of the heavy and light chains. Generally, each full-length heavy chain variable region contains four FRs (FR-H1, FR-H2, FR-H3, and FR-H4), and each full-length light chain variable region contains four FRs (FR-L1, FR-L2, FR-L3, and FR-L4).

[0153] The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well-known schemes, including those described below: Kabat et al. (1991), “Sequences of Proteins of Immunological Interest”, 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme); Al-Lazikani et al. (1997) JMB 273, 927-948 (“Chothia” numbering scheme); MacCallum et al., J. Mol. Biol. 262: 732-745 (1996), “Antibody-antigen interactions: Contact analysis and binding site topography”, J. Mol. Biol. 262, 732-745 (“Contact” numbering scheme); Lefranc MP et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig “superfamily V-like domains”, Dev Comp Immunol, January 2003; 27(1):55-77 (“IMGT” numbering scheme); Honegger A and Plückthun A, “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool”, J Mol Biol, June 8, 2001; 309(3):657-70 (“Aho” numbering scheme); and Martin et al., “Modeling antibody hypervariable loops: a combined algorithm”, PNAS, 1989, 86(23):9268-9272.

[0154] The boundaries of a given CDR or FR can vary depending on the scheme used for identification. For example, the Kabat scheme is based on structural alignment, while the Chothia scheme is based on structural information. Both the Kabat and Chothia schemes number antibodies based on the length of the most common antibody region sequence, where insertions and deletions, indicated by insert letters (e.g., "30a"), occur in some antibodies. The two schemes result in different numbers for certain insertions and deletions ("indels") located in different positions. The contact scheme is based on the analysis of complex crystal structures and is similar to the Chothia numbering scheme in several ways. The AbM scheme is a compromise between the Kabat and Chothia definitions, based on the scheme used by the AbM antibody modeling software from Oxford Molecular.

[0155] Table 1 below lists illustrative positional boundaries of CDR-L1, CDR-L2, CDR-L3 and CDR-H1, CDR-H2, CDR-H3 as identified by Kabat, Chothia, AbM and contact schemes, respectively. For CDR-H1, residue numbering is performed using both Kabat and Chothia numbering schemes. FRs are located between CDRs; for example, FR-L1 is located before CDR-L1, FR-L2 is located between CDR-L1 and CDR-L2, FR-L3 is located between CDR-L2 and CDR-L3, and so on. Note that because the Kabat numbering scheme shown results in insertions at H35A and H35B, the end of the Chothia CDR-H1 loop varies between H32 and H34 depending on the loop length when numbered using the Kabat numbering convention shown.

[0156]

[0157] 1–Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service,

[0158] National Institutes of Health, Bethesda, MD

[0159] 2-Al-Lazikani et al., (1997) JMB 273, 927-948

[0160] Therefore, unless otherwise specified, the “CDR” or “complementarity-determining region” or individually specified CDR (e.g., CDR-H1, CDR-H2, CDR-H3) of a given antibody or its regions (such as its variable regions) should be understood to encompass the complementarity-determining region (or specific complementarity-determining region) as defined by any of the foregoing schemes or other known schemes. For example, stating that a particular CDR (e.g., CDR-H3) contains a given V H or V L In the case of the amino acid sequence of the corresponding CDR in the region amino acid sequence, it should be understood that such CDR has the sequence of the corresponding CDR (e.g., CDR-H3) within the variable region as defined by any of the foregoing schemes or other known schemes. In some embodiments, a specific CDR sequence is specified. The exemplary CDR sequences of the provided antibodies are described using various numbering schemes, but it should be understood that the provided antibodies may include CDRs as described according to any other foregoing numbering scheme or other numbering schemes known to those skilled in the art.

[0161] Similarly, unless otherwise specified, the FR of a given antibody or its region (such as its variable region) or individually specified FRs (e.g., FR-H1, FR-H2, FR-H3, FR-H4) should be understood to encompass a frame region (or specific frame region) as defined by any known protocol. In some cases, a protocol for identifying a particular CDR, FR, or multiple FRs or CDRs is specified, such as a CDR as defined by Kabat, Chothia, AbM, or contact methods or other known protocols. In other cases, the specific amino acid sequence of the CDR or FR is given.

[0162] The term "variable region" or "variable domain" refers to the structural domain of the antibody heavy or light chain that participates in antibody-antigen binding. The variable regions of the heavy and light chains of natural antibodies (V1 and V2, respectively) H and V L They generally have a similar structure, where each domain contains four conserved frame regions (FRs) and three conserved core regions (CDRs). (See, for example, Kindt et al., Kuby Immunology, 6th ed., WH Freeman and Co., p. 91 (2007)). A single V H or V L The domain is sufficient to confer antigen-binding specificity. Furthermore, antibodies binding to a specific antigen can utilize the V domain derived from the antibody binding to that antigen. H or V L The domains are separated to select complementary V values ​​separately. H or V LThe domain's library. See, for example, Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0163] The antibodies included in the provided CAR are antibody fragments. An "antibody fragment" or "antigen-binding fragment" refers to a molecule, other than a complete antibody, containing the portion of the complete antibody that binds to the antigen bound by that complete antibody. Examples of antibody fragments include (but are not limited to) Fv, Fab, Fab', Fab'-SH, F(ab')2; bifunctional antibodies; linear antibodies; heavy chain variable (V) antibodies. H ) region, single-chain antibody molecules, such as scFv and those containing only V H Single-domain antibodies in the region; and multispecific antibodies formed from antibody fragments. In some embodiments, the antigen-binding domain in the provided CAR is or includes a variable heavy chain (V... H ) and variable light chains (V L Antibody fragments containing the heavy chain variable (V) region. In a particular embodiment, the antibody is an antibody containing the heavy chain variable (V) region. H ) region and / or light chain variable (V L Single-chain antibody fragments, such as scFv, in the region )

[0164] A single-domain antibody (sdAb) is an antibody fragment containing all or a portion of the variable region of the heavy chain or the variable region of the light chain. In some embodiments, the single-domain antibody is a human single-domain antibody.

[0165] Antibody fragments can be prepared using various techniques, including (but not limited to) the proteolytic digestion of intact antibodies and production from recombinant host cells. In some embodiments, the antibody is a fragment produced recombinantly, such as a fragment containing an arrangement not naturally occurring, such as those having two or more antibody regions or chains linked by synthetic linkers (e.g., peptide linkers), and / or fragments that cannot be produced by enzymatic digestion of naturally occurring intact antibodies. In some aspects, the antibody fragment is an scFv.

[0166] A "humanized" antibody is an antibody in which all or substantially all of its CDR amino acid residues are derived from a non-human CDR and all or substantially all of its FR amino acid residues are derived from a human FR. Optionally, a humanized antibody may include at least a portion of the antibody constant region derived from a human antibody. A "humanized form" of a non-human antibody refers to a variant of a non-human antibody that has been humanized (typically to reduce immunogenicity in humans) while retaining the specificity and affinity of the parent non-human antibody. In some embodiments, some FR residues in the humanized antibody are replaced by corresponding residues from a non-human antibody (e.g., an antibody from which the CDR residues are derived), for example, to restore or improve antibody specificity or affinity.

[0167] Among the anti-BCMA antibodies included in the provided CAR are human antibodies. "Human antibody" refers to an antibody of non-human origin having an amino acid sequence corresponding to the amino acid sequence of an antibody produced by humans or human cells, or having a sequence (including human antibody libraries) that uses a human antibody lineage or encodes another human antibody. This term does not include humanized forms of non-human antibodies containing non-human antigen-binding regions, such as those antibodies in which all or substantially all of the CDRs are non-human CDRs. This term includes the antigen-binding fragment of a human antibody.

[0168] Human antibodies can be prepared by administering immunogens to transgenic animals that have been modified to produce complete human antibodies in response to antigen challenge, or complete antibodies with human variable regions. These animals typically contain all or part of human immunoglobulin loci, which replace endogenous immunoglobulin loci, or are present extrachromosomally or randomly integrated into the animal's chromosome. In these transgenic animals, endogenous immunoglobulin loci are generally inactivated. Human antibodies can also be derived from human antibody libraries, including phage display libraries and cell-free libraries, containing sequences encoding antibodies derived from the human spectrum.

[0169] The antibodies included in the provided CAR are monoclonal antibodies, including monoclonal antibody fragments. As used herein, the term "monoclonal antibody" means an antibody derived from or within a substantially homogeneous group of antibodies, i.e., the individual antibodies constituting the group are identical except for naturally occurring mutations or possible variants that may arise during the production of the monoclonal antibody formulation, which are generally present in small quantities. In contrast to polyclonal antibody formulations, which typically include different antibodies targeting different epitopes, each monoclonal antibody in a monoclonal antibody formulation targets a single epitope on the antigen. This term should not be construed as requiring the production of the antibody through any particular method. Monoclonal antibodies can be produced using a variety of techniques, including (but not limited to) hybridoma, recombinant DNA methods, phage display, and other antibody display methods.

[0170] In some implementations, the CAR includes one or more BCMA-binding moieties of the antibody molecule, such as the variable heavy chain (V) of the antibody. H ) region and / or light chain variable (V L The BCMA-binding CAR contains, for example, an scFv antibody fragment. In some embodiments, the provided BCMA-binding CAR contains an antibody (such as an anti-BCMA antibody) or an antigen-binding fragment thereof that confers BCMA-binding properties to the provided CAR. In some embodiments, the antibody or antigen-binding domain may be any of the described anti-BCMA antibodies or derived from any of the described anti-BCMA antibodies. See, for example, Carpenter et al., Clin Cancer Res., 2013, 19(8):2048-2060, WO2016090320, WO2016090327, WO2010104949 and WO2017173256. Any of such anti-BCMA antibodies or antigen-binding fragments may be used in the provided CAR. In some embodiments, the anti-BCMA CAR contains an antigen-binding domain, which is a variable heavy chain (V) containing an antibody derived from WO 2016090320 or WO2016090327. H ) and / or variable light chains (V L scFv in the area.

[0171] In some embodiments, the antibody (e.g., anti-BCMA antibody) or antigen-binding fragment contains a heavy chain and / or a light chain variable (V) as described. H or V L The region sequence or sufficient antigen-binding portion thereof. In some embodiments, the anti-BCMA antibody (e.g., the antigen-binding fragment) contains V containing CDR-H1, CDR-H2 and / or CDR-H3 as described. H The region sequence or a sufficient antigen-binding portion thereof. In some embodiments, the anti-BCMA antibody (e.g., the antigen-binding fragment) contains V containing CDR-L1, CDR-L2, and / or CDR-L3 as described. L The region sequence or a sufficient antigen-binding portion thereof. In some embodiments, the anti-BCMA antibody (e.g., the antigen-binding fragment) contains a V-type antigen containing CDR-H1, CDR-H2, and / or CDR-H3 as described. H The region sequence, and contains V containing CDR-L1, CDR-L2 and / or CDR-L3 as described. L Region sequence. Among antibodies are those that have a sequence that is at least or about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to such a sequence.

[0172] In some implementations, the antibody in the provided CAR (e.g., its antigen-binding fragment) has a heavy chain variable (V) H The heavy chain variable region has an amino acid sequence selected from any of SEQ ID NO:110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774, and 814-832, or a V sequence selected from any of SEQ ID NO:110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774, and 814-832. H The amino acids in the region have an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity, or contain amino acids present in this type of V. H The sequence contains CDR-H1, CDR-H2, and / or CDR-H3. In some embodiments, the antibody or antibody fragment in the provided CAR has V of any of the antibodies or antibody-binding fragments described in WO 2016090327, WO 2016090320, or WO 2017173256. H district.

[0173] In some implementations, the V of the anti-BCMA antibody H The region is V, which includes heavy chain complementarity-determining region 3 (CDR-H3). H The region, CDR-H3 contains the amino acid sequence X1X2X3X4X5X6X7X8X9X. 10 X 11 X 12 X 13 X 14 (SEQ ID NO:355), wherein X1 is A, D, E, G, L, V, or W; X2 is A, D, G, L, P, Q, or S; X3 is A, D, G, L, or Y; X4 is D, G, P, R, S, V, Y, or not present; X5 is D, I, P, S, T, Y, or not present; X6 is A, G, I, S, T, V, Y, or not present; X7 is A, D, E, F, L, P, S, Y, or not present; X8 is P, Q, T, Y, or not present; X9 is D, G, R, Y, or not present; X 10 It can be A, F, Y, or it does not exist; X 11 It is D, F, or does not exist; X 12 F or not present; X 13 Let X be D, T, or Y; and X be... 14It can be I, L, N, V, or Y. In some such implementations, in this CDR-H3, X1 is V; X2 is D; X3 is G; X4 is D; X5 is Y; X6 is V; X7 is D; X8 does not exist; X9 does not exist; X 10 Does not exist; X 11 Does not exist; X 12 Does not exist; X 13 Let D be X; and X be X. 14 The value is Y.

[0174] In some embodiments, the antibody or its antigen-binding fragment comprises CDR-H3, which contains an amino acid sequence selected from any one of SEQ ID NO: 7-11, 149-157, 279-287, 292, 293, 376-378, 517, 595 according to Kabat numbers. In some embodiments, the V of the antibody or its antigen-binding fragment... H The region contains CDR-H3, which has an amino acid sequence comprising any one of SEQ ID NO: 7-11, 149-157, 279-287, 292, 293, 376-378, 517, and 595 according to Chothia or AbM numbers. In some embodiments, the VH region of the antibody or its antigen-binding fragment contains CDR-H3, which has an amino acid sequence comprising an amino acid sequence comprising SEQ ID NO: 606 and 613. In some embodiments, the antibody or its antigen-binding fragment contains CDR-H3, which has an amino acid sequence comprising SEQ ID NO: 517, 595, 606, or 613. In any such instance, the antibody or its antigen-binding fragment may contain V selected from any one of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774, and 814-832. H The region sequence, wherein the corresponding CDR-H3 sequence contained therein (e.g., corresponding to amino acid residues H95 to H102 according to Kabat numbers) is replaced by a CDR-H3 sequence selected from the following: any of SEQ ID NO: 7-11, 149-157, 279-287, 292, 293, 376-378, 517 and 595 according to Kabat numbers, any of SEQ ID NO: 7-11, 149-157, 279-287, 292, 293, 376-378, 517 and 595 according to Chothia or AbM numbers, or any of SEQ ID NO: 606 and 613.

[0175] In some implementations, the V of the antibody or its antigen-binding fragment HThe region contains V selected from any one of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774, and 814-832. H The CDR-H3 contained in the amino acid sequence of the region.

[0176] In some implementations, the V of the antibody or its antigen-binding fragment H The region is V, which includes heavy chain complementarity determination region 1 (CDR-H1). H The CDR-H1 contains the amino acid sequence X1X2X3MX4 (SEQ ID NO:353), where X1 is D or S; X2 is Y or S; X3 is A, G, W, or Y; and X4 is H, Q, or S. In some embodiments, in the CDR-H1, X1 is D; X2 is Y; X3 is Y; and X4 is S.

[0177] In some implementations, the V of the antibody or its antigen-binding fragment H The region contains CDR-H1, which has an amino acid sequence comprising any one of SEQ ID NO: 1-3, 140-144, 288, 289, 507, and 593 according to Kabat numbers. In some embodiments, the V of the antibody or its antigen-binding fragment... H The region contains CDR-H1, which has an amino acid sequence comprising any one of SEQ ID NO: 12-15, 158-160, 294, 295, 532, and 596 according to Chothia numbers. In some embodiments, the V of the antibody or its antigen-binding fragment H The region contains CDR-H1, which has an amino acid sequence comprising any one of SEQ ID NO: 19-22, 165-169, 298, 299, 509, 577, and 598 according to AbM numbers. In some embodiments, the V of the antibody or its antigen-binding fragment H The region contains CDR-H1, which has an amino acid sequence comprising any one of SEQ ID NO 604 and 611. In some embodiments, the V of the antibody or its antigen-binding fragment H The region contains CDR-H1, which has the amino acid sequences of SEQ ID NO: 507, 532, 577, 593, 596, 598, 604, and 611. In any such example, the antibody or its antigen-binding fragment may contain V selected from any of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774, and 814-832.H The region sequence, wherein the corresponding CDR-H1 sequence contained therein (e.g., corresponding to amino acid residues H31 to H35 according to Kabat numbers) is replaced by a CDR-H1 sequence selected from: any of SEQ ID NO: 1-3, 140-144, 288, 289, 507 and 593 according to Kabat numbers, any of SEQ ID NO: 12-15, 158-160, 294, 295, 532 and 596 according to Chothia numbers, any of SEQ ID NO: 19-22, 165-169, 509, 298, 299, 509, 577 and 598 according to AbM numbers, or any of SEQ ID NO: 604 and 611.

[0178] In some implementations, the V of the antibody or its antigen-binding fragment H The region contains CDR-H1, which includes V selected from any one of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774, and 814-832. H Within the amino acid sequence of the region.

[0179] In some implementations, the V of the antibody or its antigen-binding fragment H The region is V, which includes heavy chain complementarity determination region 2 (CDR-H2). H The region, CDR-H2 contains X1, X2, X3, X4, X5, X6, X7, X8, X9, X... 10 X 11 YX 12 X 13 X 14 X 15 X 16 X 17 The amino acid sequence of (SEQ ID NO:354), wherein X1 is F, G, H, V, W, or Y; X2 is N, R, S, or V; X3 is P, Q, S, V, W, or Y; X4 is K or absent; X5 is A or absent; X6 is D, G, N, S, or Y; X7 is G or S; X8 is G or S; X9 is E, G, N, T, or S; X 10 For I, K, or T; X 11 For E, G, N, or Y; X 12 For A or V; X 13 For A, D, or Q; X 14 For K or S; X 15 For F or V; X 16 It is K or Q; and X 17It is E or G. In some implementations, in this CDR-H2, X1 is Y; X2 is S, X3 is S; X4 does not exist; X5 does not exist; X6 is S; X7 is G; X8 is S; X9 is T; X 10 For I; X 11 For Y; X 12 For A; X 13 For D; X 14 S; X 15 For V; X 16 Let K be the number of K; and X be the number of X. 17 It is G.

[0180] In some implementations, the V of the antibody or its antigen-binding fragment H The region contains CDR-H2, which comprises an amino acid sequence selected from any one of SEQ ID NO:4-6, 145-148, 290, 291, 372-374, 513, and 594 according to Kabat numbers. In some embodiments, the V of the antibody or its antigen-binding fragment... H The region contains CDR-H2, which comprises an amino acid sequence selected from any one of SEQ ID NO: 16-18, 161-164, 296, 297, 514-516, 551, 597 according to Chothia numbers. In some embodiments, the V of the antibody or its antigen-binding fragment... H The region contains CDR-H2, which contains amino acids selected from any one of SEQ ID NO: 23-25, 170-173, 300, 301, 510-512, 587, and 599 according to AbM numbers. In some embodiments, the V of the antibody or its antigen-binding fragment... H The region contains CDR-H2, which comprises an amino acid sequence selected from either SEQ ID NO: 605 or 612. In some embodiments, the V of the antibody or its antigen-binding fragment... H The region contains CDR-H2, which has an amino acid sequence of any one of SEQ ID NO: 513, 551, 587, 594, 597, 599, 605, or 612. In any such example, the antibody or its antigen-binding fragment may contain V selected from any one of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774, and 814-832. HThe region sequence, wherein the corresponding CDR-H2 sequence contained therein (e.g., corresponding to amino acid residues H50 to H65 according to Kabat numbers) is replaced by a CDR-H2 sequence selected from the following: any of SEQ ID NOs according to Kabat numbers: 4-6, 145-148, 290, 291, 372-374, 513, and 594; any of SEQ ID NOs according to Chothia numbers: 16-18, 161-164, 296, 297, 514-516, 551, and 597; any of SEQ ID NOs according to AbM numbers: 23-25, 170-173, 300, 301, 510-512, 587, and 599; or any of SEQ ID NOs 605 or 612.

[0181] In some implementations, the V of the antibody or its antigen-binding fragment H The region contains CDR-H2, which is a V selected from any one of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774, and 814-832. H The amino acid sequence contained within the region.

[0182] In some embodiments, the antibody or its antigen-binding fragment contains CDR-H1, which is itself or contains an amino acid sequence selected from any of SEQ ID NO:1-3, 140-144, 288, 289, 507 and 593 according to Kabat numbers; CDR-H2, which is itself or contains an amino acid sequence selected from any of SEQ ID NO:4-6, 145-148, 290, 291, 372-374, 513 and 594 according to Kabat numbers; and CDR-H3, which is itself or contains an amino acid sequence selected from any of SEQ ID NO:7-11, 149-157, 279-287, 292, 293, 376-378, 517 and 595 according to Kabat numbers. In some embodiments, the antibody or its antigen-binding fragment contains CDR-H1, which is itself or contains an amino acid sequence selected from any of SEQ ID NO: 12-15, 158-160, 294, 295, 532 and 596 according to Chothia numbers; CDR-H2, which is itself or contains an amino acid sequence selected from any of SEQ ID NO: 16-18, 161-164, 296, 297, 514-516, 551 and 597 according to Chothia numbers; and CDR-H3, which is itself or contains an amino acid sequence selected from any of SEQ ID NO: 7-11, 149-157, 279-287, 292, 293, 376-378, 517 and 595 according to Chothia numbers. In some embodiments, the antibody or its antigen-binding fragment contains CDR-H1, which is itself or contains an amino acid sequence selected from any of SEQ ID NO: 19-22, 165-169, 509, 298, 299, 509, 577 and 598 according to AbM numbers; CDR-H2, which is itself or contains an amino acid sequence selected from any of SEQ ID NO: 23-25, 170-173, 300, 201, 510-512, 587 and 599 according to AbM numbers; and CDR-H3, which is itself or contains an amino acid sequence selected from any of SEQ ID NO: 7-11, 149-157, 279-287, 292, 293, 376-378, 517, 595, 606 and 613 according to AbM numbers. In some embodiments, the antibody or its antigen-binding fragment contains CDR-H1, which is or contains an amino acid sequence selected from any of SEQ ID NO: 604 and 611; CDR-H2, which is or contains an amino acid sequence selected from any of SEQ ID NO: 605 and 612; and CDR-H3, which is or contains an amino acid sequence selected from any of SEQ ID NO: 606 and 613.

[0183] In some implementations, the V of the antibody or its antigen-binding fragment H The region contains CDR-H1, CDR-H2, and / or CDR-H3 according to Kabat numbers. In some embodiments, the V of the antibody or its antigen-binding fragment... H The region includes CDR-H1, CDR-H2, and / or CDR-H3 according to Chothia designations. In some embodiments, the V of the antibody or its antigen-binding fragment... H The region contains CDR-H1, CDR-H2 and / or CDR-H3 according to AbM number.

[0184] In some embodiments, the antibody or its antigen-binding fragment comprises a V-type antigen selected from the group consisting of CDR-H1, CDR-H2, and CDR-H3. HRegion: Based on the Kabat number, CDR-H1, CDR-H2, and CDR-H3 respectively containing the amino acid sequences of SEQ ID NO:1, 4, and 7; CDR-H1, CDR-H2, and CDR-H3 respectively containing the amino acid sequences of SEQ ID NO:2, 5, and 8; CDR-H1, CDR-H2, and CDR-H3 respectively containing the amino acid sequences of SEQ ID NO:2, 5, and 9; CDR-H1, CDR-H2, and CDR-H3 respectively containing the amino acid sequences of SEQ ID NO:2, 5, and 10; CDR-H1, CDR-H2, and CDR-H3 respectively containing the amino acid sequences of SEQ ID NO:3, 6, and 11; CDR-H1, CDR-H2, and CDR-H3 respectively containing the amino acid sequences of SEQ ID NO:140, 145, and 149; respectively containing SEQ ID CDR-H1, CDR-H2, and CDR-H3 of amino acid sequences NO:141, 145, and 149; CDR-H1, CDR-H2, and CDR-H3 of amino acid sequences of SEQ ID NO:141, 145, and 150; CDR-H1, CDR-H2, and CDR-H3 of amino acid sequences of SEQ ID NO:142, 146, and 151; CDR-H1, CDR-H2, and CDR-H3 of amino acid sequences of SEQ ID NO:2, 5, and 152; CDR-H1, CDR-H2, and CDR-H3 of amino acid sequences of SEQ ID NO:143, 147, and 153; CDR-H1, CDR-H2, and CDR-H3 of amino acid sequences of SEQ ID NO:144, 148, and 154; and CDR-H3 of SEQ ID NO:141, 145, and 150. CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 6, and 155; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 5, and 156; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 5, and 157; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 6, and 376; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 372, and 376; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 6, and 376; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:3, 6, and 377;CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 373, and 152, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 5, and 378, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 374, and 9, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:288, 290, and 292, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:289, 291, and 293, respectively; CDR-H1, CDR-H2, and CDR-H3 containing the amino acid sequences of SEQ ID NO:507, 513, and 517, respectively; and CDR-H3 containing the amino acid sequences of SEQ ID NO:2, 373, and 152, respectively. The CDR-H1, CDR-H2, and CDR-H3 sequences of amino acids NO:593, 594, and 595.

[0185] For example, the antibodies or antigen-binding fragments provided herein contain V containing CDR-H1, CDR-H2, and CDR-H3. H The regions, CDR-H1, CDR-H2, and CDR-H3, respectively contain amino acid sequences selected from the following: according to Kabat numbers, SEQ ID NO: 1, 4, and 7; SEQ ID NO: 2, 5, and 8; SEQ ID NO: 2, 5, and 9; SEQ ID NO: 2, 5, and 10; SEQ ID NO: 3, 6, and 11; SEQ ID NO: 140, 145, and 149; SEQ ID NO: 141, 145, and 149; SEQ ID NO: 141, 145, and 150; SEQ ID NO: 142, 146, and 151; SEQ ID NO: 2, 5, and 152; SEQ ID NO: 143, 147, and 153; SEQ ID NO: 144, 148, and 154; SEQ ID NO: 3, 6, and 155; SEQ ID NO: 2, 5, and 156; SEQ ID NO: 2, 5, and 157; SEQ ID NO: 2, 6, and 376; SEQ ID SEQ ID NO:3, 372 and 376; SEQ ID NO:3, 6 and 376; SEQ ID NO:3, 6 and 377; SEQ ID NO:2, 373 and 152; SEQ ID NO:2, 5 and 378; SEQ ID NO:2, 374 and 9; SEQ ID NO:288, 290 and 292; SEQ ID NO:289, 291 and 293; SEQ ID NO:507, 513 and 517; and SEQ ID NO:593, 594 and 595.

[0186] In some embodiments, the CDR-H1, CDR-H2, and CDR-H3 contained in the antibody or its antigen-binding fragment respectively contain V selected from any one of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774, and 814-832. H The amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the region's amino acid sequence. In some embodiments, the CDR-H1, CDR-H2, and CDR-H3 contained in the antibody or its antigen-binding fragment respectively contain the V sequence of SEQ ID NO:609 or SEQ ID NO:617. H The amino acid sequence contained within the region includes CDR-H1, CDR-H2, and CDR-H3. In some embodiments, the antibody or its antigen-binding fragment comprises V containing CDR-H1, CDR-H2, and CDR-H3. H The regions, CDR-H1, CDR-H2 and CDR-H3 respectively contain the amino acid sequences of SEQ ID NO:593, 594 and 595; respectively contain the amino acid sequences of SEQ ID NO:596, 597 and 595; respectively contain the amino acid sequences of SEQ ID NO:598, 599 and 595; or respectively contain the amino acid sequences of SEQ ID NO:611, 612 and 613.

[0187] In some embodiments of the antibody or its antigen-binding fragment provided herein, V H The region includes any one of CDR-H1, CDR-H2, and CDR-H3 as described, and includes V that is respectively connected to any one of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774, and 814-832. H The frame regions FR1, FR2, FR3, and / or FR4 contained within the amino acid sequence of the region have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity. For example, an anti-BCMA antibody or its antigen-binding fragment may contain V selected from any one of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774, and 814-832. HThe amino acid sequences contained in the region contain CDR-H1, CDR-H2, and CDR-H3, respectively, and are related to V, which is selected from any of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774, and 814-832. H The frame regions (e.g., FR1, FR2, FR3, and / or FR4) contained within the amino acid sequence of the region have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity with the frame regions (e.g., FR1, FR2, FR3, and / or FR4). In some embodiments, V H The region comprises FR1, FR2, FR3, and / or FR4 selected from the following: FR1 comprising an amino acid sequence selected from any of SEQ ID NO: 59-63, 195-203, 308, 309, and 434-439; FR2 comprising an amino acid sequence selected from any of SEQ ID NO: 64-66, 204-209, 310, and 311; FR3 comprising an amino acid sequence selected from any of SEQ ID NO: 67-69, 210-216, 312, 313, 441, and 443; and / or FR4 comprising an amino acid sequence selected from any of SEQ ID NO: 70-71, 217-220, 314, 315, 444, and 445. In some embodiments, V H The region contains: FR1 containing the amino acid sequence of SEQ ID NO:61, FR2 containing the amino acid sequence of SEQ ID NO:65, FR3 containing the amino acid sequence of SEQ ID NO:69, and / or FR4 containing the amino acid of SEQ ID NO:70.

[0188] In some embodiments, the antibody or its antigen-binding fragment comprises a V consisting of an amino acid sequence selected from any one of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774, and 814-832. H district.

[0189] Antibodies and antigen-binding fragments thereof having sequences having at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with such sequences are also provided. For example, this document provides an antibody or antigen-binding fragment comprising V H District, V HThe region includes V selected from any one of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774, and 814-832. H The amino acid sequence of the region has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity.

[0190] In some implementations, the antibody contains only V H The region sequence or its sufficient antigen-binding portion (such as V as described above) H Single-domain antibody against any of the sequences (e.g., CDR-H1, CDR-H2, CDR-H3 and / or CDR-H4).

[0191] In some implementations, the present invention includes V H The antibody (e.g., an anti-BCMA antibody) or its antigen-binding fragment further comprises a light chain or sufficient antigen-binding moiety thereof. For example, in some embodiments, the antibody or its antigen-binding fragment contains V H District and V L District, or V H and V L The region contains a sufficient antigen-binding portion. In such implementations, V H The region sequence can be V as described above. H Any of the sequences. In some such embodiments, the antibody is an antigen-binding fragment, such as Fab or scFv. In some such embodiments, the antibody is a full-length antibody that also contains a constant region.

[0192] In some embodiments, the antibody (e.g., its antigen-binding fragment) has a light chain variable (VL) region having an amino acid sequence selected from any of SEQ ID NO:116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777, and 833-849, or a VL region selected from any of SEQ ID NO:116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777, and 833-849. L The amino acid sequence of the region has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity. In some embodiments, the antibody or antigen-binding fragment has the VL region described in any one of WO 2016090327, WO 2016090320, or WO 2017173256.

[0193] In some embodiments, the antibody described herein (e.g., anti-BCMA antibody) or its antigen-binding fragment V L The region is V, which includes light chain complementarity-determining region 3 (CDR-L3). L The region, CDR-L3 contains the amino acid sequence X1X2X3X4X5X6X7X8X9X. 10 X 11 X 12 (SEQ ID NO:358), wherein X1 is A, C, G, H, I, Q, or S; X2 is A, Q, S, or V; X3 is S, W, or Y; X4 is D, F, G, H, or Y; X5 is D, G, M, R, S, or T; X6 is A, G, H, L, R, S, T, or Y; X7 is L, P, R, S, or not present; X8 is D, G, N, R, S, T, or not present; X9 is A, G, H, L, P, or not present; X 10 F, S, or not present; X 11 It can be L, P, W, or Y; and X 12 For S, T, or V. In some implementations, in this CDR-L3, X1 is H; X2 is V; X3 is W; X4 is D; X5 is R; X6 is S; X7 is R; X8 is D; X9 is H; X 10 Does not exist; X 11 Let Y be X; and X be X 12 V.

[0194] In some embodiments, the antibody or its antigen-binding fragment contains a CDR-L3 comprising an amino acid sequence selected from any of SEQ ID NO:47-58, 184-194, 306, 307, 415-427, 429-433, 591, and 603 according to Kabat, Chothia, or AbM numbers. In some embodiments, the antibody or its antigen-binding fragment contains a CDR-L3 having an amino acid sequence having SEQ ID NO:591 or 603 according to Kabat, Chothia, or AbM numbers. In any such example, the antibody or its antigen-binding fragment may contain a V selected from any of SEQ ID NO:116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777, and 833-849. LThe region sequence, wherein the corresponding CDR-L3 sequence contained therein (e.g., corresponding to amino acid residues L89 to L97 according to the Kabat number) is replaced by a CDR-L3 sequence selected from any one of SEQ ID NO: 47-58, 184-194, 306, 307, 415-427, 429-433, 591 and 603 according to the Kabat number, Chothia number or AbM number.

[0195] In some implementations, the V of the antibody or its antigen-binding fragment L The region contains V selected from any one of SEQ ID NO: 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777, and 833-849. L The CDR-L3 contained within the amino acid sequence of the region. In some embodiments, the V of the antibody or its antigen-binding fragment... L The region contains V of SEQ ID NO:610 or SEQ ID NO:618 L The CDR-L3 contained in the amino acid sequence of the region.

[0196] In some embodiments, the antibody described herein (e.g., anti-BCMA antibody) or its antigen-binding fragment V L The region is V including light chain complementarity-determining region 1 (CDR-L1). L The region, CDR-L1 contains the amino acid sequence: X1X2X3X4X5X6X7X8X9X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 (SEQ ID NO:356), wherein X1 is G, K, R, S, or T; X2 is A, G, or S; X3 is G, N, S, or T; X4 is G, K, N, Q, R, or S; X5 is S or does not exist; X6 is D, N, V, or does not exist; X7 is L, V, or does not exist; X8 is H, S, Y, or does not exist; X9 is S, T, or does not exist; X 10 S or does not exist; X 11 For D, G, I, N, S or not present; X 12 The inequality is D, E, G, K, I, N, or it does not exist; X 13 For F, G, K, N, R, S, Y, or not present; X 14 For D, K, N, T, or none; X 15 For A, D, G, L, N, S, T, or Y; X 16 For L or V; X17 The values ​​are A, H, N, Q, or S. In some implementations, X1 is G; X2 is A; X3 is N; X4 is N; X5 does not exist; X6 does not exist; X7 does not exist; X8 does not exist; X9 does not exist; X 10 Does not exist; X 11 For I; X 12 For G; X 13 S; X 14 K; X 15 S; X 16 For V; X 17 For H.

[0197] In some embodiments, the antibody or its antigen-binding fragment contains a CDR-L1 comprising an amino acid sequence selected from any of SEQ ID NO:26-36, 174-178, 302, 303, 380-392, 394-398, 589, or 601 according to the Kabat, Chothia, or AbM number. In some embodiments, the antibody or its antigen-binding fragment contains a CDR-L1 comprising an amino acid sequence selected from any of SEQ ID NO:607 and 614. In some embodiments, the antibody or its antigen-binding fragment contains a CDR-L1 having an amino acid sequence having SEQ ID NO:589 or 601 according to the Kabat, Chothia, or AbM number. In any such instance, the antibody or its antigen-binding fragment may contain V selected from any of SEQ ID NO: 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777, and 833-849. L The region sequence, wherein the corresponding CDR-L1 sequence contained therein (e.g., corresponding to amino acid residues L24 to L34 according to the Kabat number) is replaced by a CDR-L1 sequence selected from any one of SEQ ID NO: 26-36, 174-178, 302, 303, 380-392, 394-398, 589 or 601 according to the Kabat number, Chothia number or AbM number.

[0198] In some implementations, the V of the antibody or its antigen-binding fragment L The region contains V selected from any one of SEQ ID NO: 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777, and 833-849. L The CDR-L1 contained within the amino acid sequence of the region. In some embodiments, the V of the antibody or its antigen-binding fragment... LThe region contains V of SEQ ID NO: 589, 601, 607 or 614 L The CDR-L1 contained in the amino acid sequence of the region.

[0199] In some embodiments, the antibody described herein (e.g., anti-BCMA antibody) or its antigen-binding fragment V L The region is V, which includes light chain complementarity-determining region 2 (CDR-L2). L The CDR-L2 contains the amino acid sequence X1X2X3X4X5X6X7 (SEQ ID NO:357), wherein X1 is A, D, E, N, S, V, or W; X2 is A, D, N, S, or V; X3 is A, D, H, I, N, or S; X4 is D, K, N, Q, R, or T; X5 is L, R, or V; X6 is A, E, P, or Q; and X7 is A, D, S, or T. In some embodiments, X1 is D; X2 is D; X3 is D; X4 is D; X5 is R; X6 is P; and X7 is S.

[0200] In some embodiments, the antibody or its antigen-binding fragment contains a CDR-L2 comprising an amino acid sequence selected from any of SEQ ID NO:37-46, 179-183, 304, 305, 399-409, 411-414, 590, and 602 according to Kabat, Chothia, or AbM numbers. In some embodiments, the antibody or its antigen-binding fragment contains a CDR-L2 comprising an amino acid sequence selected from any of SEQ ID NO:608 and 615. In some embodiments, the antibody or its antigen-binding fragment contains a CDR-L2 having an amino acid sequence having SEQ ID NO:590 or SEQ ID NO:602 according to Kabat, Chothia, or AbM numbers. In any such example, the antibody or its antigen-binding fragment may contain a VL region sequence selected from any of SEQ ID NO:116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777, and 833-849, wherein the corresponding CDR-L2 sequence contained therein (e.g., corresponding to amino acid residues L50 to L56 according to Kabat numbers) is replaced by a CDR-L2 sequence selected from any of SEQ ID NO:37-46, 179-183, 304, 305, 399-409, 411-414, 590, and 602 according to Kabat numbers, Chothia numbers, or AbM numbers, or by any of SEQ ID NO:608 and 615.

[0201] In some implementations, the V of the antibody or its antigen-binding fragmentL The region contains V selected from any one of SEQ ID NO: 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777, and 833-849. L The CDR-L2 contained within the amino acid sequence of the region. In some embodiments, the VL region of the antibody or its antigen-binding fragment contains the V of SEQ ID NO: 589, 601, 607 or 614. L The CDR-L2 contained within the amino acid sequence of the region.

[0202] In some embodiments, the antibody or its antigen-binding fragment contains a CDR-L1 that is itself or contains an amino acid sequence selected from any of the following according to the Kabat, Chothia, or AbM numbers: SEQ ID NO: 26-36, 174-178, 302, 303, 380-392, 394-398, 589, or 601; a CDR-L2 that is itself or contains an amino acid sequence selected from any of the following according to the Kabat, Chothia, or AbM numbers: SEQ ID NO: 37-46, 179-183, 304, 305, 399-409, 411-414, 590, and 602; and a CDR-L2 that is itself or contains an amino acid sequence selected from any of the following according to the Kabat, Chothia, or AbM numbers: SEQ ID NO: 26-36, 174-178, 302, 303, 380-392, 394-398, 589, or .... CDR-L3 of any of the amino acid sequences of NO:47-58, 184-194, 306, 307, 415-427, 429-433, 591 and 603.

[0203] In some implementations, the V of the antibody or its antigen-binding fragment L The region contains CDR-L1, CDR-L2, and / or CDR-L3 according to Kabat designations. In some embodiments, the V of the antibody or its antigen-binding fragment... L The region includes CDR-L1, CDR-L2, and / or CDR-L3 according to Chothia designations. In some embodiments, the V of the antibody or its antigen-binding fragment... L The region contains CDR-L1, CDR-L2 and / or CDR-L3 according to AbM numbering.

[0204] In some embodiments of the antibody or its antigen-binding fragment provided herein, V LThe region comprises CDR-L1, CDR-L2, and CDR-L3 selected from the following: CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NO:26, 37, and 47, respectively; CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NO:27, 38, and 48, respectively; CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NO:28, 39, and 49, respectively; CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NO:29, 40, and 50, respectively; CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NO:30, 39, and 51, respectively; CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NO:31, 41, and 52, respectively; and CDR-L3 comprising the amino acid sequences of SEQ ID NO:26, 37, and 47, respectively. CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences NO:32, 42, and 53; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:30, 39, and 54; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:33, 43, and 55; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:34, 44, and 56; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:35, 45, and 57; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:36, 46, and 58; and CDR-L3 of SEQ ID NO:30, 39, and 54. CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences NO:174, 179, and 184; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:174, 179, and 185; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:174, 179, and 186; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:174, 179, and 187; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:175, 180, and 188; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:174, 179, and 189 ...5, 180, and 188; CDR-L1, CDR-L2, and CDR-L3 of CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences NO:176, 181, and 190;The following amino acid sequences are included: CDR-L1, CDR-L2, and CDR-L3, respectively, containing the amino acid sequences of SEQ ID NO: 177, 182, and 191; CDR-L1, CDR-L2, and CDR-L3, respectively, containing the amino acid sequences of SEQ ID NO: 174, 179, and 192; CDR-L1, CDR-L2, and CDR-L3, respectively, containing the amino acid sequences of SEQ ID NO: 178, 183, and 193; CDR-L1, CDR-L2, and CDR-L3, respectively, containing the amino acid sequences of SEQ ID NO: 178, 183, and 194; CDR-L1, CDR-L2, and CDR-L3, respectively, containing the amino acid sequences of SEQ ID NO: 30, 399, and 415; CDR-L1, CDR-L2, and CDR-L3, respectively, containing the amino acid sequences of SEQ ID NO: 380, 400, and 416; and CDR-L3, respectively, containing the amino acid sequences of SEQ ID NO: 177, 182, and 191; and CDR-L3, respectively, containing the amino acid sequences of SEQ ID NO: 174, 179, and 192; CDR-L1, CDR-L2, and CDR-L3, respectively, containing the amino acid sequences of SEQ ID NO: 178, 183, and 193; CDR-L1, CDR-L2, and CDR-L3, respectively, containing the amino acid sequences of SEQ ID NO: 30, 399, and 415; and CDR-L3, respectively, containing the amino acid sequences of SEQ ID NO: 380, 400, and 416; and CDR-L3, respectively, containing the amino acid CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences NO:33, 43, and 421; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:381, 401, and 417 respectively; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:382, 402, and 418 respectively; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:383, 403, and 419 respectively; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:384, 39, and 54 respectively; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:385, 180, and 58 respectively; and CDR-L3 of SEQ ID NO:384, 39, and 54 respectively. CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences NO:175, 180, and 188; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:386, 404, and 420; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:387, 405, and 422; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:388, 406, and 423; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:388, 407, and 424; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO:389, 408, and 425; and CDR-L3 of SEQ ID NO:386, 404, and 420. CDR-L1, CDR-L2, and CDR-L3 of the amino acid sequences of IDNO:390, 183, and 193;The following amino acid sequences are included: CDR-L1, CDR-L2, and CDR-L3, respectively, containing the amino acid sequences of SEQ ID NO:391, 409, and 426; CDR-L1, CDR-L2, and CDR-L3, respectively, containing the amino acid sequences of SEQ ID NO:392, 40, and 427; CDR-L1, CDR-L2, and CDR-L3, respectively, containing the amino acid sequences of SEQ ID NO:394, 39, and 429; CDR-L1, CDR-L2, and CDR-L3, respectively, containing the amino acid sequences of SEQ ID NO:395, 411, and 430; CDR-L1, CDR-L2, and CDR-L3, respectively, containing the amino acid sequences of SEQ ID NO:396, 412, and 431; CDR-L1, CDR-L2, and CDR-L3, respectively, containing the amino acid sequences of SEQ ID NO:396, 412, and 58; and CDR-L3, respectively, containing the amino acid sequences of SEQ ID NO:396, 412, and 58. CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO: 397, 413, and 432; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO: 398, 414, and 433; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO: 302, 304, and 306; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO: 303, 305, and 307; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO: 589, 590, and 591; CDR-L1, CDR-L2, and CDR-L3 of amino acid sequences of SEQ ID NO: 607, 608, and 591; and CDR-L3 of SEQ ID NO: 398, 414, and 433. CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NO: 601, 602, and 603; and CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NO: 614, 615, and 603, respectively. In some embodiments of the antibody or its antigen-binding fragment provided herein, the VL region comprises CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NO: 589, 590, and 591; SEQ ID NO: 607, 608, and 591; SEQ ID NO: 601, 602, and 603, respectively; or SEQ ID NO: 614, 615, and 603, respectively.

[0205] For example, the antibodies or antigen-binding fragments provided herein contain V containing CDR-L1, CDR-L2, and CDR-L3. LThe CDR-L1, CDR-L2, and CDR-L3 regions comprise amino acid sequences selected from the following: SEQ ID NO: 26, 37, and 47; SEQ ID NO: 27, 38, and 48; SEQ ID NO: 28, 39, and 49; SEQ ID NO: 29, 40, and 50; SEQ ID NO: 30, 39, and 51; SEQ ID NO: 31, 41, and 52; SEQ ID NO: 32, 42, and 53; SEQ ID NO: 30, 39, and 54; SEQ ID NO: 33, 43, and 55; SEQ ID NO: 34, 44, and 56; SEQ ID NO: 35, 45, and 57; SEQ ID NO: 36, 46, and 58; SEQ ID NO: 174, 179, and 184; SEQ ID NO: 174, 179, and 185; SEQ ID NO: 174, 179, and 186; SEQ ID SEQ ID NO: 174, 179 and 187; SEQ ID NO: 175, 180 and 188; SEQ ID NO: 174, 179 and 189; SEQ ID NO: 176, 181 and 190; SEQ ID NO: 177, 182 and 191; SEQ ID NO: 174, 179 and 192; SEQ ID NO: 178, 183 and 193; SEQ ID NO: 178, 183 and 194; SEQ ID NO: 30, 399 and 415; SEQ ID NO: 380, 400 and 416; SEQ ID NO: 33, 43 and 421; SEQ ID NO: 381, 401 and 417; SEQ ID NO: 382, ​​402 and 418; SEQ ID NO: 383, 403 and 419; SEQ ID NO: 384, 39 and 54; SEQ ID SEQ ID NO:385, 180 and 58; SEQ ID NO:175, 180 and 188; SEQ ID NO:386, 404 and 420; SEQ ID NO:387, 405 and 422; SEQ ID NO:388, 406 and 423; SEQ ID NO:388, 407 and 424; SEQ ID NO:389, 408 and 425; SEQ ID NO:390, 183 and 193; SEQ ID NO:391, 409 and 426; SEQ ID NO:392, 40 and 427; SEQ ID NO:394, 39 and 429; SEQ ID NO:395, 411 and 430; SEQ ID NO:396, 412 and 431; SEQ ID NO:396, 412 and 58; SEQ ID NO:397, 413 and 432; SEQ ID NO:398, 414 and 433;SEQ ID NO: 589, 590, and 591; SEQ ID NO: 607, 608, and 591; SEQ ID NO: 601, 602, and 603; or SEQ ID NO: 614, 615, and 603.

[0206] In some embodiments, the antibody or its antigen-binding fragment contains V selected from any one of SEQ ID NO: 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777, and 833-849. L The amino acid sequences of the regions contain CDR-L1, CDR-L2, and CDR-L3, respectively. In some embodiments, the antibody contains V selected from SEQ ID NO:610 or SEQ ID NO:618. L The amino acid sequences in the region contain CDR-L1, CDR-L2 and CDR-L3, respectively.

[0207] In some embodiments, the antibody or its antigen-binding fragment comprises a VL region including CDR-L1, CDR-L2 and CDR-L3, wherein CDR-L1, CDR-L2 and CDR-L3 respectively comprise the amino acid sequences of SEQ ID NO:601, 602 and 603; or respectively comprise the amino acid sequences of SEQ ID NO:614, 615 and 603.

[0208] In some embodiments of the antibody or its antigen-binding fragment provided herein, V L The region includes any one of CDR-L1, CDR-L2, and CDR-L3 as described, and includes V that is respectively connected to any one of SEQ ID NO: 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777, and 833-849. L The frame regions FR1, FR2, FR3, and / or FR4 contained within the amino acid sequence of the region have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity. For example, an anti-BCMA antibody or its antigen-binding fragment may contain V selected from any one of SEQ ID NO: 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777, and 833-849. LThe amino acid sequences contained in the region contain CDR-L1, CDR-L2, and CDR-L3, and are associated with V, which is selected from any of SEQ ID NO: 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777, and 833-849. L The frame regions (e.g., FR1, FR2, FR3, and / or FR4) contained within the amino acid sequence of the region have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% sequence identity with the frame regions (e.g., FR1, FR2, FR3, and / or FR4). In some embodiments, V L The region comprises FR1, FR2, FR3, and / or FR4 selected from the following: FR1 comprising an amino acid sequence selected from any of SEQ ID NO:72-82, 221-227, 316, 317, 446-459, and 461-466; FR2 comprising an amino acid sequence selected from any of SEQ ID NO:83-92, 228-232, 318, 319, 467-477, and 479-482; FR3 comprising an amino acid sequence selected from any of SEQ ID NO:93-101, 233-242, 320, 321, 483-495, and 497-501; and / or FR4 comprising an amino acid sequence selected from any of SEQ ID NO:102-109, 243-246, 322, 323, 502-506, and 508. In some embodiments, V L The region contains FR1 containing the amino acid sequence of SEQ ID NO:79, FR2 containing the amino acid sequence of SEQ ID NO:89, FR3 containing the amino acid sequence of SEQ ID NO:98, and / or FR4 containing the amino acid sequence of SEQ ID NO:108.

[0209] In some embodiments, the antibody or its antigen-binding fragment comprises a V consisting of an amino acid sequence selected from any one of SEQ ID NO: 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777, and 833-849. L In some embodiments, the antibody or its antigen-binding fragment contains a V-shaped structure comprising the amino acid sequence of SEQ ID NO:610 or SEQ ID NO:618. L district.

[0210] Antibodies with sequences having at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with such sequences are also provided.

[0211] In some implementations, the V of the antibody or fragment H The region contains an amino acid sequence selected from any one of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774, and 814-832, and the V of the antibody or fragment... L The region contains an amino acid sequence selected from any one of SEQ ID NO:116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777 and 833-849.

[0212] Antibodies and antigen-binding fragments thereof having a sequence having at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with such sequences are also provided. For example, this document provides an antibody or antigen-binding fragment containing a V that comprises a sequence selected from SEQ ID NO: 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777, and 833-849. L V refers to an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity. L The region and / or contains V that is selected from any of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774 and 814-832. H The region's amino acid sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity. In some embodiments, the antibody or antigen-binding fragment contains a V-shaped structure comprising an amino acid sequence selected from any one of SEQ ID NO: 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 618, 775-777, and 833-849. L The region and V selected from any one of SEQ ID NO: 110-115, 247-256, 324, 325, 518-531, 533, 609, 617, 772-774 and 814-832 H district.

[0213] In some implementation schemes, V H The region is or contains a V that is any one of SEQ ID NO: 617, 110-115, 247-256, 324, 325, 518-531, 533, 609, 772-774 or 814-832. H The region sequence has an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity; and V L The region is an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the VL region sequence of any of SEQ ID NO: 618, 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 775-777, or 833-849.

[0214] In some implementation schemes, V H District and V L The regions respectively contain the sequences of SEQ ID NO:617 and 618 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:110 and 116 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain sequences of SEQ ID NO:111 and 117 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:110 and 118 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain sequences of SEQ ID NO:110 and 119 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:110 and 120 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:110 and 121 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:110 and 122 or amino acid sequences having at least 90% identity with them; VH District and V L The regions respectively contain the sequences of SEQ ID NO:110 and 123 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain sequences of SEQ ID NO:112 and 124 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:113 and 125 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:114 and 126 or amino acid sequences having at least 90% identity with them; V H District and V L The VH and VL regions respectively contain the sequences of SEQ ID NO: 115 and 127 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 247 and 257 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:248 and 258, or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:249 and 259 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:250 and 260 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:251 and 261 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:252 and 262 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain sequences of SEQ ID NO:253 and 263 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain sequences of SEQ ID NO:254 and 264 or amino acid sequences having at least 90% identity with them; V H District and V LThe regions respectively contain the sequences of SEQ ID NO:255 and 265 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:256 and 266 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:256 and 267 or amino acid sequences having at least 90% identity with them; V H District and V LThe VH and VL regions respectively contain the sequences of SEQ ID NO: 518 and 534 or amino acid sequences with at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 519 and 535 or amino acid sequences with at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 115 and 536 or amino acid sequences with at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 520 and 264 or amino acid sequences with at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 521 and 537 or amino acid sequences with at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 522 and 538 or amino acid sequences with at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 523 and 539 or amino acid sequences with at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 518 and 534 or amino acid sequences with at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 519 and 535 ...9 and 535 or amino acid sequences with at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 5 The sequences of SEQ ID NO:519 and 540 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO:524 and 541 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO:525 and 261 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO:526 and 542 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO:527 and 543 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO:528 and 544 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO:529 and 545 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO:529 and 545 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO:529 and 541 ... The sequences of SEQ ID NO: 528 and 546 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 522 and 547 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 256 and 548 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 530 and 549 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 531 and 550 or amino acid sequences having at least 90% identity with them;The VH and VL regions respectively contain the sequences of SEQ ID NO: 519 and 552 or amino acid sequences with at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 110 and 553 or amino acid sequences with at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 533 and 554 or amino acid sequences with at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 115 and 555 or amino acid sequences with at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 524 and 556 or amino acid sequences with at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 519 and 557 or amino acid sequences with at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 519 and 557; the VH and VL regions respectively contain the sequences of SEQ ID NO: 519 and 552 or amino acid sequences with at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 519 and 552 ... The sequences of SEQ ID NO: 324 and 326 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 325 and 327 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 609 and 610 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 772 and 775 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 773 and 776 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 774 and 777 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 815 and 833 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 324 and 326 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 325 and 327 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 609 and 610 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 772 and 775 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 773 and 776 or amino acid sequences having at least 90% identity with them; the VH and VL regions respectively contain the sequences of SEQ ID NO: 774 and 777 or amino The sequences of SEQ ID NO: 816 and 834 or amino acid sequences having at least 90% identity with them; the VH region and VL region respectively contain the sequences of SEQ ID NO: 817 and 835 or amino acid sequences having at least 90% identity with them; the VH region and VL region respectively contain the sequences of SEQ ID NO: 818 and 836 or amino acid sequences having at least 90% identity with them; V; H District and V L The regions respectively contain sequences of SEQ ID NO:819 and 837 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:820 and 838, or amino acid sequences having at least 90% identity with them; V H District and V LThe regions respectively contain sequences of SEQ ID NO:821 and 839, or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain sequences of SEQ ID NO:822 and 840, or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:823 and 841, or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:824 and 842 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:825 and 843, or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain sequences of SEQ ID NO:826 and 844, or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:827 and 845 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:828 and 846, or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain sequences of SEQ ID NO:829 and 847 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain sequences of SEQ ID NO: 830 and 847 or amino acid sequences having at least 90% identity with them; V H District and V L The regions respectively contain the sequences of SEQ ID NO:831 and 848 or amino acid sequences having at least 90% identity with them; or V H District and V L The regions respectively contain the sequences of SEQ ID NO:832 and 849 or amino acid sequences that are at least 90% identical to them.

[0215] In some implementations, the V of the antibody or its antigen-binding fragment HThe regions containing CDR-H1, CDR-H2, and CDR-H3 respectively contain V values ​​selected from any one of SEQ ID NO: 617, 110-115, 247-256, 324, 325, 518-531, 533, 609, 772-774, and 814-832. H The amino acid sequences contained within the region's amino acid sequence include CDR-H1, CDR-H2, and CDR-H3; and the CDR-L1, CDR-L2, and CDR-L3 contained therein each contain a V sequence selected from any one of SEQ ID NO: 618, 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 775-777, and 833-849. L The amino acid sequences of CDR-L1, CDR-L2 and CDR-L3 contained in the region's amino acid sequence.

[0216] In some implementation schemes, V H For or included in SEQ ID NO:617 V H The sequence contains CDR-H1, CDR-H2, and CDR-H3; and V L For or included in SEQ ID NO:618 V L The sequence contains CDR-L1, CDR-L2, and CDR-L3; V H For or included in SEQ ID NO:256 V H The sequence contains CDR-H1, CDR-H2, and CDR-H3; and V L For or included in SEQ ID NO:267 V L The sequence contains CDR-L1, CDR-L2, and CDR-L3; V H For or included in SEQ ID NO:519 V H The sequence contains CDR-H1, CDR-H2, and CDR-H3; and V L For or included in SEQ ID NO:535 V L The sequence contains CDR-L1, CDR-L2, and CDR-L3; V H For or included in SEQ ID NO:115 V H The sequence contains CDR-H1, CDR-H2, and CDR-H3; and V L For or included in SEQ ID NO:536 V L The sequence contains CDR-L1, CDR-L2, and CDR-L3; V H For or included in SEQ ID NO:609 VH The sequence contains CDR-H1, CDR-H2, and CDR-H3; and V L For or included in SEQ ID NO:610 V L The sequence contains CDR-L1, CDR-L2, and CDR-L3. In some implementations, V H The region contains the V shown in SEQ ID NO:617 H The amino acid sequence of the region contains CDR-H1, CDR-H2, and CDR-H3; and V L The region contains the V shown in SEQ ID NO:618 L The amino acid sequence of the region contains CDR-L1, CDR-L2, and CDR-L3; V H The region contains the V shown in SEQ ID NO:256 H The amino acid sequence of the region contains CDR-H1, CDR-H2, and CDR-H3; and V L The region contains the V shown in SEQ ID NO:267 L The amino acid sequence of the region contains CDR-L1, CDR-L2, and CDR-L3; V H The region contains the V shown in SEQ ID NO:519 H The amino acid sequence of the region contains CDR-H1, CDR-H2, and CDR-H3; and V L The region contains the V shown in SEQ ID NO:535 L The amino acid sequence of the region contains CDR-L1, CDR-L2, and CDR-L3; V H The region contains the V shown in SEQ ID NO:115 H The amino acid sequence of the region contains CDR-H1, CDR-H2, and CDR-H3; and V L The region contains the V shown in SEQ ID NO:536 L The amino acid sequence of the region contains CDR-L1, CDR-L2, and CDR-L3; or V H The region contains the V shown in SEQ ID NO:609 H The amino acid sequence of the region contains CDR-H1, CDR-H2, and CDR-H3; and V L The region contains the V shown in SEQ ID NO:610 L The amino acid sequence of the region contains CDR-L1, CDR-L2 and CDR-L3.

[0217] In some implementation schemes, V HThe region is or includes (a) a CDR-H1 containing a sequence selected from any one of SEQ ID NO: 593, 611, 1-3, 140-144, 288, 289, 294, 295, 507, 532, 596, or 604; (b) a CDR-H2 containing a sequence selected from any one of SEQ ID NO: 594, 612, 4-6, 145-148, 290, 291, 296, 297, 372-374, 513, 551, 597, or 605; and (c) a CDR-H3 containing a sequence selected from any one of SEQ ID NO: 595, 613, 7-11, 149-157, 279-287, 292, 293, 376-378, 517, or 606; and V L The region is or includes (a) a CDR-L1 containing a sequence selected from any one of SEQ ID NO: 601, 614, 26-36, 174-178, 302, 303, 380-392, 394-398, 589 or 607; (b) a CDR-L2 containing a sequence selected from any one of SEQ ID NO: 602, 615, 37-46, 179-183, 304, 305, 399-409, 411-414, 590 or 608; and (c) a CDR-L3 containing a sequence selected from any one of SEQ ID NO: 603, 47-58, 184-194, 306, 307, 415-427, 429-433 or 591.

[0218] In some implementation schemes, V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 593, 594, and 595, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 601, 602, and 603; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:1, 4, and 7, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, which respectively contain sequences of SEQ ID NO:26, 37, and 47; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:2, 5, and 8, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, which respectively contain sequences of SEQ ID NO:27, 38, and 48; V HThe region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:1, 4, and 7, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO:28, 39, and 49; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:1, 4, and 7, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO:29, 40, and 50; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:1, 4, and 7, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 30, 39, and 51; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:1, 4, and 7, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO:31, 41, and 52; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:1, 4, and 7, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO:32, 42, and 53; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:1, 4, and 7, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, which respectively contain sequences of SEQ ID NO: 30, 39, and 54; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:2, 5, and 9, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO:33, 43, and 55; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:2, 5, and 10, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO:34, 44, and 56; VH The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:3, 6, and 11, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO:35, 45, and 57; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:2, 5, and 10, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO:36, 46, and 58; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 140, 145, and 149, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 174, 179, and 184; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 141, 145, and 149, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 174, 179, and 185; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 141, 145, and 150, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 174, 179, and 186; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 142, 146, and 151, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 174, 179, and 187; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:2, 5, and 152, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 175, 180, and 188; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 143, 147, and 153, and V LThe region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 174, 179, and 189; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 144, 148, and 154, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 176, 181, and 190; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:3, 6, and 155, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 177, 182, and 191; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 2, 5, and 156, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 174, 179, and 192; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:2, 5, and 157, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 178, 183, and 193; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:2, 5, and 157, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 178, 183, and 194; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:2, 6, and 376, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, which respectively contain sequences of SEQ ID NO: 30, 399, and 415; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 1, 4, and 7, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 380, 400, and 416; V HThe region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:2, 5, and 10, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO:33, 43, and 421; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:3, 6, and 155, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 177, 182, and 191; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:3, 372, and 376, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO:381, 401, and 417; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:3, 6, and 376, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO:382, 402, and 418; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:3, 6, and 377, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 383, 403, and 419; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:1, 4, and 7, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 384, 39, and 54; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:2, 5, and 10, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 385, 180, and 58; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 2, 373, and 152, and V LThe region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 175, 180, and 188; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:3, 6, and 11, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 386, 404, and 420; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:2, 5, and 378, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO:33, 43, and 421; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:2, 5, and 9, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 387, 405, and 422; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 2, 5, and 9, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 388, 406, and 423; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:2, 5, and 9, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 388, 407, and 424; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:3, 6, and 376, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 389, 408, and 425; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:2, 5, and 157, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 390, 183, and 193; V HThe region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:2, 374, and 9, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO:391, 409, and 426; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:1, 4, and 7, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO:392, 40, and 427; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:1, 4, and 7, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 394, 39, and 429; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:1, 4, and 7, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 395, 411, and 430; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:1, 4, and 7, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO:28, 39, and 49; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:2, 5, and 10, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 396, 412, and 431; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:2, 5, and 10, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 396, 412, and 58; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 2, 5, and 10, and V LThe region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 397, 413, and 432; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO:1, 4, and 7, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 398, 414, and 433; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 288, 290, and 292, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 302, 304, and 306; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 288, 290, and 292, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 302, 304, and 306; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 289, 291, and 293, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 303, 305, and 307; V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 289, 291, and 293, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 303, 305, and 307; or V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 507, 513, and 517, and V L The region contains CDR-L1, CDR-L2 and CDR-L3, which respectively contain sequences of SEQ ID NO:589, 590 and 591.

[0219] In some implementation schemes, V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 596, 597, and 595, and V LThe region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 601, 602, and 603. In some embodiments, V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 598, 599, and 595, and V L The region contains CDR-L1, CDR-L2, and CDR-L3, respectively, containing sequences of SEQ ID NO: 601, 602, and 603. In some embodiments, V H The region contains CDR-H1, CDR-H2, and CDR-H3, which respectively contain sequences of SEQ ID NO: 611, 612, and 613, and V L The region contains CDR-L1, CDR-L2 and CDR-L3, which respectively contain sequences of SEQ ID NO:614, 615 and 603.

[0220] In some implementation schemes, V H The region is or contains a sequence of any one of SEQ ID NO: 617, 110-115, 247-256, 324, 325, 518-531, 533, 609, 772-774, or 814-832; and V L The region is a sequence that is or contains any of SEQ ID NO: 618, 116-127, 257-267, 326, 327, 534-550, 552-557, 610, 775-777 or 833-849.

[0221] In some implementations, the V of the antibody or its antigen-binding fragment H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:110 and 116; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:111 and 117; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:110 and 118; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:110 and 119; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:110 and 120; V of the antibody or its antigen-binding fragment. H and V LThe regions respectively contain the amino acid sequences of SEQ ID NO:110 and 121; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:110 and 122; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:110 and 123; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:112 and 124; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:113 and 125; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:114 and 126; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:115 and 127; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:247 and 257; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:248 and 258; V of the antibody or its antigen-binding fragment H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:249 and 259; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:250 and 260; V of the antibody or its antigen-binding fragment H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:251 and 261; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:252 and 262; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:253 and 263; V of the antibody or its antigen-binding fragment H and V LThe regions respectively contain the amino acid sequences of SEQ ID NO:254 and 264; V of the antibody or its antigen-binding fragment H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:255 and 265; V of the antibody or its antigen-binding fragment H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:256 and 266; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:256 and 267; V of the antibody or its antigen-binding fragment H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:518 and 534; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:519 and 535; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:115 and 536; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:520 and 264; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:521 and 537; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:522 and 538; V of the antibody or its antigen-binding fragment H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:523 and 539; V of the antibody or its antigen-binding fragment H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:519 and 540; V of the antibody or its antigen-binding fragment H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:524 and 541; V of the antibody or its antigen-binding fragment H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:525 and 261; V of the antibody or its antigen-binding fragment. H and V LThe regions respectively contain the amino acid sequences of SEQ ID NO:526 and 542; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:527 and 543; V of the antibody or its antigen-binding fragment H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:528 and 544; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:529 and 545; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:528 and 546; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:522 and 547; V of the antibody or its antigen-binding fragment H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:256 and 548; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:530 and 549; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:531 and 550; V of the antibody or its antigen-binding fragment H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:519 and 552; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:110 and 553; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:110 and 118; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:533 and 554; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:115 and 555; V of the antibody or its antigen-binding fragment. H and V LThe regions respectively contain the amino acid sequences of SEQ ID NO:524 and 556; V of the antibody or its antigen-binding fragment H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:519 and 557; V of the antibody or its antigen-binding fragment H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:324 and 326; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:325 and 327; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:609 and 610; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:617 and 618; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:772 and 775; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:773 and 776; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:774 and 777; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:815 and 833; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:816 and 834; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:817 and 835; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:818 and 836; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:819 and 837; V of the antibody or its antigen-binding fragment. H and V LThe regions respectively contain the amino acid sequences of SEQ ID NO:820 and 838; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:821 and 839; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:822 and 840; V of the antibody or its antigen-binding fragment H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:823 and 841; V of the antibody or its antigen-binding fragment H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:824 and 842; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:825 and 843; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:826 and 844; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:827 and 845; V of the antibody or its antigen-binding fragment H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:828 and 846; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:829 and 847; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:830 and 847; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:831 and 848; V of the antibody or its antigen-binding fragment. H and V L The regions respectively contain the amino acid sequences of SEQ ID NO:832 and 849, or are related to the above V. H and V L Any of them has at least 90% sequence identity, such as any antibody or antigen-binding fragment thereof that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with them.

[0222] For example, the V of the antibody or its antigen-binding fragment provided therein H and V LThe region contains amino acid sequences selected from the following: SEQ ID NO: 110 and 116; SEQ ID NO: 111 and 117; SEQ ID NO: 110 and 118; SEQ ID NO: 110 and 119; SEQ ID NO: 110 and 120; SEQ ID NO: 110 and 121; SEQ ID NO: 110 and 122; SEQ ID NO: 110 and 123; SEQ ID NO: 112 and 124; SEQ ID NO: 113 and 125; SEQ ID NO: 114 and 126; SEQ ID NO: 115 and 127; SEQ ID NO: 247 and 257; SEQ ID NO: 248 and 258; SEQ ID NO: 249 and 259; SEQ ID NO: 250 and 260; SEQ ID NO: 251 and 261; SEQ ID NO: 252 and 262; SEQ ID NO: 253 and 263; SEQ ID NO: 110 and 116; SEQ ID NO: 111 and 117; SEQ ID NO: 110 and 118; SEQ ID NO: 110 and 119; SEQ ID NO: 110 and 120; SEQ ID NO: 110 and 121; SEQ ID NO: 110 and 122; SEQ ID NO: 110 and 123; SEQ ID NO: 112 and 124; SEQ ID NO: 113 and 125; SEQ ID NO: 114 and 126; SEQ ID NO: 115 and 127; SEQ ID NO: 247 and 257; SEQ ID NO: 248 and 258; SEQ ID NO: SEQ ID NO: 254 and 264; SEQ ID NO: 255 and 265; SEQ ID NO: 256 and 266; SEQ ID NO: 256 and 267; SEQ ID NO: 518 and 534; SEQ ID NO: 519 and 535; SEQ ID NO: 115 and 536; SEQ ID NO: 520 and 264; SEQ ID NO: 521 and 537; SEQ ID NO: 522 and 538; SEQ ID NO: 523 and 539; SEQ ID NO: 519 and 540; SEQ ID NO: 524 and 541; SEQ ID NO: 525 and 261; SEQ ID NO: 526 and 542; SEQ ID NO: 527 and 543; SEQ ID NO: 528 and 544; SEQ ID NO: 529 and 545; SEQ ID NO: 528 and 546; SEQ ID NO: 522 and 547; SEQ SEQ ID NO: 256 and 548; SEQ ID NO: 530 and 549; SEQ ID NO: 531 and 550; SEQ ID NO: 519 and 552; SEQ ID NO: 110 and 553; SEQ ID NO: 110 and 118; SEQ ID NO: 533 and 554; SEQ ID NO: 115 and 555; SEQ ID NO: 524 and 556; SEQ ID NO: 519 and 557; SEQ ID NO: 324 and 326; SEQ ID NO: 325 and 327; SEQ ID NO: 609 and 610; SEQ ID NO: 617 and 618; SEQ ID NO: 772 and 775; SEQ ID NO: 773 and 776;SEQ ID NO: 774 and 777; SEQ ID NO: 815 and 833; SEQ ID NO: 816 and 834; SEQ ID NO: 817 and 835; SEQ ID NO: 818 and 836; SEQ ID NO: 819 and 837; SEQ ID NO: 820 and 838; SEQ ID NO: 821 and 839; NO: 822 and 840; SEQ ID NO: 823 and 841; SEQ ID NO: 824 and 842; SEQ ID NO: 825 and 843; SEQ ID NO: 826 and 844; SEQ ID NO: 827 and 845; SEQ ID NO: 828 and 846; SEQ ID NO: 829 and 847; SEQ ID NO: 830 and 847; SEQ ID NO: 831 and 848; and SEQ ID NO: 832 and 849, or V above; H and V L Any of the above has at least 90% sequence identity, such as any antibody or antigen-binding fragment thereof having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity, or containing the above V. H and V L V of any of them H The region contains CDR-H1, CDR-H2, and CDR-H3, as well as their V... L Any antibodies or antigen-binding fragments of CDR-L1, CDR-L2, and CDR-L3 contained within the region.

[0223] In some embodiments, the provided antibody or its antigen-binding fragment V H and V L The region contains amino acid sequences selected from the following: SEQ ID NO: 617 and 618; SEQ ID NO: 256 and 267; SEQ ID NO: 519 and 535; SEQ ID NO: 115 and 536; or SEQ ID NO: 609 and 610; or the same as above. H and V L Any of the above has at least 90% sequence identity, such as any antibody or antigen-binding fragment thereof having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity, or containing the above V. H and V L V of any of them H The region contains CDR-H1, CDR-H2, and CDR-H3, as well as their V... LAny antibodies or antigen-binding fragments of CDR-L1, CDR-L2, and CDR-L3 contained within the region.

[0224] In some embodiments, the provided antibody or its antigen-binding fragment V H and V L The region contains amino acid sequences selected from the following: SEQ ID NO: 617 and 618, or the same as those mentioned above. H and V L Any of the above has at least 90% sequence identity, such as any antibody or antigen-binding fragment thereof having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity, or containing the above V. H and V L V of any of them H The region contains CDR-H1, CDR-H2, and CDR-H3, as well as their V... L Any antibodies or antigen-binding fragments of CDR-L1, CDR-L2, and CDR-L3 contained within the region.

[0225] In some embodiments, the antibody or its antigen-binding fragment is a single-chain antibody fragment, such as a single-chain variable fragment (scFv), a bifunctional antibody, or a single-domain antibody (sdAb). In some embodiments, the antibody or antigen-binding fragment contains only V... H Single-domain antibodies in the region. In some embodiments, the antibody or antigen-binding fragment is a variable heavy chain (V). H ) region and light chain variable (V L The scFv of the heavy chain variable region. In some embodiments, the single-chain antibody fragment (e.g., scFv) includes a region connecting two antibody domains or regions, such as the heavy chain variable region (V). H ) region and light chain variable (V L One or more linkers in the region. Linkers are typically peptide linkers, such as flexible and / or soluble peptide linkers. Among the linkers are those rich in glycine and serine and / or, in some cases, rich in threonine. In some embodiments, the linker further includes charged residues that improve solubility, such as lysine and / or glutamic acid. In some embodiments, the linker further includes one or more proline residues.

[0226] Therefore, the anti-BCMA antibodies provided include single-chain antibody fragments, such as scFv and bifunctional antibodies, especially human single-chain antibody fragments, which typically contain two antibody domains or regions (such as V). H and V L The linker (region). The linker is usually a peptide linker, such as a flexible and / or soluble peptide linker, such as a peptide linker rich in glycine and serine.

[0227] In some aspects, the linker rich in glycine and serine (and / or threonine) comprises at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of such amino acids. In some embodiments, it comprises at least or at least about 50%, 55%, 60%, 70%, or 75% of glycine, serine, and / or threonine. In some embodiments, the linker is substantially entirely composed of glycine, serine, and / or threonine. The length of the linker is generally between about 5 and about 50 amino acids, typically between 10 or about 10 and 30 or about 30, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, and in some instances, between 10 and 25 amino acids. Exemplary linkers include linkers having various numbers of repeats (such as repeats of such sequences between 2, 3, 4, and 5) of the sequence GGGGS (4GS; SEQ ID NO: 359) or GGGS (3GS; SEQ ID NO: 360). Exemplary linkers include those having the sequence shown in SEQ ID NO: 361 (GGGGSGGGGSGGGGS) or composed thereof. Exemplary connectors further include those having or consisting of the sequence shown in SEQ ID NO:362 (GSTSGSGKPGSGEGSTKG). Exemplary connectors further include those having or consisting of the sequence shown in SEQ ID NO:778 (SRGGGGSGGGGSGGGGSLEMA).

[0228] Therefore, in some embodiments, the provided embodiments include single-chain antibody fragments (e.g., scFv) containing one or more of the aforementioned adapters, such adapters being glycine / serine-rich adapters, including repeating adapters having GGGS (SEQ ID NO:360) or GGGGS (SEQ ID NO:359), such as the adapter shown in SEQ ID NO:361.

[0229] In some embodiments, the linker has an amino acid sequence containing the sequence shown in SEQ ID NO:361. The fragment (e.g., scFv) may include V H The area or part thereof, followed by a connector, followed by a V L A region or a portion thereof. A fragment (e.g., scFv) may include V. L The area or part thereof, followed by a connector, followed by a V H The district or a part thereof.

[0230] In some embodiments, the antigen-binding domain comprises a sequence selected from any one of SEQ ID NO:478, 128-139, 268-278, 329, 442, 558-576, 578-583, 585, or 769-771, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with a sequence selected from any one of SEQ ID NO:478, 128-139, 268-278, 329, 442, 558-576, 578-583, 585, or 769-771.

[0231] In some aspects, the scFv provided herein comprises an amino acid sequence selected from any of SEQ ID NO:128-139, 268-278, 328, 329, 442, 478, 558-576, 578-583, 585, 586 and 769-771, or an amino acid sequence having at least or at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with any of SEQ ID NO:128-139, 268-278, 328, 329, 442, 478, 558-576, 578-583, 585, 586 and 769-771.

[0232] For example, the scFv provided herein includes those selected from SEQ ID NO: 128, 129, 130, 132, 133, 136, 137, 269, 273, 274, 275, 276, 277, 278, 328, 329, 442, 478, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, The amino acid sequence of any one of SEQ ID NO is 583, 585, 586, 769, 770, 771, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, or 813, or has an amino acid sequence that is selected from SEQ ID NO. NO:128, 129, 130, 132, 133, 136, 137, 269, 273, 274, 275, 276, 277, 278, 328, 329, 442, 478, 558, 559, 560, 561, 562, 563, 5 64,565,566,567,568,569,570,571,572,573,574,575,576,577,578,579,580,581,582,583,585,586,769,770,771,7 The amino acid sequence of any one of 81, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, or 813 has an amino acid sequence identity of at least or at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.

[0233] Table 2 provides SEQ ID NOs of exemplary antigen-binding domains (such as antibodies or antigen-binding fragments) that may be included in the provided BCMA-binding receptors (such as anti-BCMA chimeric antigen receptors (CARs)). In some embodiments, the BCMA-binding receptor contains a BCMA-binding antibody or a fragment thereof, which includes a V sequence comprising the CDR-H1, CDR-H2, and CDR-H3 sequences shown in each column of Table 2 below. HThe region and the V containing the CDR-L1, CDR-L2 and CDR-L3 sequences shown therein L The region (encoded via Kabat). In some embodiments, the BCMA-binding receptor contains the V region shown in SEQ ID NO as listed in each column of Table 2 below. H Region sequence and V L BCMA-binding antibodies or fragments thereof containing the region sequence, or containing the V sequence shown in SEQ ID NO as listed in each column of Table 2 below. H Region sequence and V L The region sequence has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity. H and V L Antibodies containing the amino acid sequence of the region. In some embodiments, the BCMA-binding receptor contains V, which is shown as SEQ ID NO in each column of Table 2 below. H Region sequence and V L The BCMA-binding receptor comprises a BCMA-binding antibody or a fragment thereof comprising the scFv sequence shown in each column of Table 2 below, or an antibody comprising an scFv amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the scFv sequence shown in each column of Table 2 below. In some embodiments, the BCMA-binding receptor comprises a BCMA-binding antibody or a fragment thereof comprising the scFv sequence shown in each column of Table 2 below.

[0234]

[0235]

[0236]

[0237] The antibody (e.g., antigen-binding fragment) in the provided CAR is a human antibody. In some embodiments of the provided human anti-BCMA antibody (e.g., antigen-binding fragment), the human antibody contains a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence encoded by the V region of the human germline nucleotide heavy chain, a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence encoded by the D region of the human germline nucleotide heavy chain, and / or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence encoded by the J region of the human germline nucleotide heavy chain. H The region; and / or containing a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence encoded by the human κ or λ chain V region of the germline nucleotide and / or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the amino acid sequence encoded by the human κ or λ chain J region of the germline nucleotide. L District. In some implementation schemes, V H The regions correspond to CDR-H1, CDR-H2, and / or CDR-H3. In some implementations, V H The regions partially correspond to frame regions 1 (FR1), FR2, FR3, and / or FR4. In some implementations, V L The regions correspond to CDR-L1, CDR-L2, and / or CDR-L3. In some implementations, V L The regions correspond to FR1, FR2, FR3 and / or FR4.

[0238] In some embodiments, the human antibody (e.g., an antigen-binding fragment) contains a CDR-H1 that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the corresponding CDR-H1 region within the sequence encoded by the V segment of the human heavy chain germline nucleotides. For example, in some embodiments, the human antibody contains a CDR-H1 whose sequence is 100% identical to or has no more than one, two, or three amino acid differences compared to the corresponding CDR-H1 region within the sequence encoded by the V segment of the human heavy chain germline nucleotides.

[0239] In some embodiments, the human antibody (e.g., an antigen-binding fragment) contains a CDR-H2 that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the corresponding CDR-H2 region within the sequence encoded by the V segment of the human heavy chain germline nucleotides. For example, in some embodiments, the human antibody contains a CDR-H2 whose sequence is 100% identical to or has no more than one, two, or three amino acid differences compared to the corresponding CDR-H2 region within the sequence encoded by the V segment of the human heavy chain germline nucleotides.

[0240] In some embodiments, the human antibody (e.g., an antigen-binding fragment) contains a CDR-H3 that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the corresponding CDR-H3 region within the sequence encoded by the V, D, and J regions of the human germline nucleotide heavy chain. For example, in some embodiments, the human antibody contains a CDR-H3 whose sequence is 100% identical to or has no more than one, two, or three amino acid differences compared to the corresponding CDR-H3 region within the sequence encoded by the V, D, and J regions of the human germline nucleotide heavy chain.

[0241] In some embodiments, the human antibody (e.g., an antigen-binding fragment) contains a CDR-L1 with at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the corresponding CDR-L1 region within the sequence encoded by the V region of the human light chain germline nucleotides. For example, in some embodiments, the human antibody contains a CDR-L1 whose sequence is 100% identical to or has no more than one, two, or three amino acid differences compared to the corresponding CDR-L1 region within the sequence encoded by the V region of the human light chain germline nucleotides.

[0242] In some embodiments, the human antibody (e.g., an antigen-binding fragment) contains a CDR-L2 that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the corresponding CDR-L2 region within the sequence encoded by the V region of the human light chain germline nucleotides. For example, in some embodiments, the human antibody contains a CDR-L2 whose sequence is 100% identical to or has no more than one, two, or three amino acid differences compared to the corresponding CDR-L2 region within the sequence encoded by the V region of the human light chain germline nucleotides.

[0243] In some embodiments, the human antibody (e.g., an antigen-binding fragment) contains a CDR-L3 that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the corresponding CDR-L3 region within the sequence encoded by the V and J regions of the human light chain germline nucleotides. For example, in some embodiments, the human antibody contains a CDR-L3 whose sequence is 100% identical to or has no more than one, two, or three amino acid differences compared to the corresponding CDR-L3 region within the sequence encoded by the V and J regions of the human light chain germline nucleotides.

[0244] In some embodiments, the human antibody (e.g., an antigen-binding fragment) contains a frame region containing a segment sequence of a human germline gene. For example, in some embodiments, the human antibody contains V... H The frame regions, wherein the frame regions (e.g., FR1, FR2, FR3, and FR4) have at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with frame regions encoded by human germline antibody segments (such as the V and / or J segments). In some embodiments, the human antibody contains V... L The frame regions, wherein the frame regions (e.g., FR1, FR2, FR3, and FR4) have at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with frame regions encoded by human germline antibody segments (such as the V and / or J segments). For example, in some such embodiments, V... H Zone and / or V L The frame region sequence contained within the region differs from the frame region sequence encoded by the human germline antibody segment by no more than 10 amino acids, such as no more than 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid.

[0245] In some implementations, the reference antibody may be the mouse anti-BCMAscFv described in International Patent Application Publication No. WO 2010 / 104949.

[0246] Antibodies (e.g., antigen-binding fragments) may contain at least a portion of an immunoglobulin constant region, such as one or more constant region domains. In some embodiments, the constant region includes a light chain constant region and / or a heavy chain constant region 1 (C1). H 1). In some implementations, the antibody includes C H 2 and / or C H 3. Domains, such as the Fc region. In some implementations, the Fc region is the Fc region of human IgG (such as IgG1 or IgG4).

[0247] 2. Spacer

[0248] In some embodiments, the recombinant receptor (such as a CAR) comprising the antibody (e.g., an antigen-binding fragment) provided herein further includes a spacer or spacer region. The spacer is a polypeptide spacer and is generally located within the CAR between its antigen-binding domain and transmembrane domain. In some aspects, the spacer may be or include at least a portion of an immunoglobulin constant region or a variant or modified form thereof, such as a hinge region of an immunoglobulin (e.g., an IgG hinge region, such as IgG4 or an IgG4-derived hinge region) and / or C H 1 / CL and / or Fc regions. In some embodiments, the constant region or one or more portions thereof are derived from human IgG, such as from human IgG4, IgG1, or IgG2. Generally, a spacer, such as a portion of the constant region, acts as a spacer region located between an antigen recognition component (e.g., scFv) and a transmembrane domain. In some embodiments, the length and / or composition of the spacer are designed to optimize or facilitate certain properties of the interaction between the CAR and its target; in some aspects, it is designed to optimize the biomolecular synaptic distance between the CAR-expressing cell and the CAR-expressing target cell during, when, or after the CAR binds to its target on a cell expressing the target; in some embodiments, the CAR is expressed by T cells, and the length of the spacer is a length compatible with T cell activation or to optimize CAR T cell efficacy. In some embodiments, the spacer is a spacer region located between the ligand-binding domain and the transmembrane domain of a recombinant receptor (e.g., CAR). In some embodiments, the spacer region is a region located between the ligand-binding domain and the transmembrane domain of a recombinant receptor (e.g., CAR).

[0249] In some embodiments, the spacer may have an increased length that provides increased cellular reactivity after antigen binding compared to the absence of a spacer and / or the presence of different spacers (e.g., differing in length by only one). In some embodiments, the spacer is at least 100 amino acids long, such as at least 110, 125, 130, 135, 140, 145, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, or 250 amino acids. In some embodiments, the spacer is about 12 amino acids long, or no more than 12 amino acids long. Exemplary spacers include those having at least about 10 to 300 amino acids, about 10 to 200 amino acids, about 50 to 175 amino acids, about 50 to 150 amino acids, about 10 to 125 amino acids, about 50 to 100 amino acids, about 100 to 300 amino acids, about 100 to 250 amino acids, about 125 to 250 amino acids, or about 200 to 250 amino acids and including any integer between the endpoints of any of the listed ranges. In some embodiments, the length of the spacer or spacer region is at least about 12 amino acids, at least about 119 amino acids or less, at least about 125 amino acids, at least about 200 amino acids, or at least about 220 amino acids or at least about 225 amino acids.

[0250] In some embodiments, the length of the spacer is 125 to 300 amino acids, 125 to 250 amino acids, 125 to 230 amino acids, 125 to 200 amino acids, 125 to 180 amino acids, 125 to 150 amino acids, 150 to 300 amino acids, 150 to 250 amino acids, 150 to 230 amino acids, 150 to 200 amino acids, 150 to 180 amino acids, 180 to 300 amino acids, 180 to 250 amino acids, 180 to 230 amino acids, 180 to 200 amino acids, 200 to 300 amino acids, 200 to 250 amino acids, 200 to 230 amino acids, 230 to 300 amino acids, 230 to 250 amino acids, or 250 to 300 amino acids. In some embodiments, the spacer is at least or at least about or about 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 221, 222, 223, 224, 225, 226, 227, 228 or 229 amino acids in length, or between any of the foregoing.

[0251] Exemplary spacers include spacers containing one or more portions of the immunoglobulin constant region, such as those containing Ig hinges (such as IgG hinge domains). In some aspects, spacers include only IgG hinges, and those with C... H 2 and / or C H One or more IgG hinges connected in the 3 domains, or with C H A 3-domain connected IgG hinge. In some embodiments, the IgG hinge, CH2, and / or CH3 may be wholly or partially derived from IgG4 or IgG2. In some embodiments, the spacer may be a hinge containing IgG4, IgG2, and / or IgG2 and IgG4, C H 2 and / or C H A chimeric polypeptide comprising one or more of the three sequences. In some embodiments, the hinge region comprises all or a portion of the IgG4 hinge region and / or all or a portion of the IgG2 hinge region, wherein the IgG4 hinge region is optionally a human IgG4 hinge region and the IgG2 hinge region is optionally a human IgG2 hinge region; C H Region 2 contains IgG4 C H All or part of region 2 and / or IgG2 C H All or part of region 2, in which IgG4 C H Region 2 is a randomized control of human IgG4 C. H Region 2 and IgG2 C H Region 2 is a randomized control of human IgG2 C. H Zone 2; and / or C H Region 3 contains IgG4 C H All or part of region 3 and / or IgG2 C H All or part of region 3, including IgG4 C H Region 3 is a randomized control of human IgG4 C. H Region 3 and IgG2 C H The 3rd region is a randomized area for human IgG2 C. H Zone 3. In some implementations, hinges, C H 2 and C H 3 contains the hinge region from IgG4, C H 2 and C H All or part of each of the three. In some embodiments, the hinge region is chimeric and includes hinge regions from human IgG4 and human IgG2; the CH2 region is chimeric and includes C from human IgG4 and human IgG2. H Region 2; and / or region CH3 are chimeric and contain C from human IgG4 and human IgG2. HRegion 3. In some embodiments, the spacer comprises an IgG4 / 2 chimeric hinge or a modified IgG4 hinge containing at least one amino acid substitution compared to the human IgG4 hinge region; human IgG2 / 4 chimeric C H Region 2; and human IgG4 C H Zone 3.

[0252] In some embodiments, the spacer may be wholly or partially derived from IgG4 and / or IgG2, and may contain mutations, such as one or more single amino acid mutations in one or more domains. In some instances, the amino acid is modified to replace serine (S) with proline (P) in the hinge region of IgG4. In some embodiments, the amino acid is modified to replace asparagine (N) with glutamine (Q) to reduce glycosylation heterogeneity, such as C in the full-length IgG4 Fc sequence shown in SEQ ID NO:750. H The N177Q mutation at position 177 in region 2 or the C mutation in the full-length IgG2 Fc sequence shown in SEQ ID NO:749 H The N176Q mutation is located at position 176 in region 2. In some embodiments, the spacer is or contains an IgG4 / 2 chimeric hinge or a modified IgG4 hinge; IgG2 / 4 chimeric C H Zone 2; and IgG4 C H Region 3, optionally with a length of about 228 amino acids; or the spacer shown in SEQ ID NO:649. In some embodiments, the spacer comprises the amino acid sequence: ESKYGPPCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO:649), which is encoded by a polynucleotide optimized for codon expression and / or elimination of splice sites (such as cryptic splice sites). In some embodiments, the coding sequence of the spacer comprises the nucleic acid sequence shown in SEQ ID NO:622. In some implementations, the coding sequence of the spacer contains the nucleic acid sequence shown in SEQ ID NO:855 or 856.

[0253] Other exemplary spacers include (but are not limited to) those described in Hudecek et al. (2013) Clin. Cancer Res., 19:3153, Hudecek et al. (2015) Cancer Immunol. Res., 3(2):125-135, or International Patent Application Publication No. WO2014031687. In some embodiments, the nucleotide sequence of the spacer is optimized to reduce RNA heterogeneity after expression. In some embodiments, the nucleotide sequence of the spacer is optimized to reduce cryptic splice sites or decrease the likelihood of splicing events occurring at splice sites.

[0254] In some embodiments, the spacer has the amino acid sequence shown in SEQ ID NO:363 and is encoded by the polynucleotide sequence shown in SEQ ID NO:364. In some embodiments, the spacer has the amino acid sequence shown in SEQ ID NO:365. In some embodiments, the spacer has the amino acid sequence shown in SEQ ID NO:366. In some embodiments, the spacer has the amino acid sequence shown in SEQ ID NO:630 and is encoded by the polynucleotide sequence shown in SEQ ID NO:629. In some embodiments, the spacer has the amino acid sequence shown in SEQ ID NO:649 and is encoded by the polynucleotide sequence shown in SEQ ID NO:621, 622, 855, or 856 or a polynucleotide sequence showing at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more than 99% sequence identity with SEQ ID NO:621, 622, 855, or 856. In some embodiments, the spacer has an amino acid sequence exhibiting at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher sequence identity with SEQ ID NO:649, encoded by a polynucleotide that has optionally been optimized for codon use and / or to reduce RNA heterogeneity.

[0255] In some embodiments, the spacer is or contains an amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO:622.

[0256] 3. Transmembrane domains and intracellular signal transduction components

[0257] Antigen recognition components are typically linked to one or more intracellular signaling domains containing signaling components, such as signaling components that mimic stimulation and / or activation via signals from antigen receptor complexes (e.g., the TCR complex in the case of CARs) and / or via another cell surface receptor. Therefore, in some embodiments, BCMA-binding molecules (e.g., antibodies or their antigen-binding fragments) are linked to one or more transmembrane domains (such as those described herein) and an intracellular signaling domain or domain containing one or more intracellular components (such as those described herein). In some embodiments, the transmembrane domain is fused to an extracellular domain. In one embodiment, a transmembrane domain naturally associated with a domain in a receptor (e.g., a CAR) is used. In some cases, the transmembrane domain may be selectively or modified by amino acid substitution to prevent such domains from binding to transmembrane domains of the same or different surface membrane proteins, thereby minimizing interactions with other members of the receptor complex.

[0258] In some embodiments, the transmembrane domain is derived from a natural or synthetic source. In the case of a natural source, in some aspects, the domain is derived from any membrane-binding protein or transmembrane protein. The transmembrane domain includes those derived from (i.e., at least the following transmembrane domains): the α, β, or ζ chain of the T cell receptor; CD3ε, CD4, CD5, CD8, CD9, CD16, CD22, CD28, CD33, CD37, CD45, CD64, CD80, CD86, CD134, CD137, and / or CD154. For example, the transmembrane domain may be a CD28 transmembrane domain comprising the amino acid sequence shown in SEQ ID NO:624 encoded by the nucleic acid sequence shown in SEQ ID NO:623 or SEQ ID NO:688. Alternatively, in some embodiments, the transmembrane domain is synthetic. In some aspects, the synthetic transmembrane domain primarily comprises hydrophobic residues such as leucine and valine. In some embodiments, a triplet of phenylalanine, tryptophan, and valine will be found at each end of the synthetic transmembrane domain. In some embodiments, these are linked by a linker, a spacer, and / or one or more transmembrane domains.

[0259] Intracellular signal transduction regions or domains are those that mimic or approximate signals transmitted via natural antigen receptors, signals transmitted via a combination of such receptors and co-stimulatory receptors, and / or signals transmitted vi...

Claims

1. A chimeric antigen receptor comprising (a) an extracellular antigen binding domain that specifically recognizes B-cell maturation antigen (BCMA); (b) a spacer that is at least 125 amino acids in length; (c) a transmembrane domain; and (d) an intracellular signaling region.

2. The chimeric antigen receptor of claim 1, wherein the spacer comprises a portion of an immunoglobulin constant region.

3. The chimeric antigen receptor of claim 1 or claim 2, wherein the spacer comprises the sequence of a hinge region, C H 2 region, and C H 3 region.

4. The chimeric antigen receptor of claim 3, wherein the hinge region comprises all or a portion of an IgG4 hinge region and / or all or a portion of an IgG2 hinge region, wherein the IgG4 hinge region is optionally a human IgG4 hinge region and the IgG2 hinge region is optionally a human IgG2 hinge region; The C H 2 region comprises all or a portion of an IgG4 C H 2 region and / or an IgG2 C H 2 region, wherein the IgG4 C H 2 region is optionally a human IgG4 C H 2 region; and the IgG2 C H 2 region is optionally a human IgG2 C H 2 region; and / or The C H 3 region comprises all or a portion of an IgG4 C H 3 region and / or an IgG2 C H 3 region, wherein the IgG4 C H 3 region is optionally a human IgG4 C H 3 region, and the IgG2 C H 3 region is optionally a human IgG2 C H 3 region.

5. The chimeric antigen receptor of claim 3 or claim 4, wherein the hinge, C H 2 and C H 3 comprise all or a portion of each of a hinge region from IgG4, C H 2 and C H 3.

6. The chimeric antigen receptor of claim 3 or claim 4, wherein: the hinge region is chimeric and comprises hinge regions from human IgG4 and human IgG2; The C H 2 region is chimeric and comprises C H 2 regions from human IgG4 and human IgG2; and / or the C H 3 region is chimeric and comprises C H 3 regions from human IgG4 and human IgG2.

7. The chimeric antigen receptor of any one of claims 1 to 6, wherein the spacer comprises an IgG4 / 2 chimeric hinge or a modified IgG4 hinge comprising at least one amino acid substitution as compared to a human IgG4 hinge region; a human IgG2 / 4 chimeric C H 2 region; and a human IgG4 C H 3 region.

8. The chimeric antigen receptor of any one of claims 1-4, 6, and 7, wherein the spacer is or comprises (i) the sequence set forth in SEQ ID NO: 649; (ii) a functional variant of SEQ ID NO: 649 having at least 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 649; or (iii) a contiguous portion of (i) or (ii) that is at least 125 amino acids in length.

9. The chimeric antigen receptor of any one of claims 1-3, and 6-8, wherein the spacer is or comprises the sequence set forth in SEQ ID NO:

649.

10. A chimeric antigen receptor comprising: (a) an extracellular antigen binding domain that specifically recognizes B-cell maturation antigen (BCMA); (b) a spacer set forth in SEQ ID NO: 649; (c) a transmembrane domain; and (d) an intracellular signaling region.

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