Calcium voltage-gated channel accessory subunit gamma 1 (CACNG1) binding proteins and CACNG1-mediated delivery to skeletal muscle

Abstract

The present disclosure provides calcium voltage-gated channel accessory subunit gamma 1 (CACNG1) antigen binding proteins and protein-drug conjugates comprising the CACNG1 antigen binding protein conjugated to a molecular cargo (e.g., a polynucleotide molecule, a polypeptide molecule, a carrier, or a small molecule) for delivery of the molecular cargo to skeletal muscle tissue and / or cells. Methods for treating, preventing, or reducing the likelihood of various skeletal muscle diseases and / or disorders using such antigen binding proteins or protein-drug conjugates are also provided.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 382,418, filed November 4, 2022, U.S. Provisional Patent Application No. 63 / 422,845, filed November 4, 2022, and U.S. Provisional Patent Application No. 63 / 525,901, filed July 10, 2023, the disclosures of each of which are incorporated by reference herein in their entireties.

[0002] (Sequence Listing) This application contains a Sequence Listing that has been submitted electronically in XML file format, which is incorporated herein by reference in its entirety. The XML copy, created on October 31, 2023, is named 250298_000557_SL.xml and is 522,807 bytes in size.

[0003] FIELD OF THE INVENTION The present disclosure relates to Calcium Voltage-Gated Channel Auxiliary Subunit Gamma 1 (CACNG1) antigen binding proteins, and protein-drug conjugates comprising the CACNG1 antigen binding protein conjugated to a molecular cargo, and methods of treating, preventing, or reducing the likelihood of disease using such protein-drug conjugates. [Background technology]

[0004] Recent advances in the field of genetic medicine have led to the development of therapies with the potential to treat several muscle diseases. However, because skeletal muscle is a large tissue, comprising approximately 40% of total body weight, delivery of these therapies to muscle remains a major challenge. Targeted therapies to muscle are typically achieved through high-dose systemic delivery, which often results in inefficient muscle uptake, as well as uptake in other organs and adverse events (e.g., liver toxicity). Therefore, there remains a need to develop skeletal muscle-specific therapies with efficient muscle uptake that can disrupt the onset and / or progression of muscle diseases (e.g., facioscapulohumeral muscular dystrophy, myotonic dystrophy, Duchenne muscular dystrophy), particularly to improve the quality of life of people suffering from such diseases. Summary of the Invention [Means for solving the problem]

[0005] The present disclosure provides calcium voltage-gated channel accessory subunit gamma 1 (CACNG1) antigen binding proteins, and protein-drug conjugates comprising the CACNG1 antigen binding protein conjugated to a molecular cargo (e.g., a polynucleotide molecule, a polypeptide molecule, a carrier, or a small molecule) for delivery of the molecular cargo to skeletal muscle tissue and / or cells. The antigen binding protein comprises a heavy chain variable region (HCVR or VVR). H ) and a light chain variable region (LCVR or V L ) and a steroid drug conjugate. Methods for treating, preventing, or reducing the likelihood of various skeletal muscle diseases and / or disorders using such antigen binding proteins or protein-drug conjugates are also provided.

[0006] In one aspect, provided herein is an antigen binding protein that specifically binds to calcium voltage-gated channel accessory subunit gamma 1 (CACNG1), comprising: (i) an HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 1, 9, 17, 25, 33, 41, 49, 57, 65, 73, 81, 89, 97, 105, 113, 121, 129, 137, 429, or 451 (or a variant thereof); and / or (ii) An antigen binding protein is provided, comprising an LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 5, 13, 21, 29, 37, 45, 53, 61, 69, 77, 85, 93, 101, 109, 117, 125, 133, 141, 437, or 459 (or a variant thereof).

[0007] In some embodiments of the above antigen binding proteins, the antigen binding protein (1) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence shown in SEQ ID NO: 1 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence shown in SEQ ID NO: 5 (or a variant thereof); (2) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 9, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence shown in SEQ ID NO: 13 (or a variant thereof); (3) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 17, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence shown in SEQ ID NO: 21 (or a variant thereof); (4) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 25 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence shown in SEQ ID NO: 29 (or a variant thereof); (5) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 33 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence shown in SEQ ID NO: 37 (or a variant thereof); (6) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 41 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence shown in SEQ ID NO: 45 (or a variant thereof); (7) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 49 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence shown in SEQ ID NO: 53 (or a variant thereof); (8) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 57 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence shown in SEQ ID NO: 61 (or a variant thereof); (9) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 65 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence shown in SEQ ID NO: 69 (or a variant thereof); (10) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 73 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence shown in SEQ ID NO: 77 (or a variant thereof); (11) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 81 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence shown in SEQ ID NO: 85 (or a variant thereof); (12) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 89 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence shown in SEQ ID NO: 93 (or a variant thereof); (13) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 97 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 101 (or a variant thereof); (14) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 105 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 109 (or a variant thereof); (15) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 113 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 117 (or a variant thereof); (16) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 121 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 125 (or a variant thereof); (17) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 129 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 133 (or a variant thereof); (18) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 141 (or a variant thereof); (19) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 429 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 437 (or a variant thereof); or (20) An antigen-binding protein comprising an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 451 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 459 (or a variant thereof).

[0008] In some embodiments of the above antigen binding proteins, the antigen binding protein is (a) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 2 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 3 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 4 (or a variant thereof); an LCVR comprising an LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 6 (or a variant thereof), an LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 7 (or a variant thereof), and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 8 (or a variant thereof); (b) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 10 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 11 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 12 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 14 (or a variant thereof), an LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 15 (or a variant thereof), and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 16 (or a variant thereof); (c) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 18 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 19 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 20 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 22 (or a variant thereof), an LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 23 (or a variant thereof), and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 24 (or a variant thereof); (d) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 30 (or a variant thereof), an LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 31 (or a variant thereof), and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 32 (or a variant thereof); (e) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 38 (or a variant thereof), an LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 39 (or a variant thereof), and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 40 (or a variant thereof); (f) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 42 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 43 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 44 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 46 (or a variant thereof), an LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 47 (or a variant thereof), and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 48 (or a variant thereof); (g) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 50 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 51 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 52 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 54 (or a variant thereof), an LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 55 (or a variant thereof), and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 56 (or a variant thereof); (h) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 58 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 59 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 60 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 62 (or a variant thereof), an LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 63 (or a variant thereof), and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 64 (or a variant thereof); (i) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 66 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 70 (or a variant thereof), an LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 71 (or a variant thereof), and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 72 (or a variant thereof); (j) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 74 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 75 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 78 (or a variant thereof), an LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 79 (or a variant thereof), and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 80 (or a variant thereof); (k) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 82 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 83 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 84 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 86 (or a variant thereof), an LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 87 (or a variant thereof), and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 88 (or a variant thereof); (l) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 90 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 91 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 92 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96 (or a variant thereof); (m) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 98 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 99 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 100 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 102 (or a variant thereof), an LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 103 (or a variant thereof), and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 104 (or a variant thereof); (n) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 107 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 108 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 110 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 111 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112 (or a variant thereof); (o) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 114 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 115 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 118 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 119 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof); (p) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 123 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 124 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 126 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 127 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128 (or a variant thereof); (q) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 131 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136 (or a variant thereof); (r) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 142 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 143 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 144 (or a variant thereof); (s) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 431 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 433 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 435 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 439 (or a variant thereof), an LCDR2 comprising the amino acid sequence YNS (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 441 (or a variant thereof); or (t) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 453 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 455 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 457 (or a variant thereof); and It includes an LCVR comprising an LCDR1 having the amino acid sequence set forth in SEQ ID NO: 461 (or a variant thereof), an LCDR2 having the amino acid sequence RNN (or a variant thereof), and an LCDR3 having the amino acid sequence set forth in SEQ ID NO: 463 (or a variant thereof).

[0009] In some embodiments of any of the above antigen binding proteins, the antigen binding protein is (1) an HCVR comprising the amino acid sequence shown in SEQ ID NO: 1 (or a variant thereof), and an LCVR comprising the amino acid sequence shown in SEQ ID NO: 5 (or a variant thereof); (2) an HCVR comprising the amino acid sequence shown in SEQ ID NO: 9 and an LCVR comprising the amino acid sequence shown in SEQ ID NO: 13 (or a variant thereof); (3) HCVR comprising the amino acid sequence shown in SEQ ID NO: 17 and LCVR comprising the amino acid sequence shown in SEQ ID NO: 21 (or a variant thereof); (4) HCVR comprising the amino acid sequence shown in SEQ ID NO: 25 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 29 (or a variant thereof); (5) HCVR comprising the amino acid sequence shown in SEQ ID NO: 33 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 37 (or a variant thereof); (6) HCVR comprising the amino acid sequence shown in SEQ ID NO: 41 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 45 (or a variant thereof); (7) HCVR comprising the amino acid sequence shown in SEQ ID NO: 49 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 53 (or a variant thereof); (8) HCVR comprising the amino acid sequence shown in SEQ ID NO: 57 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 61 (or a variant thereof); (9) HCVR comprising the amino acid sequence shown in SEQ ID NO: 65 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 69 (or a variant thereof); (10) HCVR comprising the amino acid sequence shown in SEQ ID NO: 73 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 77 (or a variant thereof); (11) An HCVR comprising the amino acid sequence set forth in SEQ ID NO: 81 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 85 (or a variant thereof); or (12) HCVR comprising the amino acid sequence shown in SEQ ID NO: 89 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 93 (or a variant thereof); (13) HCVR comprising the amino acid sequence shown in SEQ ID NO: 97 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 101 (or a variant thereof); (14) HCVR comprising the amino acid sequence shown in SEQ ID NO: 105 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 109 (or a variant thereof); (15) HCVR comprising the amino acid sequence set forth in SEQ ID NO: 113 (or a variant thereof), and LCVR comprising the amino acid sequence set forth in SEQ ID NO: 117 (or a variant thereof); (16) HCVR comprising the amino acid sequence set forth in SEQ ID NO: 121 (or a variant thereof), and LCVR comprising the amino acid sequence set forth in SEQ ID NO: 125 (or a variant thereof); (17) HCVR comprising the amino acid sequence set forth in SEQ ID NO: 129 (or a variant thereof), and LCVR comprising the amino acid sequence set forth in SEQ ID NO: 133 (or a variant thereof); (18) HCVR comprising the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof), and LCVR comprising the amino acid sequence set forth in SEQ ID NO: 141 (or a variant thereof); (19) HCVR comprising the amino acid sequence set forth in SEQ ID NO: 429 (or a variant thereof) and LCVR comprising the amino acid sequence set forth in SEQ ID NO: 437 (or a variant thereof); or (20) An HCVR comprising the amino acid sequence set forth in SEQ ID NO: 451 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 459 (or a variant thereof).

[0010] In some embodiments of any of the above antigen binding proteins, the antigen binding protein is (a) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 145 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 146 (or a variant thereof); (b) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 147 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 148 (or a variant thereof); (c) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 149 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 150 (or a variant thereof); (d) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 151 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 152 (or a variant thereof); (e) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 153 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 154 (or a variant thereof); (f) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 155 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 156 (or a variant thereof); (g) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 157 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 158 (or a variant thereof); (h) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 159 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 160 (or a variant thereof); (i) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 161 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 162 (or a variant thereof); (j) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 163 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 164 (or a variant thereof); (k) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 165 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 166 (or a variant thereof); (l) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 167 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 168 (or a variant thereof); (m) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 169 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 170 (or a variant thereof); (n) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 171 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 172 (or a variant thereof); (o) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 173 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 174 (or a variant thereof); (p) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 175 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 176 (or a variant thereof); (q) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 177 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 178 (or a variant thereof); (r) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 179 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 180 (or a variant thereof); (s) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 443 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 447 (or a variant thereof); or (t) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 465 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 469 (or a variant thereof).

[0011] In another aspect, provided herein is an antigen binding protein that binds to the same epitope on CACNG1 as an antibody comprising a HCVR / LCVR amino acid sequence pair shown in Table 1-1.

[0012] In another aspect, provided herein is an antigen binding protein that competes for binding to CACNG1 with an antibody comprising an HCVR / LCVR amino acid sequence pair shown in Table 1-1.

[0013] In some embodiments of any of the above antigen binding proteins, the antigen binding protein comprises an antibody or an antigen-binding fragment thereof.

[0014] In some embodiments of any of the above antigen binding proteins, the antigen binding protein is a humanized antibody or antigen-binding fragment thereof, a human antibody or antigen-binding fragment thereof, a murine antibody or antigen-binding fragment thereof, a chimeric antibody or antigen-binding fragment thereof, a monovalent Fab', a bivalent Fab2, a F(ab)'3 fragment, a single-chain fragment variable (scFv), a bis-scFv, an (scFv)2, a diabody, a minibody, a nanobody, a triabody, a tetrabody, a disulfide stabilized Fv (dsFv), a single-domain antibody (sdAb), an Ig NAR, a single heavy chain antibody, a bispecific antibody or binding fragment thereof, a bi-specific T-cell engager (BiTE), a triabody, or a chemically modified derivative thereof.

[0015] In some embodiments, the antigen binding protein comprises a fragment antigen-binding region (Fab).

[0016] In some embodiments, the antigen binding protein comprises a single chain fragment variable (scFv).

[0017] In some embodiments, the scFv comprises variable regions arranged from N-terminus to C-terminus in the following orientation: HCVR-LCVR.

[0018] In some embodiments, the scFv comprises variable regions arranged from N-terminus to C-terminus in the following orientation: LCVR-HCVR.

[0019] In some embodiments, the variable regions in the scFv are connected by a linker.

[0020] In some embodiments, the linker is a peptide linker.

[0021] In some embodiments, the peptide linker is -(GGGGS)n- (SEQ ID NO: 411), where n is any integer selected from 1-10.

[0022] In some embodiments of any of the above antigen binding proteins, the antigen binding protein specifically binds to human CACNG1.

[0023] In some embodiments, the antigen binding protein is about 1 x 10 -7 K of M D or binds to human hCACNG1 with stronger affinity.

[0024] In some embodiments, the anti-hCACNG1 antibody or antigen-binding fragment thereof is about 1 x 10 -7 ~Approx. 1×10 -10 K D It binds to hCACNG1.

[0025] In some embodiments, the anti-hCACNG1 antibody or antigen-binding fragment thereof is about 5×10 -9 ~Approx. 1×10 -10 K D It binds to hCACNG1.

[0026] In another aspect, provided herein is an isolated polynucleotide encoding an antigen binding protein described herein.

[0027] In another aspect, provided herein is a vector comprising an isolated polynucleotide described herein.

[0028] In another aspect, provided herein is a host cell comprising an antigen binding protein described herein, an isolated polynucleotide described herein, or a vector described herein.

[0029] In some embodiments, the host cells described herein may be Chinese hamster ovary (CHO) cells.

[0030] In another aspect, provided herein is a protein-drug conjugate comprising an antigen-binding protein that specifically binds to calcium voltage-gated channel accessory subunit gamma 1 (CACNG1) and is conjugated to a molecular cargo.

[0031] In some embodiments of the above protein-drug conjugates, the antigen binding protein comprises any of the antigen binding proteins described above.

[0032] In some embodiments of any of the above protein-drug conjugates, the antigen binding protein and the molecular cargo are conjugated via a linker.

[0033] In some embodiments of any of the above protein-drug conjugates, the molecular cargo comprises a polynucleotide molecule, a polypeptide molecule, a carrier, or a small molecule.

[0034] In some embodiments, the molecular cargo comprises a polynucleotide molecule.

[0035] In some embodiments, the polynucleotide molecule is an interfering nucleic acid molecule, a guide RNA, a ribozyme, an aptamer, a mixer, a multimer, or an mRNA.

[0036] In some embodiments, the interfering nucleic acid molecule is an siRNA, shRNA, miRNA, an antisense oligonucleotide, or a gapmer.

[0037] In some embodiments, the interfering nucleic acid molecule is an siRNA.

[0038] In some embodiments, the siRNA comprises a sense strand that is 21 nucleotides in length.

[0039] In some embodiments, the siRNA comprises an antisense strand that is 23 nucleotides in length.

[0040] In some embodiments, the siRNA comprises two phosphorothioate linkages at the first and second internucleoside linkages at the 5' end of the sense strand.

[0041] In some embodiments, the siRNA comprises two phosphorothioate linkages at the first and second internucleoside linkages at the 3'-end and / or 5'-end of the antisense strand.

[0042] In some embodiments, the interfering nucleic acid is an antisense oligonucleotide.

[0043] In some embodiments, the polynucleotide molecule is a guide RNA.

[0044] In some embodiments, the polynucleotide molecule targets a gene or gene product associated with a skeletal muscle disease or disorder.

[0045] In some embodiments, the gene or gene product associated with a skeletal muscle disease or disorder is selected from the group consisting of Double Homeobox 4 (DUX4), myotonic dystrophy protein kinase (DMPK), dystrophin (DMD), F-Box Only Protein 32 (FBX032), Tripartite Motif Containing 63 (TRIM63), Inhibin Subunit Beta A (INHBA), myostatin (MSTN), Myocyte Enhancer Factor 2D (MEF2D), KLF Transcription Factor 15 (KLF15), Mediator Complex Subunit 1 (MED1), and Mediator Complex Subunit 13 (MED1). 13 (MED13), Protein Phosphatase 1 Regulatory Subunit 3A (PPP1R3A), Myosin Light Chain Kinase (MLCK1), Activin A Receptor Type 1B (ACVR1B), Type II SH2-domain-containing inositol 5-phosphatase (SHIP2), or a gene disclosed in Tables 1-3.

[0046] In some embodiments, the polynucleotide molecule comprises one or more modified nucleotides.

[0047] In some embodiments, the molecular cargo comprises a polynucleotide molecule.

[0048] In some embodiments, the polypeptide molecule is an enzyme or antigen-binding protein that binds to a target other than CACNG1.

[0049] In some embodiments, the polypeptide molecule is associated with a skeletal muscle disease or disorder.

[0050] In some embodiments, the molecular cargo comprises a small molecule.

[0051] In some embodiments, the small molecule is an androgen, a glucocorticoid, a β2-adrenergic receptor agonist, rapamycin or an analog thereof, a MAPK inhibitor, or a histone deacetylase inhibitor.

[0052] In some embodiments, the small molecule is an androgen.

[0053] In some embodiments, the androgen is dihydrotestosterone (DHT).

[0054] In some embodiments, the small molecule is a glucocorticoid.

[0055] In some embodiments, the glucocorticoid is budesonide.

[0056] In some embodiments, the antigen binding protein and small molecule are conjugated via a valine-citrulline para-aminobenzylcarbamate (VC-PAB) and / or glutamic acid-valine-citrulline para-aminobenzylcarbamate (EVC-PAB) linker.

[0057] In some embodiments, any of the above protein-drug conjugates can be used to treat, prevent, or reduce the likelihood of a skeletal muscle disease or disorder.

[0058] In some embodiments, the skeletal muscle disease or disorder is muscular dystrophy, muscular atrophy, inflammatory myopathy, a disease of the peripheral nerves, a disease of the neuromuscular junction, a metabolic disease of muscle, central core disease, hyperthyroid myopathy, congenital myotonia, myotubular myopathy, nemaline myopathy, congenital paramyotonia, periodic paralysis-hypokalemia-hyperkalemia, centronuclear myopathy, distal Laing myopathy, myofibrillar myopathy, or a disease or disorder disclosed in Tables 1-3.

[0059] In some embodiments, the muscular dystrophy is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), congenital muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, myotonic muscular dystrophy, or oculopharyngeal muscular dystrophy.

[0060] In some embodiments, the muscle atrophy is spinal muscular atrophy, or muscle atrophy induced by cancer cachexia, disuse, heart failure, chronic obstructive pulmonary disease, or chronic infection.

[0061] In some embodiments, the spinal muscular atrophy is amyotrophic lateral sclerosis (ALS), infantile progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, or adult spinal muscular atrophy.

[0062] In some embodiments, the inflammatory myopathy is dermatomyositis, polymyositis, or inclusion body myositis.

[0063] In some embodiments, the peripheral nerve disease is Charcot-Marie-Tooth disease, Dejerine-Sottas disease, or Friedreich's ataxia.

[0064] In some embodiments, the neuromuscular junction disorder is myasthenia gravis, Lambert-Eaton syndrome, or botulism.

[0065] In some embodiments, the muscle metabolic disorder is acid maltase deficiency, carnitine deficiency, carnitine palmityltransferase deficiency, debranching enzyme deficiency, lactate dehydrogenase deficiency, mitochondrial myopathy, myoadenylate deaminase deficiency, phosphorylase deficiency, phosphofructokinase deficiency, or phosphoglycerate kinase deficiency.

[0066] In some embodiments, the polypeptide molecule is double homeobox 4 (DUX4), myotonic dystrophy protein kinase (DMPK), dystrophin (DMD), F-box only protein 32 (FBX032), tripartite motif-containing 63 (TRIM63), inhibin subunit beta A (INHBA), myostatin (MSTN), myocyte enhancer factor 2D (MEF2D), KLF transcription factor 15 (KLF15), mediator complex subunit 1 (MED1), mediator complex subunit 13 (MED13), protein phosphatase 1 regulatory subunit 3A (PPP1R3A), myosin light chain kinase (MLCK1), activin A receptor type 1B (ACVR1B), type II SH2 domain-containing inositol 5-phosphatase (SHIP2), or a protein disclosed in Tables 1-3.

[0067] In some embodiments, the molecular cargo comprises a carrier.

[0068] In some embodiments, the carrier is a lipid-based carrier.

[0069] In some embodiments, the lipid-based carrier is a lipid nanoparticle (LNP), a liposome, a lipidoid, or a lipoplex.

[0070] In some embodiments, the lipid-based carrier is a lipid nanoparticle (LNP).

[0071] In some embodiments, the LNP further comprises a polynucleotide molecule and / or a polypeptide molecule.

[0072] In some embodiments, the LNP comprises one or more components of a gene editing system.

[0073] In some embodiments, the LNPs described herein comprise: (a) a Cas nuclease or a nucleic acid encoding a Cas nuclease, and / or (b) a guide RNA or one or more DNAs encoding the guide RNA; Includes.

[0074] In some embodiments, the Cas nuclease is a Cas9 protein.

[0075] In some embodiments, the Cas9 protein is derived from a Streptococcus pyogenes Cas9 protein, a Staphylococcus aureus Cas9 protein, a Campylobacter jejuni Cas9 protein, a Streptococcus thermophilus Cas9 protein, or a Neisseria meningitidis Cas9 protein.

[0076] In some embodiments, the nucleic acid encoding the Cas nuclease is codon-optimized for expression in mammalian cells.

[0077] In some embodiments, the nucleic acid encoding the Cas nuclease is codon-optimized for expression in human cells.

[0078] In some embodiments, the nucleic acid encoding the Cas nuclease is mRNA.

[0079] In some embodiments, the guide RNA is a single guide RNA (sgRNA).

[0080] In some embodiments, the LNPs described herein comprise zinc finger nucleases (ZFNs) or transcription activator-like effector nucleases (TALENs).

[0081] In some embodiments, the LNP comprises a cationic lipid, a neutral lipid, a helper lipid, a stealth lipid, or any combination thereof.

[0082] In some embodiments, the neutral lipid is distearoylphosphatidylcholine (DSPC).

[0083] In some embodiments, the helper lipid is cholesterol.

[0084] In some embodiments, the stealth lipid is PEG2k-DMG.

[0085] In another aspect, provided herein is a pharmaceutical composition comprising an antigen binding protein described herein, an isolated polynucleotide described herein, a vector described herein, or a protein-drug conjugate described herein, and a pharmaceutically acceptable carrier.

[0086] In another aspect, provided herein is a composition or kit comprising an antigen binding protein described herein, an isolated polynucleotide described herein, a vector described herein, a protein-drug conjugate described herein, or a pharmaceutical agent described herein, and an additional therapeutic agent.

[0087] In another aspect, provided herein is a complex comprising an antigen binding protein described herein or a protein-drug conjugate described herein bound to calcium voltage-gated channel accessory subunit gamma 1 (CACNG1).

[0088] In another aspect, provided herein is a method for making an antigen binding protein described herein, the method comprising culturing a host cell comprising a polynucleotide encoding the antigen binding protein in a culture medium under conditions favorable for expression of the antigen binding protein.

[0089] In some embodiments of the above methods for making an antigen binding protein, the method comprises: (a) introducing the polynucleotide into a host cell; (b) culturing the host cells under conditions favorable for expression of the antigen binding protein; (c) optionally isolating the antigen binding protein from the culture medium and / or the host cell; (d) optionally conjugating the antigen binding protein to a molecular cargo.

[0090] In another aspect, provided herein is an antigen binding protein produced by or obtainable by any of the above methods for making an antigen binding protein.

[0091] In another aspect, provided herein is a method for making a protein-drug conjugate described herein, comprising: (a) contacting an antigen binding protein with a molecular cargo under conditions favoring conjugation of the antigen binding protein to the molecular cargo; (b) optionally isolating the protein-drug conjugate produced in step (a).

[0092] In another aspect, provided herein is a method for making a protein-drug conjugate described herein, wherein the molecular cargo comprises a polypeptide molecule, and the method comprises: (a) culturing a host cell containing a polynucleotide encoding a protein-drug conjugate under conditions that allow expression of the protein-drug conjugate; (b) optionally isolating the protein-drug conjugate produced in step (a).

[0093] In another aspect, provided herein is a protein-drug conjugate produced or obtainable by any of the above methods for making a protein-drug conjugate.

[0094] In another aspect, provided herein is a container or injection device comprising an antigen binding protein described herein, an isolated polynucleotide described herein, a vector described herein, or a protein-drug conjugate described herein.

[0095] In another aspect, provided herein is a method for imaging skeletal muscle in a subject in need thereof, comprising introducing into the body of the subject an antigen binding protein described herein, wherein the antigen binding protein is conjugated to a detectable biosensor or radioisotope.

[0096] In some embodiments, the radioisotope comprises a radionuclide.

[0097] In some embodiments, the antigen binding protein conjugated to a detectable biosensor or radioisotope is introduced into a subject via intramuscular, intravenous, or subcutaneous administration.

[0098] In another aspect, provided herein is a method for causing internalization of a small molecule by a muscle fiber, comprising contacting the muscle fiber with an antigen binding protein described herein, wherein the antigen binding protein is conjugated to the small molecule.

[0099] In some embodiments, the small molecule is an androgen, a glucocorticoid, a β2-adrenergic receptor agonist, rapamycin or an analog thereof, a MAPK inhibitor, or a histone deacetylase inhibitor.

[0100] In some embodiments, the small molecule is an androgen.

[0101] In some embodiments, the androgen is dihydrotestosterone (DHT).

[0102] In some embodiments, the small molecule is a glucocorticoid.

[0103] In some embodiments, the glucocorticoid is budesonide.

[0104] In some embodiments, the small molecule comprises a detectable biosensor or radioisotope.

[0105] In some embodiments, the detectable radioisotope moiety comprises a radionuclide.

[0106] In some embodiments of any of the above methods for causing internalization of a small molecule by a muscle fiber, the contacting comprises administering the antigen binding protein conjugated to a small molecule intramuscularly, intravenously, or subcutaneously in a subject in need thereof.

[0107] In some embodiments of any of the above methods for causing internalization of a small molecule by a muscle fiber, the contacting comprises culturing the muscle fiber in vitro with the antigen binding protein conjugated to the small molecule.

[0108] In some embodiments of any of the above methods for causing internalization of a small molecule by a muscle fiber, the antigen binding protein is conjugated to the small molecule via a valine-citrulline para-aminobenzylcarbamate (VC-PAB) and / or glutamic acid-valine-citrulline para-aminobenzylcarbamate (EVC-PAB) linker.

[0109] In another aspect, provided herein is a method for administering an antigen binding protein described herein, an isolated polynucleotide described herein, a vector described herein, or a protein-drug conjugate described herein in a subject in need thereof, the method comprising introducing the antigen binding protein, polynucleotide, vector, or protein-drug conjugate into the body of the subject.

[0110] In some embodiments, the antigen binding protein, polynucleotide, vector, or protein-drug conjugate is introduced into the subject's body via intramuscular, subcutaneous, or intravenous administration.

[0111] In another aspect, provided herein is a method for delivering molecular cargo to skeletal muscle tissues and / or cells in the body in a subject in need thereof, comprising administering to the subject a protein-drug conjugate described herein or a medicament described herein.

[0112] In another aspect, provided herein is a method for treating, preventing, or reducing the likelihood of a skeletal muscle disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an antigen binding protein described herein, an isolated polynucleotide described herein, a vector described herein, a protein-drug conjugate described herein, or a pharmaceutical composition described herein.

[0113] In some embodiments of the above-described methods for treating, preventing, or reducing the likelihood of a skeletal muscle disease or disorder in a subject in need thereof, the antigen binding protein, polynucleotide, vector, or protein-drug conjugate is administered via intramuscular, subcutaneous, or intravenous administration.

[0114] In some embodiments, the skeletal muscle disease or disorder is muscular dystrophy, muscular atrophy, inflammatory myopathy, a disease of the peripheral nerves, a disease of the neuromuscular junction, a metabolic disease of muscle, central core disease, hyperthyroid myopathy, congenital myotonia, myotubular myopathy, nemaline myopathy, congenital paramyotonia, periodic paralysis-hypokalemia-hyperkalemia, centronuclear myopathy, distal Laing myopathy, myofibrillar myopathy, or a disease or disorder disclosed in Tables 1-3.

[0115] In some embodiments, the muscular dystrophy is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), congenital muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, myotonic muscular dystrophy, or oculopharyngeal muscular dystrophy.

[0116] In some embodiments, the muscle atrophy is spinal muscular atrophy, or muscle atrophy induced by cancer cachexia, disuse, heart failure, chronic obstructive pulmonary disease, or chronic infection.

[0117] In some embodiments, the spinal muscular atrophy is amyotrophic lateral sclerosis (ALS), infantile progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, or adult spinal muscular atrophy.

[0118] In some embodiments, the inflammatory myopathy is dermatomyositis, polymyositis, or inclusion body myositis.

[0119] In some embodiments, the peripheral nerve disease is Charcot-Marie-Tooth disease, Dejerine-Sottas disease, or Friedreich's ataxia.

[0120] In some embodiments, the neuromuscular junction disorder is myasthenia gravis, Lambert-Eaton syndrome, or botulism.

[0121] In some embodiments, the muscle metabolic disorder is acid maltase deficiency, carnitine deficiency, carnitine palmityltransferase deficiency, debranching enzyme deficiency, lactate dehydrogenase deficiency, mitochondrial myopathy, myoadenylate deaminase deficiency, phosphorylase deficiency, phosphofructokinase deficiency, or phosphoglycerate kinase deficiency.

[0122] In some embodiments of any of the above methods for treating, preventing, or reducing the likelihood of a skeletal muscle disease or disorder in a subject in need thereof, the method may further include administering to the subject an additional treatment.

[0123] In some embodiments, the additional treatment comprises physical exercise.

[0124] In some embodiments, the additional treatment comprises administering testosterone and / or glucocorticoids. [Brief explanation of the drawings]

[0125] [Figure 1]Figure 1 shows human myotube acetylcholine-induced calcium flux after addition of calcium voltage-gated channel accessory subunit gamma 1 (CACNG1) antibody, isotype control antibody, or nicardipine (positive control for calcium blockade). [Figure 2] 1 shows binding of CACNG1 antibody to single muscle fibers ex vivo. [Figure 3] 1 illustrates the internalization of a fluorophore-conjugated CACNG1 antibody in a single muscle fiber ex vivo. [Figure 4] 1 shows the biodistribution of CACNG1 antibodies in vivo as assessed by cryofluorescence tomography. [Figure 5A] Figure 5 shows the in vivo biodistribution of CACNG1 antibody to skeletal muscle assessed by immunofluorescence imaging of tissue sections obtained from the gastrocnemius / plantaris / soleus complex (Figure 5A), tibialis anterior (Figure 5B), diaphragm (Figure 5C), tongue (Figure 5D), triceps (Figure 5E), trapezius (Figure 5F), and pelvic floor muscles (Figure 5G). [Figure 5B] Figure 5 shows the in vivo biodistribution of CACNG1 antibody to skeletal muscle assessed by immunofluorescence imaging of tissue sections obtained from the gastrocnemius / plantaris / soleus complex (Figure 5A), tibialis anterior (Figure 5B), diaphragm (Figure 5C), tongue (Figure 5D), triceps (Figure 5E), trapezius (Figure 5F), and pelvic floor muscles (Figure 5G). [Figure 5C] Figure 5 shows the in vivo biodistribution of CACNG1 antibody to skeletal muscle assessed by immunofluorescence imaging of tissue sections obtained from the gastrocnemius / plantaris / soleus complex (Figure 5A), tibialis anterior (Figure 5B), diaphragm (Figure 5C), tongue (Figure 5D), triceps (Figure 5E), trapezius (Figure 5F), and pelvic floor muscles (Figure 5G). [Figure 5D] Figure 5 shows the in vivo biodistribution of CACNG1 antibody to skeletal muscle assessed by immunofluorescence imaging of tissue sections obtained from the gastrocnemius / plantaris / soleus complex (Figure 5A), tibialis anterior (Figure 5B), diaphragm (Figure 5C), tongue (Figure 5D), triceps (Figure 5E), trapezius (Figure 5F), and pelvic floor muscles (Figure 5G). [Figure 5E]Figure 5 shows the in vivo biodistribution of CACNG1 antibody to skeletal muscle assessed by immunofluorescence imaging of tissue sections obtained from the gastrocnemius / plantaris / soleus complex (Figure 5A), tibialis anterior (Figure 5B), diaphragm (Figure 5C), tongue (Figure 5D), triceps (Figure 5E), trapezius (Figure 5F), and pelvic floor muscles (Figure 5G). [Figure 5F] Figure 5 shows the in vivo biodistribution of CACNG1 antibody to skeletal muscle assessed by immunofluorescence imaging of tissue sections obtained from the gastrocnemius / plantaris / soleus complex (Figure 5A), tibialis anterior (Figure 5B), diaphragm (Figure 5C), tongue (Figure 5D), triceps (Figure 5E), trapezius (Figure 5F), and pelvic floor muscles (Figure 5G). [Figure 5G] Figure 5 shows the in vivo biodistribution of CACNG1 antibody to skeletal muscle assessed by immunofluorescence imaging of tissue sections obtained from the gastrocnemius / plantaris / soleus complex (Figure 5A), tibialis anterior (Figure 5B), diaphragm (Figure 5C), tongue (Figure 5D), triceps (Figure 5E), trapezius (Figure 5F), and pelvic floor muscles (Figure 5G). [Figure 6A] Figure 6 shows the in vivo biodistribution of antibodies to non-muscle tissues as assessed by immunofluorescence imaging of tissue sections obtained from the liver (Figure 6A), kidney (Figure 6B), spleen (Figure 6C), and brown fat (Figure 6D). [Figure 6B] Figure 6 shows the in vivo biodistribution of antibodies to non-muscle tissues as assessed by immunofluorescence imaging of tissue sections obtained from the liver (Figure 6A), kidney (Figure 6B), spleen (Figure 6C), and brown fat (Figure 6D). [Figure 6C] Figure 6 shows the in vivo biodistribution of antibodies to non-muscle tissues as assessed by immunofluorescence imaging of tissue sections obtained from the liver (Figure 6A), kidney (Figure 6B), spleen (Figure 6C), and brown fat (Figure 6D). [Figure 6D] Figure 6 shows the in vivo biodistribution of antibodies to non-muscle tissues as assessed by immunofluorescence imaging of tissue sections obtained from the liver (Figure 6A), kidney (Figure 6B), spleen (Figure 6C), and brown fat (Figure 6D). [Figure 7]This demonstrates that exercise and dose alter CACNG1 antibody distribution to muscle. An exemplary experimental timeline is shown schematically (upper panel). Photomicrographs (lower panel) show CACNG1 antibody distribution to the soleus muscle under sedentary and exercise conditions at either a 10 mg / kg or 50 mg / kg (high) dose. [Figure 8A] 1 illustrates that CACNG1 is highly and specifically expressed in human skeletal muscle tissue. [Figure 8B] 1 illustrates that CACNG1 is highly and specifically expressed in human skeletal muscle tissue. [Figure 9A] We demonstrate that CACNG1 does not regulate skeletal muscle size or function. CACNG1 knockout mice are indistinguishable from wild-type mice with respect to muscle size (FIG. 9A) and muscle function (FIG. 9B). Bar graphs of intact muscle twitch (1 Hz) and tetanic (125 Hz) contractile force characteristics of muscles from wild-type versus CACNG1 knockout mice are shown in FIG. 9C. TA (Tibialis anterior), tibialis anterior; GA, gastrocnemius; EDL (extensor digitorum longus), extensor digitorum longus. [Figure 9B] We demonstrate that CACNG1 does not regulate skeletal muscle size or function. CACNG1 knockout mice are indistinguishable from wild-type mice with respect to muscle size (FIG. 9A) and muscle function (FIG. 9B). Bar graphs of intact muscle twitch (1 Hz) and tetanic (125 Hz) contractile force characteristics of muscles from wild-type versus CACNG1 knockout mice are shown in FIG. 9C. TA (Tibialis anterior), tibialis anterior; GA, gastrocnemius; EDL (extensor digitorum longus), extensor digitorum longus. [Figure 9C]We demonstrate that CACNG1 does not regulate skeletal muscle size or function. CACNG1 knockout mice are indistinguishable from wild-type mice with respect to muscle size (FIG. 9A) and muscle function (FIG. 9B). Bar graphs of intact muscle twitch (1 Hz) and tetanic (125 Hz) contractile force characteristics of muscles from wild-type versus CACNG1 knockout mice are shown in FIG. 9C. TA (Tibialis anterior), tibialis anterior; GA, gastrocnemius; EDL (extensor digitorum longus), extensor digitorum longus. [Figure 10A] In vitro and ex vivo evaluation of CACNG1 antibody properties is shown. Mouse and human myotubes were used as in vitro models of muscle to assess CACNG1 antibody cell binding (FIGS. 10A-10B), internalization (FIG. 10C), and localization (FIG. 10D). Incubation of live myotubes with anti-CACNG1 antibodies, followed by fluorophore-conjugated secondary detection, was performed to assess antibody binding (FIGS. 10A-10B). Incubation of myotubes with anti-CACNG1 antibodies, such as REGN7854 and other anti-CACNG1 antibodies described herein, followed by duocarmycin-conjugated secondary (2° Ab-cytotoxic drug) was performed to assess antibody internalization via cell killing (FIG. 10C). Immunostaining of CACNG1 in a single muscle fiber of CACNG1 Hu / Hu mice (FIG. 10D, left panel) and in muscle tissue cross-sections (FIG. 10D, right panel) shows the expression of CACNG1 on the surface of muscle fiber cells. [Figure 10B]In vitro and ex vivo evaluation of CACNG1 antibody properties is shown. Mouse and human myotubes were used as in vitro models of muscle to assess CACNG1 antibody cell binding (FIGS. 10A-10B), internalization (FIG. 10C), and localization (FIG. 10D). Incubation of live myotubes with anti-CACNG1 antibodies, followed by fluorophore-conjugated secondary detection, was performed to assess antibody binding (FIGS. 10A-10B). Incubation of myotubes with anti-CACNG1 antibodies, such as REGN7854 and other anti-CACNG1 antibodies described herein, followed by duocarmycin-conjugated secondary (2° Ab-cytotoxic drug) was performed to assess antibody internalization via cell killing (FIG. 10C). Immunostaining of CACNG1 in a single muscle fiber of CACNG1Hu / Hu mice (FIG. 10D, left panel) and in muscle tissue cross-sections (FIG. 10D, right panel) shows the expression of CACNG1 on the surface of muscle fiber cells. [Figure 10C] In vitro and ex vivo evaluation of CACNG1 antibody properties is shown. Mouse and human myotubes were used as in vitro models of muscle to assess CACNG1 antibody cell binding (FIGS. 10A-10B), internalization (FIG. 10C), and localization (FIG. 10D). Incubation of live myotubes with anti-CACNG1 antibodies, followed by fluorophore-conjugated secondary detection, was performed to assess antibody binding (FIGS. 10A-10B). Incubation of myotubes with anti-CACNG1 antibodies, such as REGN7854 and other anti-CACNG1 antibodies described herein, followed by duocarmycin-conjugated secondary (2° Ab-cytotoxic drug) was performed to assess antibody internalization via cell killing (FIG. 10C). Immunostaining of CACNG1 in a single muscle fiber of CACNG1Hu / Hu mice (FIG. 10D, left panel) and in muscle tissue cross-sections (FIG. 10D, right panel) shows the expression of CACNG1 on the surface of muscle fiber cells. [Figure 10D]In vitro and ex vivo evaluation of CACNG1 antibody properties is shown. Mouse and human myotubes were used as in vitro models of muscle to assess CACNG1 antibody cell binding (FIGS. 10A-10B), internalization (FIG. 10C), and localization (FIG. 10D). Incubation of live myotubes with anti-CACNG1 antibodies, followed by fluorophore-conjugated secondary detection, was performed to assess antibody binding (FIGS. 10A-10B). Incubation of myotubes with anti-CACNG1 antibodies, such as REGN7854 and other anti-CACNG1 antibodies described herein, followed by duocarmycin-conjugated secondary (2° Ab-cytotoxic drug) was performed to assess antibody internalization via cell killing (FIG. 10C). Immunostaining of CACNG1 in a single muscle fiber of CACNG1Hu / Hu mice (FIG. 10D, left panel) and in muscle tissue cross-sections (FIG. 10D, right panel) shows the expression of CACNG1 on the surface of muscle fiber cells. [Figure 11A] We demonstrate specific knockdown of DMPK by anti-CACNG1-DM1 protein kinase (DMPK) siRNA conjugates in skeletal muscle compared to other tissues. A schematic diagram of an exemplary anti-CACNG1-DMPK siRNA conjugate is shown in Figure 11A. Graphs showing DMPK mRNA expression levels (relative to PBS) measured in gastrocnemius (Figure 11B), soleus (Figure 11C), tibialis anterior (Figure 11D), quadriceps (Figure 11E), diaphragm (Figure 11F), heart (Figure 11G), liver (Figure 11H), kidney (Figure 11I), spleen (Figure 11J), and lung (Figure 11K) at 0.3 mg / kg, 1 mg / kg, and 3 mg / kg doses of total siRNA are shown in Figures 11B-11K. [Figure 11B]We demonstrate specific knockdown of DMPK by anti-CACNG1-DM1 protein kinase (DMPK) siRNA conjugates in skeletal muscle compared to other tissues. A schematic diagram of an exemplary anti-CACNG1-DMPK siRNA conjugate is shown in Figure 11A. Graphs showing DMPK mRNA expression levels (relative to PBS) measured in gastrocnemius (Figure 11B), soleus (Figure 11C), tibialis anterior (Figure 11D), quadriceps (Figure 11E), diaphragm (Figure 11F), heart (Figure 11G), liver (Figure 11H), kidney (Figure 11I), spleen (Figure 11J), and lung (Figure 11K) at 0.3 mg / kg, 1 mg / kg, and 3 mg / kg doses of total siRNA are shown in Figures 11B-11K. [Figure 11C] We demonstrate specific knockdown of DMPK by anti-CACNG1-DM1 protein kinase (DMPK) siRNA conjugates in skeletal muscle compared to other tissues. A schematic diagram of an exemplary anti-CACNG1-DMPK siRNA conjugate is shown in Figure 11A. Graphs showing DMPK mRNA expression levels (relative to PBS) measured in gastrocnemius (Figure 11B), soleus (Figure 11C), tibialis anterior (Figure 11D), quadriceps (Figure 11E), diaphragm (Figure 11F), heart (Figure 11G), liver (Figure 11H), kidney (Figure 11I), spleen (Figure 11J), and lung (Figure 11K) at 0.3 mg / kg, 1 mg / kg, and 3 mg / kg doses of total siRNA are shown in Figures 11B-11K. [Figure 11D] We demonstrate specific knockdown of DMPK by anti-CACNG1-DM1 protein kinase (DMPK) siRNA conjugates in skeletal muscle compared to other tissues. A schematic diagram of an exemplary anti-CACNG1-DMPK siRNA conjugate is shown in Figure 11A. Graphs showing DMPK mRNA expression levels (relative to PBS) measured in gastrocnemius (Figure 11B), soleus (Figure 11C), tibialis anterior (Figure 11D), quadriceps (Figure 11E), diaphragm (Figure 11F), heart (Figure 11G), liver (Figure 11H), kidney (Figure 11I), spleen (Figure 11J), and lung (Figure 11K) at 0.3 mg / kg, 1 mg / kg, and 3 mg / kg doses of total siRNA are shown in Figures 11B-11K. [Figure 11E]We demonstrate specific knockdown of DMPK by anti-CACNG1-DM1 protein kinase (DMPK) siRNA conjugates in skeletal muscle compared to other tissues. A schematic diagram of an exemplary anti-CACNG1-DMPK siRNA conjugate is shown in Figure 11A. Graphs showing DMPK mRNA expression levels (relative to PBS) measured in gastrocnemius (Figure 11B), soleus (Figure 11C), tibialis anterior (Figure 11D), quadriceps (Figure 11E), diaphragm (Figure 11F), heart (Figure 11G), liver (Figure 11H), kidney (Figure 11I), spleen (Figure 11J), and lung (Figure 11K) at 0.3 mg / kg, 1 mg / kg, and 3 mg / kg doses of total siRNA are shown in Figures 11B-11K. [Figure 11F] We demonstrate specific knockdown of DMPK by anti-CACNG1-DM1 protein kinase (DMPK) siRNA conjugates in skeletal muscle compared to other tissues. A schematic diagram of an exemplary anti-CACNG1-DMPK siRNA conjugate is shown in Figure 11A. Graphs showing DMPK mRNA expression levels (relative to PBS) measured in gastrocnemius (Figure 11B), soleus (Figure 11C), tibialis anterior (Figure 11D), quadriceps (Figure 11E), diaphragm (Figure 11F), heart (Figure 11G), liver (Figure 11H), kidney (Figure 11I), spleen (Figure 11J), and lung (Figure 11K) at 0.3 mg / kg, 1 mg / kg, and 3 mg / kg doses of total siRNA are shown in Figures 11B-11K. [Figure 11G] We demonstrate specific knockdown of DMPK by anti-CACNG1-DM1 protein kinase (DMPK) siRNA conjugates in skeletal muscle compared to other tissues. A schematic diagram of an exemplary anti-CACNG1-DMPK siRNA conjugate is shown in Figure 11A. Graphs showing DMPK mRNA expression levels (relative to PBS) measured in gastrocnemius (Figure 11B), soleus (Figure 11C), tibialis anterior (Figure 11D), quadriceps (Figure 11E), diaphragm (Figure 11F), heart (Figure 11G), liver (Figure 11H), kidney (Figure 11I), spleen (Figure 11J), and lung (Figure 11K) at 0.3 mg / kg, 1 mg / kg, and 3 mg / kg doses of total siRNA are shown in Figures 11B-11K. [Figure 11H]We demonstrate specific knockdown of DMPK by anti-CACNG1-DM1 protein kinase (DMPK) siRNA conjugates in skeletal muscle compared to other tissues. A schematic diagram of an exemplary anti-CACNG1-DMPK siRNA conjugate is shown in Figure 11A. Graphs showing DMPK mRNA expression levels (relative to PBS) measured in gastrocnemius (Figure 11B), soleus (Figure 11C), tibialis anterior (Figure 11D), quadriceps (Figure 11E), diaphragm (Figure 11F), heart (Figure 11G), liver (Figure 11H), kidney (Figure 11I), spleen (Figure 11J), and lung (Figure 11K) at 0.3 mg / kg, 1 mg / kg, and 3 mg / kg doses of total siRNA are shown in Figures 11B-11K. [Figure 11I] We demonstrate specific knockdown of DMPK by anti-CACNG1-DM1 protein kinase (DMPK) siRNA conjugates in skeletal muscle compared to other tissues. A schematic diagram of an exemplary anti-CACNG1-DMPK siRNA conjugate is shown in Figure 11A. Graphs showing DMPK mRNA expression levels (relative to PBS) measured in gastrocnemius (Figure 11B), soleus (Figure 11C), tibialis anterior (Figure 11D), quadriceps (Figure 11E), diaphragm (Figure 11F), heart (Figure 11G), liver (Figure 11H), kidney (Figure 11I), spleen (Figure 11J), and lung (Figure 11K) at 0.3 mg / kg, 1 mg / kg, and 3 mg / kg doses of total siRNA are shown in Figures 11B-11K. [Figure 11J] We demonstrate specific knockdown of DMPK by anti-CACNG1-DM1 protein kinase (DMPK) siRNA conjugates in skeletal muscle compared to other tissues. A schematic diagram of an exemplary anti-CACNG1-DMPK siRNA conjugate is shown in Figure 11A. Graphs showing DMPK mRNA expression levels (relative to PBS) measured in gastrocnemius (Figure 11B), soleus (Figure 11C), tibialis anterior (Figure 11D), quadriceps (Figure 11E), diaphragm (Figure 11F), heart (Figure 11G), liver (Figure 11H), kidney (Figure 11I), spleen (Figure 11J), and lung (Figure 11K) at 0.3 mg / kg, 1 mg / kg, and 3 mg / kg doses of total siRNA are shown in Figures 11B-11K. [Figure 11K]We demonstrate specific knockdown of DMPK by anti-CACNG1-DM1 protein kinase (DMPK) siRNA conjugates in skeletal muscle compared to other tissues. A schematic diagram of an exemplary anti-CACNG1-DMPK siRNA conjugate is shown in Figure 11A. Graphs showing DMPK mRNA expression levels (relative to PBS) measured in gastrocnemius (Figure 11B), soleus (Figure 11C), tibialis anterior (Figure 11D), quadriceps (Figure 11E), diaphragm (Figure 11F), heart (Figure 11G), liver (Figure 11H), kidney (Figure 11I), spleen (Figure 11J), and lung (Figure 11K) at 0.3 mg / kg, 1 mg / kg, and 3 mg / kg doses of total siRNA are shown in Figures 11B-11K. [Figure 12A] 1 shows a schematic diagram of an exemplary siRNA (siRNA1) against DMPK. [Figure 12B] 1 shows a schematic diagram of an exemplary siRNA (siRNA1) against DMPK. [Figure 13A] 10 illustrates that α-CACNG1-Dmpk siRNA conjugate knocks down Dmpk in skeletal muscle one week after administration. [Figure 13B] 10 illustrates that α-CACNG1-Dmpk siRNA conjugate knocks down Dmpk in skeletal muscle one week after administration. [Figure 13C] 10 illustrates that α-CACNG1-Dmpk siRNA conjugate knocks down Dmpk in skeletal muscle one week after administration. [Figure 13D] 10 illustrates that α-CACNG1-Dmpk siRNA conjugate knocks down Dmpk in skeletal muscle one week after administration. [Figure 13E] 10 illustrates that α-CACNG1-Dmpk siRNA conjugate knocks down Dmpk in skeletal muscle one week after administration. [Figure 14A] 1 illustrates that the α-CACNG1-Dmpk siRNA conjugate does not knock down Dmpk in other tissues (eg, liver, heart, kidney) one week after administration. [Figure 14B] 1 illustrates that the α-CACNG1-Dmpk siRNA conjugate does not knock down Dmpk in other tissues (eg, liver, heart, kidney) one week after administration. [Figure 14C] 1 illustrates that the α-CACNG1-Dmpk siRNA conjugate does not knock down Dmpk in other tissues (eg, liver, heart, kidney) one week after administration. [Figure 15A] This figure illustrates that the α-CACNG1-Dmpk siRNA conjugate knocks down Dmpk in skeletal muscle after 3 weeks of administration (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). TA, tibialis anterior; Quad, quadriceps; Gastroc, gastrocnemius. [Figure 15B] This figure illustrates that the α-CACNG1-Dmpk siRNA conjugate knocks down Dmpk in skeletal muscle after 3 weeks of administration (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). TA, tibialis anterior; Quad, quadriceps; Gastroc, gastrocnemius. [Figure 15C] This figure illustrates that the α-CACNG1-Dmpk siRNA conjugate knocks down Dmpk in skeletal muscle after 3 weeks of administration (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). TA, tibialis anterior; Quad, quadriceps; Gastroc, gastrocnemius. [Figure 15D] This figure illustrates that the α-CACNG1-Dmpk siRNA conjugate knocks down Dmpk in skeletal muscle after 3 weeks of administration (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). TA, tibialis anterior; Quad, quadriceps; Gastroc, gastrocnemius. [Figure 15E]This figure illustrates that the α-CACNG1-Dmpk siRNA conjugate knocks down Dmpk in skeletal muscle after 3 weeks of administration (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). TA, tibialis anterior; Quad, quadriceps; Gastroc, gastrocnemius. [Figure 16A] This figure illustrates that the α-CACNG1-Dmpk siRNA conjugate knocks down Dmpk in skeletal muscle after 6 weeks of administration (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). TA, tibialis anterior; Quad, quadriceps; Gastroc, gastrocnemius. [Figure 16B] This figure illustrates that the α-CACNG1-Dmpk siRNA conjugate knocks down Dmpk in skeletal muscle after 6 weeks of administration (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). TA, tibialis anterior; Quad, quadriceps; Gastroc, gastrocnemius. [Figure 16C] This figure illustrates that the α-CACNG1-Dmpk siRNA conjugate knocks down Dmpk in skeletal muscle after 6 weeks of administration (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). TA, tibialis anterior; Quad, quadriceps; Gastroc, gastrocnemius. [Figure 16D] This figure illustrates that the α-CACNG1-Dmpk siRNA conjugate knocks down Dmpk in skeletal muscle after 6 weeks of administration (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). TA, tibialis anterior; Quad, quadriceps; Gastroc, gastrocnemius. [Figure 16E] This figure illustrates that the α-CACNG1-Dmpk siRNA conjugate knocks down Dmpk in skeletal muscle after 6 weeks of administration (*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001). TA, tibialis anterior; Quad, quadriceps; Gastroc, gastrocnemius. [Figure 17A]This illustrates that the α-CACNG1-Dmpk siRNA conjugate does not knock down Dmpk in other tissues (eg, heart, liver, kidney) 3 weeks after administration. [Figure 17B] This illustrates that the α-CACNG1-Dmpk siRNA conjugate does not knock down Dmpk in other tissues (eg, heart, liver, kidney) 3 weeks after administration. [Figure 17C] This illustrates that the α-CACNG1-Dmpk siRNA conjugate does not knock down Dmpk in other tissues (eg, heart, liver, kidney) 3 weeks after administration. [Figure 18A] This illustrates that the α-CACNG1-Dmpk siRNA conjugate does not knock down Dmpk in other tissues (eg, heart, liver, kidney) 6 weeks after administration. [Figure 18B] This illustrates that the α-CACNG1-Dmpk siRNA conjugate does not knock down Dmpk in other tissues (eg, heart, liver, kidney) 6 weeks after administration. [Figure 18C] This illustrates that the α-CACNG1-Dmpk siRNA conjugate does not knock down Dmpk in other tissues (eg, heart, liver, kidney) 6 weeks after administration. [Figure 19] 1 shows an example of an antibody-steroid conjugation scheme described herein. [Figure 20] 1 shows a preparative size-exclusion chromatography (SEC) chromatogram of the CACNG 1-linker conjugation mixture. [Figure 21] 1 shows a preparative SEC chromatogram of a CACNG1-steroid conjugation mixture. [Figure 22] 1 shows an analytical SEC chromatogram of purified CACNG1-steroid antibody-drug conjugate (ADC). [Figure 23]Liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) spectra of CACNG1-steroid ADC samples are shown. The calculated mean drug-to-antibody ration (DAR) value was 3.94. [Figure 24] The levels of androgen receptor (AR) activation are shown in terms of relative light units (RLU; y-axis) after 24 hours of incubation of an LNCaP cell line (AR.Luc) modified to express luciferase upon androgen receptor activation with various concentrations (Log[concentration (M)], x-axis) of dihydrotestosterone (DHT) alone (M608, unconjugated DHT), an anti-human CACNG1 (hCACNG1) antibody (REGN14570, REGN14571, REGN14572, REGN14573, REGN14574, or REGN14647) conjugated to DHT (M3004) via a VC-PAB linker, or an anti-FelD isotype control antibody (REGN3892) conjugated to DHT (M3004) via a VC-PAB linker. [Figure 25A]The levels of androgen receptor (AR) activation are shown in terms of relative light units (RLU, y-axis) after 24, 48, or 72 hours of incubation of an hCACNG1-expressing LNCaP cell line (hCACNG1.AR.Luc), which was also modified to express luciferase upon androgen receptor activation, with various concentrations (Log[concentration (M)], x-axis) of dihydrotestosterone (DHT) alone (M608, unconjugated DHT), an anti-hCACNG1 antibody (REGN14570, REGN14571, REGN14572, REGN14573, REGN14574, or REGN14647) conjugated to DHT (M3004) via a VC-PAB linker, or an anti-FelD isotype control antibody (REGN3892) conjugated to DHT (M3004) via a VC-PAB linker. [Figure 25B] The levels of androgen receptor (AR) activation are shown in terms of relative light units (RLU, y-axis) after 24, 48, or 72 hours of incubation of an hCACNG1-expressing LNCaP cell line (hCACNG1.AR.Luc), which was also modified to express luciferase upon androgen receptor activation, with various concentrations (Log[concentration (M)], x-axis) of dihydrotestosterone (DHT) alone (M608, unconjugated DHT), an anti-hCACNG1 antibody (REGN14570, REGN14571, REGN14572, REGN14573, REGN14574, or REGN14647) conjugated to DHT (M3004) via a VC-PAB linker, or an anti-FelD isotype control antibody (REGN3892) conjugated to DHT (M3004) via a VC-PAB linker. [Figure 25C]The levels of androgen receptor (AR) activation are shown in terms of relative light units (RLU, y-axis) after 24, 48, or 72 hours of incubation of an hCACNG1-expressing LNCaP cell line (hCACNG1.AR.Luc), which was also modified to express luciferase upon androgen receptor activation, with various concentrations (Log[concentration (M)], x-axis) of dihydrotestosterone (DHT) alone (M608, unconjugated DHT), an anti-hCACNG1 antibody (REGN14570, REGN14571, REGN14572, REGN14573, REGN14574, or REGN14647) conjugated to DHT (M3004) via a VC-PAB linker, or an anti-FelD isotype control antibody (REGN3892) conjugated to DHT (M3004) via a VC-PAB linker. [Figure 25D] The levels of androgen receptor (AR) activation are shown in terms of relative light units (RLU, y-axis) after 24, 48, or 72 hours of incubation of an hCACNG1-expressing LNCaP cell line (hCACNG1.AR.Luc), which was also modified to express luciferase upon androgen receptor activation, with various concentrations (Log[concentration (M)], x-axis) of dihydrotestosterone (DHT) alone (M608, unconjugated DHT), an anti-hCACNG1 antibody (REGN14570, REGN14571, REGN14572, REGN14573, REGN14574, or REGN14647) conjugated to DHT (M3004) via a VC-PAB linker, or an anti-FelD isotype control antibody (REGN3892) conjugated to DHT (M3004) via a VC-PAB linker. [Figure 25E]The levels of androgen receptor (AR) activation are shown in terms of relative light units (RLU, y-axis) after 24, 48, or 72 hours of incubation of an hCACNG1-expressing LNCaP cell line (hCACNG1.AR.Luc), which was also modified to express luciferase upon androgen receptor activation, with various concentrations (Log[concentration (M)], x-axis) of dihydrotestosterone (DHT) alone (M608, unconjugated DHT), an anti-hCACNG1 antibody (REGN14570, REGN14571, REGN14572, REGN14573, REGN14574, or REGN14647) conjugated to DHT (M3004) via a VC-PAB linker, or an anti-FelD isotype control antibody (REGN3892) conjugated to DHT (M3004) via a VC-PAB linker. [Figure 25F] The levels of androgen receptor (AR) activation are shown in terms of relative light units (RLU, y-axis) after 24, 48, or 72 hours of incubation of an hCACNG1-expressing LNCaP cell line (hCACNG1.AR.Luc), which was also modified to express luciferase upon androgen receptor activation, with various concentrations (Log[concentration (M)], x-axis) of dihydrotestosterone (DHT) alone (M608, unconjugated DHT), an anti-hCACNG1 antibody (REGN14570, REGN14571, REGN14572, REGN14573, REGN14574, or REGN14647) conjugated to DHT (M3004) via a VC-PAB linker, or an anti-FelD isotype control antibody (REGN3892) conjugated to DHT (M3004) via a VC-PAB linker. [Figure 25G]The levels of androgen receptor (AR) activation are shown in terms of relative light units (RLU, y-axis) after 24, 48, or 72 hours of incubation of an hCACNG1-expressing LNCaP cell line (hCACNG1.AR.Luc), which was also modified to express luciferase upon androgen receptor activation, with various concentrations (Log[concentration (M)], x-axis) of dihydrotestosterone (DHT) alone (M608, unconjugated DHT), an anti-hCACNG1 antibody (REGN14570, REGN14571, REGN14572, REGN14573, REGN14574, or REGN14647) conjugated to DHT (M3004) via a VC-PAB linker, or an anti-FelD isotype control antibody (REGN3892) conjugated to DHT (M3004) via a VC-PAB linker. [Figure 25H] The levels of androgen receptor (AR) activation are shown in terms of relative light units (RLU, y-axis) after 24, 48, or 72 hours of incubation of an hCACNG1-expressing LNCaP cell line (hCACNG1.AR.Luc), which was also modified to express luciferase upon androgen receptor activation, with various concentrations (Log[concentration (M)], x-axis) of dihydrotestosterone (DHT) alone (M608, unconjugated DHT), an anti-hCACNG1 antibody (REGN14570, REGN14571, REGN14572, REGN14573, REGN14574, or REGN14647) conjugated to DHT (M3004) via a VC-PAB linker, or an anti-FelD isotype control antibody (REGN3892) conjugated to DHT (M3004) via a VC-PAB linker. [Figure 25I]The levels of androgen receptor (AR) activation are shown in terms of relative light units (RLU, y-axis) after 24, 48, or 72 hours of incubation of an hCACNG1-expressing LNCaP cell line (hCACNG1.AR.Luc), which was also modified to express luciferase upon androgen receptor activation, with various concentrations (Log[concentration (M)], x-axis) of dihydrotestosterone (DHT) alone (M608, unconjugated DHT), an anti-hCACNG1 antibody (REGN14570, REGN14571, REGN14572, REGN14573, REGN14574, or REGN14647) conjugated to DHT (M3004) via a VC-PAB linker, or an anti-FelD isotype control antibody (REGN3892) conjugated to DHT (M3004) via a VC-PAB linker. [Figure 26A] Figure 26 illustrates that budesonide-conjugated CACNG1 antibody (Ab) increases the expression of the glucocorticoid-responsive genes kidney-enriched krueppel-like factor 15 (Klf15) (Figure 26A), pyruvate dehydrogenase kinase 4 (Pdk4) (Figure 26B), and FKBP prolyl isomerase 5 (Fkbp5) (Figure 26C) in C2C12 myotubes. [Figure 26B] Figure 26 illustrates that budesonide-conjugated CACNG1 antibody (Ab) increases the expression of the glucocorticoid-responsive genes kidney-enriched krueppel-like factor 15 (Klf15) (Figure 26A), pyruvate dehydrogenase kinase 4 (Pdk4) (Figure 26B), and FKBP prolyl isomerase 5 (Fkbp5) (Figure 26C) in C2C12 myotubes. [Figure 26C]Figure 26 illustrates that budesonide-conjugated CACNG1 antibody (Ab) increases the expression of the glucocorticoid-responsive genes kidney-enriched krueppel-like factor 15 (Klf15) (Figure 26A), pyruvate dehydrogenase kinase 4 (Pdk4) (Figure 26B), and FKBP prolyl isomerase 5 (Fkbp5) (Figure 26C) in C2C12 myotubes. [Figure 27A] Anti-CACNG1 biosensor binding and cleavage are demonstrated in primary human skeletal myotubes (HuSKM) and primary mouse myotubes (C2C12). [Figure 27B] Anti-CACNG1 biosensor binding and cleavage are demonstrated in primary human skeletal myotubes (HuSKM) and primary mouse myotubes (C2C12). [Figure 27C] Anti-CACNG1 biosensor binding and cleavage are demonstrated in primary human skeletal myotubes (HuSKM) and primary mouse myotubes (C2C12). [Figure 27D] Anti-CACNG1 biosensor binding and cleavage are demonstrated in primary human skeletal myotubes (HuSKM) and primary mouse myotubes (C2C12). [Figure 28A] Quantification of anti-CACNG1 biosensor cleavage in primary human skeletal myotubes (HuSKM) and primary mouse myotubes (C2C12) is illustrated. [Figure 28B] Quantification of anti-CACNG1 biosensor cleavage in primary human skeletal myotubes (HuSKM) and primary mouse myotubes (C2C12) is illustrated. [Figure 28C] Quantification of anti-CACNG1 biosensor cleavage in primary human skeletal myotubes (HuSKM) and primary mouse myotubes (C2C12) is illustrated. [Figure 28D] Quantification of anti-CACNG1 biosensor cleavage in primary human skeletal myotubes (HuSKM) and primary mouse myotubes (C2C12) is illustrated. DETAILED DESCRIPTION OF THE INVENTION

[0126] The present disclosure provides an antigen-binding protein, or an antigenic fragment thereof, that specifically binds to calcium voltage-gated channel accessory subunit gamma 1 (CACNG1). The present disclosure further provides a protein-drug conjugate comprising an antigen-binding protein that specifically binds to CACNG1 or an antigenic fragment thereof and is conjugated to a molecular cargo. Such conjugates are useful, for example, for delivering molecular cargo to skeletal muscle tissue and / or cells (e.g., muscle fibers) within the body. Delivery of molecular cargo using a protein-drug conjugate comprising a CACNG1 antigen-binding protein disclosed herein can be particularly advantageous when it is particularly desirable to target skeletal muscle tissue and cells present therein while avoiding targeting other muscle tissues, such as smooth muscle tissue, non-skeletal muscle tissue (off-targets). The conjugates described herein are capable of efficiently delivering molecular cargo to skeletal muscle tissue and cells present therein and can therefore be used in treating, preventing, or reducing the likelihood of diseases and disorders, such as skeletal muscle diseases and disorders.

[0127] Skeletal muscle is the largest organ in the body, comprising approximately 40% of total body weight. Skeletal muscle is one of the three major muscle tissues in the human body. Each skeletal muscle consists of thousands of muscle fibers wrapped together by connective tissue sheaths. The individual muscle fiber bundles in a skeletal muscle are known as fasciculi. The outermost connective tissue sheath that surrounds the entire muscle is known as the epimysium. The connective tissue sheath that covers each bundle is known as the perimysium, and the innermost sheath that surrounds individual muscle fibers is known as the perimysium. Each muscle fiber is composed of many myofibrils, which contain multiple myofilaments.

[0128] When bundled together, all myofibrils are arranged in a unique muscle pattern to form the sarcomere, the basic contractile unit of skeletal muscle. The two most important myofilaments are actin and myosin filaments, which are characteristically arranged to form various bands on skeletal muscle.

[0129] The primary function of skeletal muscle occurs through its intrinsic excitation-contraction coupling process. When muscles are attached to bones and tendons, muscle contraction results in the movement of those bones, allowing specific movements to be performed. Skeletal muscle also provides structural support and helps maintain body posture. Skeletal muscle also acts as a storage source of amino acids that can be used by different organs of the body to synthesize organ-specific proteins. Skeletal muscle also acts as a site of glucose disposal in the form of muscle glycogen. Skeletal muscle also plays a central role in maintaining body temperature and serves as an energy source during starvation. Thus, skeletal muscle plays an important role in locomotor activity, thermoregulation, and the control of whole-body metabolism.

[0130] In many muscle diseases, as well as during normal aging, the size and function of skeletal muscle tissue decreases, leading to impaired functional mobility and, in severe muscle diseases, long-term disability and premature death.

[0131] Treatments for muscle wasting (also referred to herein as muscle atrophy or muscular atrophy) and genetic muscle diseases described herein typically consist of broad-spectrum acting therapies, such as testosterone or dihydrotestosterone (DHT) therapy for muscle wasting and glucocorticoids (e.g., budesonide) for muscular dystrophies. Non-targeted delivery of these therapies reduces the efficiency of specific muscle uptake while also resulting in significant deleterious off-target effects on other organs.

[0132] In some aspects, the present disclosure addresses the need in the art for anti-human antibodies that can bind to muscle-specific markers (e.g., CACNG1) and result in internalization of therapeutic payloads by muscle cells.

[0133] In accordance with the present disclosure, one may employ conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art, such techniques being explained fully in the literature. For example, Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY (herein referred to as "Sambrook, et al., 1989"), DNA Cloning: A Practical Approach, Volumes I and II (DNGlover ed.1985), Oligonucleotide Synthesis (MJGait ed.1984), Nucleic Acid Hybridization(BDHames & SJHiggins eds.(1985)), Transcription And Translation(BDHames & SJHiggins,eds.1984), Animal Cell Culture(RIFreshney,ed.(1986)), Immobilized Cells And Enzymes(IRL Press,(1986)), B.Perbal,A Practical Guide To Molecular Cloning (1984), FMAsubel, et al. See, e.g., J. et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, Inc. (1994).

[0134] The term "about," when used in reference to a particular recited numerical value, means that the value may vary by no more than 1% from the recited value. For example, the phrase "about 100" includes 99 and 101 and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0135] Polynucleotides include DNA and RNA. The present disclosure includes any polynucleotide described herein operably linked to a promoter or other expression control sequence.

[0136] The term "CACNG1" refers to calcium voltage-gated channel accessory subunit gamma 1. Voltage-gated calcium channels are generally composed of five subunits. The protein encoded by the CACNG1 gene represents the gamma subunit of these subunits. "CACNG1" includes the protein encoded by the CACNG1 gene and is one of two known gamma subunit proteins. CACNG1 is part of the skeletal muscle 1,4-dihydropyridine-sensitive calcium channel and is an integral membrane protein that plays a role in excitation-contraction coupling. CACNG1 is part of the functionally diverse eight-member protein subfamily of the PMP-22 / EMP / MP20 family and is located in a cluster with two family members that function as transmembrane AMPA receptor regulatory proteins (TARPs). CACNG1 is highly and specifically expressed in skeletal muscle. The gene encoding human CACNG1 (CACNG1) is located on the long arm of chromosome 17. CACNG1 contains four exons and is approximately 12,244 bases in length. An example of the sequence of human CACNG1 mRNA is available under NCBI accession number NM_000727.4: ACTCCCAGCTCGACAACCACTGCCACCCCCCAAGCTCGGCTTGTCACCT GCCCTAGGAGACGCAGCCGCCGGACCCTGCCCAGGGCACCCACGCCTCGGCGACCA CCATGTCCCAGACCAAAATGCTGAAGGTCCGCGTGACCCTCTTCTGCATCCTGGCAGG CATCGTGCTGGCCATGACAGCCGTGGTAACCGACCACTGGGCTGTGCTGAGCCCCCA CATGGAGCACCACAACACTACCTGCGAGGCGGCCCACTTCGGCCTCTGGCGGATTTG TACCAAGCGCATCCCCATGGACGACAGCAAGACCTGCGGGCCCATCACCCTGCCCGG GGAGAAGAACTGTTCCTACTTCAGGCATTTTAACCCCGGCGAGAGCTCGGAGATCTTC GAATTCACCACTCAGAAGGAGTACAGCATCTCGGCAGCCGCCATCGCCATCTTCAGCC TTGGCTTCATCATCCTGGGCAGCCTCTGTGTCCTCCTGTCCCTCGGGAAGAAGAGGGA CTATCTGCTGCGACCCGCGTCCATGTTCTATGCCTTTGCAGGTCTCTGCATCCTCGTC TCGGTGGAGGTCATGCGGCAGTCGGTGAAGCGCATGATTGACAGTGAGGACACCGTC TGGATCGAGTACTATTACTCCTGGTCCTTTGCCTGCGCCTGTGCCGCCTTCATCCTCC TCTTTCTCGGCGGTCTCGCCCTCCTGCTGTTCTCCCTGCCTCGAATGCCCCGGAACCC ATGGGAGTCCTGCATGGATGCTGAGCCCGAGCACTAACCCTCCTGCGGCCCTAGCGA CCCTCAGGCTTCTTCCCCAGGAAGCGGGGTCTTGGCCTGGAACCTTCCAGAGAGGAG GCGGGAGCAATTTTAGCCCCACCCTGCTCCCATCTGCCCCCCTGCAACAGTCGCAGG CTGCTTCCTCTCTCTGAGTTCCTCTGGGCTGCCGCAGGCTCCCCTGGGAATAGAGCAAGACGTGAGTCCTAACCTGGCCACAGTTGGGGGAGGCAGAGCCAGCAGGTGGACAGG TGTTTGCAGGGGCCCAACTTCCCCTGGAGCTCAGAGGTGTCCCCACTGTACCAGCCT CTGATAAGCTGCCTCCAGTTGTCCTTTATGAACATTGCAGGGACAACCTGTGTTTGCCCA GCTGGGTGTTCCGTGTAAATAGCCAGCCTGTCTCTTTCTCGGTGATAAAACACACCCT CTCTGGTGAGCCCAGCGTCCCCTCCTTGGCTTCCAGGAGCCCTGGGAAGCATTTTTAA CTGGGTAGAATCTGACTGTGGCTTGAAATAAAAAGCTCTCAGAAAA (SEQ ID NO: 473) has been assigned.

[0137] An exemplary human CACNG1 protein is identified under NCBI accession number NP_000718: MSQTKMLKVRVTLFCILAGIVLAMTAVVTDHWAVLSPHMEHHNTTCEAAHF GLWRICTKRIPMDDSKTCGPITLPGEKNCSYFRHFNPGESSEIFEFTTQKEYSISAAAIAIFSL GFIILGSLCVLLSLGKKRDYLLRPASMFYAFAGLCILVSVEVMRQSVKRMIDSEDTVWIEYYY SWSFACACAAFILLFLGGLALLLFSLPRMPRNPWESCMDAEPEH (SEQ ID NO: 474) has been assigned.

[0138] The antigen-binding proteins (e.g., antibodies and antigen-binding fragments) described herein can bind to soluble CACNG1 and / or cell surface-expressed CACNG1. Soluble CACNG1 includes naturally occurring CACNG1 protein as well as recombinant CACNG1 protein variants that lack the transmembrane domain or are not otherwise associated with the cell membrane.

[0139] The phrase "cell surface-expressed CACNG1" refers to one or more CACNG1 proteins expressed on the surface of a cell in vitro or in vivo, such that at least a portion of the CACNG1 protein is exposed to the extracellular side of the cell membrane and is accessible to the antigen-binding portion of an antibody. "Cell surface-expressed CACNG1" can include or consist of a CACNG1 protein expressed on the surface of a cell that normally expresses CACNG1 protein. Alternatively, "cell surface-expressed CACNG1" can include or consist of a CACNG1 protein expressed on the surface of a cell that does not normally express human CACNG1 on its surface but has been artificially engineered to express CACNG1 on its surface.

[0140] CACNG1-binding proteins and protein-drug conjugates In one aspect, the disclosure provides an antigen binding protein that specifically binds to CACNG1.

[0141] An antigen-binding protein that specifically binds to CACNG1 is one that binds to CACNG1 or a fusion protein thereof at about 25°C, e.g., a K D Approximately 1×10 -7 The antigen-binding protein can bind with M or stronger affinity to a tag, such as PADRE-Flag-His, fused to human CACNG1. Such an antigen-binding protein can be referred to as "anti-CACNG1."

[0142] In some embodiments, an antigen binding protein that specifically binds to CACNG1 can comprise an antibody or an antigen binding fragment of an antibody, such as a fragment antigen binding region (Fab) or a single chain fragment variable (scFv).

[0143] The present disclosure provides CACNG1-binding protein-drug conjugates. The CACNG1-binding protein-drug conjugates specifically bind to CACNG1, such as human CACNG1, and include an optional signal peptide connected to an antigen-binding protein (e.g., an antibody or an antigen-binding fragment of an antibody, such as a fragment antigen-binding region (Fab) or single-chain fragment variable (scFv)) that is conjugated (optionally by a linker) to a molecular cargo. The CACNG1-binding protein-drug conjugates described herein can deliver the conjugated molecular cargo to a desired tissue (e.g., skeletal muscle tissue) and / or a desired cell type (e.g., muscle fiber) within the body.

[0144] The term "conjugate" refers to an entity in which two substances are covalently or non-covalently linked. The term "covalent bond" refers to the characteristic of at least two molecules being linked to each other by one or more covalent bonds. In various embodiments, the two molecules can be covalently linked to each other by a single bond, such as a disulfide bridge or disulfide bond, that acts as a linker between the molecules. In some embodiments, two or more molecules can be covalently linked together by a molecule that acts as a linker, binding at least two molecules together through multiple covalent bonds. In certain embodiments, the linker can be a cleavable linker or a non-cleavable linker. A conjugate can be a direct link between two substances or a linker between two substances. In the present disclosure, one of the two substances is an antigen-binding protein, such as an antibody or antigen-binding fragment thereof, and the other is a drug (e.g., a polynucleotide, polypeptide, small molecule, liposome, or LNP disclosed herein). In the present disclosure, the linker can be a cleavable linker or a non-cleavable linker. In some embodiments, two polypeptide molecules that are covalently linked, either directly or indirectly (eg, by a linker), can be expressed from one single polynucleotide molecule.

[0145] As used herein, the term "antibody-drug conjugate" or "ADC" refers to a conjugate of an antibody or antigen-binding fragment thereof and a drug (e.g., a polynucleotide, polypeptide, small molecule, liposome, or LNP disclosed herein). Affinity for an antigen is imparted to the drug by conjugating the antibody or antigen-binding fragment thereof to the drug (e.g., a polynucleotide disclosed herein, or a liposome or LNP), thereby increasing the efficiency of delivery of the drug to a target site in vivo. As used herein, "antibody-drug conjugate" or "ADC" also encompasses fusion proteins in which an antibody or antigen-binding fragment thereof is fused to another polypeptide molecule.

[0146] The antigen-binding molecules described herein include antibodies and antigen-binding fragments of antibodies. Thus, the present disclosure includes antibodies and antigen-binding fragments thereof, such as Fab and scFv, that specifically bind to CACNG1, such as human CACNG1.

[0147] An antibody as described herein can be any antigen-binding molecule or molecular complex comprising at least one complementarity determining region (CDR) that specifically binds to or interacts with a particular antigen (e.g., CACNG1). In some embodiments, the term "antibody" refers to an immunoglobulin molecule comprising four polypeptide chains, two heavy chains (HC) and two light chains (LC), interconnected by disulfide bonds (e.g., IgG). In one embodiment, each antibody heavy chain (HC) comprises a heavy chain variable region ("HCVR" or "VH") and a heavy chain constant region, which may comprise three domains, CH1, CH2, and CH3, and each antibody light chain (LC) comprises a light chain variable region ("LCVR" or "VL") and a light chain constant region (CL). The VH and VL regions can be further subdivided into regions of hypervariability, called complementarity-determining regions (CDRs), which are embedded in more conserved regions, called framework regions (FRs). Each VH and VL contains three CDRs and four FRs. The three CDRs and four FRs may be arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 (heavy chain CDRs may be abbreviated as HCDR1, HCDR2, and HCDR3). Light chain CDRs may be abbreviated as LCDR1, LCDR2, and LCDR3. The term "antibody" also includes antigen-binding fragments of complete antibody molecules.

[0148] The antibody can include any type of antibody, e.g., monoclonal or polyclonal. Furthermore, the antibody can be of any origin, e.g., mammalian or non-mammalian. In one embodiment, the antibody can be mammalian or avian. In a further embodiment, the antibody can be of human origin and can even be a human monoclonal antibody.

[0149] The phrase "heavy chain" or "immunoglobulin heavy chain" includes immunoglobulin heavy chain constant region sequences from any organism, and includes a heavy chain variable domain unless otherwise specified. The heavy chain variable domain includes three heavy chain CDRs and four FR regions, unless otherwise specified. Fragments of heavy chains include CDRs, CDRs and FRs, and combinations thereof. A typical heavy chain has (from N- to C-terminus) a CH1 domain, hinge, CH2 domain, and CH3 domain following the variable domain. Functional fragments of heavy chains include those that can specifically recognize an antigen (e.g., recognize an antigen with a KD in the micromolar, nanomolar, or picomolar range), can be expressed and secreted from cells, and contain at least one CDR.

[0150] The term "light chain" includes immunoglobulin light chain constant region sequences from any organism, including human kappa and lambda light chains unless otherwise specified. A light chain variable (VL) domain typically includes three light chain CDRs and four framework (FR) regions, unless otherwise specified. A full-length light chain generally includes a VL domain, including, from the amino terminus to the carboxyl terminus, FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, and a light chain constant domain. Potentially useful light chains include, for example, light chains that do not selectively bind to either the first antigen or the second antigen selectively bound by the antigen-binding protein. Suitable light chains include those that can be identified by screening the most commonly used light chains in existing antibody libraries (wet libraries or in silico), where the light chain does not substantially interfere with the affinity and / or selectivity of the antigen-binding domain of the antigen-binding protein. Suitable light chains include those capable of binding to one or both epitopes bound by the antigen-binding region of the antigen-binding protein.

[0151] The phrase "variable domain" includes the amino acid sequence of an immunoglobulin light or heavy chain (modified as desired) which comprises, from N- to C-terminus, the following amino acid regions (unless otherwise indicated): FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. A "variable domain" comprises an amino acid sequence that can fold into a canonical domain (VH or VL) having a double beta-sheet structure, the beta-sheets being connected by a disulfide bond between residues of the first and second beta-sheets.

[0152] The term "complementarity-determining region" or "CDR" includes amino acid sequences encoded by the nucleic acid sequence of an organism's immunoglobulin genes that normally (i.e., in wild-type animals) appear between two framework regions within the variable region of a light or heavy chain of an immunoglobulin molecule (e.g., an antibody or T-cell receptor). CDRs can be encoded, for example, by germline sequences, or by rearranged or unrearranged sequences, for example, by naive or mature B or T cells. In some situations (e.g., in the case of CDR3s), CDRs can be encoded by two or more sequences (e.g., germline sequences) that are not contiguous (e.g., in unrearranged nucleic acid sequences) but are contiguous in B-cell nucleic acid sequences, for example, as a result of splicing or joining of sequences (e.g., formation of a heavy chain CDR3 by VDJ recombination).

[0153] In one embodiment, the assignment of amino acids to each framework or CDR domain in an immunoglobulin follows the definitions in Sequences of Proteins of Immunological Interest, Kabat et al.; National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991), Kabat (1978) Adv. Prot. Chem. 32:1-75, Kabat et al., (1977) J. Biol. Chem. 252:6609-6616, Chothia, et al., (1987) J Mol. Biol. 196:901-917, or Chothia, et al., (1989) Nature 342:878-883. Thus, the present disclosure includes antibodies and antigen-binding fragments comprising the CDRs of the VH and the CDRs of the VL, wherein the VH and VL comprise the amino acid sequences set forth herein (see, e.g., the sequences in Table 1-1 or variants thereof), and the CDRs are as defined according to Kabat and / or Chothia.

[0154] The phrase "Fc-containing protein" includes antibodies, multispecific antibodies (e.g., bispecific antibodies), immunoadhesins, and other binding proteins that contain at least a functional portion of an immunoglobulin CH2 and CH3 region. A "functional portion" refers to a CH2 and CH3 region that is capable of binding to an Fc receptor (e.g., FcyR, or FcRn, i.e., neonatal Fc receptor). A CH2 and CH3 region is not functional if it contains deletions, substitutions, and / or insertions or other modifications that render it unable to bind to any Fc receptor or activate complement.

[0155] An Fc-containing protein may contain modifications in the immunoglobulin domain, including where the modifications affect one or more effector functions of the binding protein (e.g., modifications that affect FcyR binding, FcRn binding, and therefore half-life and / or CDC activity). Such modifications include, but are not limited to, the following modifications and combinations thereof, based on EU numbering of immunoglobulin constant regions: 238, 239, 248, 249, 250, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294, 295, 296, 297, 298, 301, 303, 305, 307, 308, 309, 311, 312, 315, 318, 320, 322, 324, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 337, 338, 339, 340, 342, 344, 356, 358, 359, 360, 361, 362, 373, 375, 376, 378, 380, 382, ​​383, 384, 386, 388, 389, 398, 414, 416, 419, 428, 430, 433, 434, 435, 437, 438, and 439.

[0156] The term "antigen-binding protein," as used herein, refers to a polypeptide or protein (one or more polypeptides complexed as a functional unit) that specifically recognizes an epitope on an antigen, such as a cell-specific antigen and / or a target antigen (e.g., CACNG1) described herein. An antigen-binding protein may be multispecific. The term "multispecific" with respect to an antigen-binding protein means that the protein recognizes different epitopes on the same antigen or on different antigens. The multispecific antigen-binding proteins described herein may be a single multifunctional polypeptide or a multimeric complex of two or more polypeptides that are covalently or noncovalently linked to each other. The term "antigen-binding protein" includes an antibody or fragment thereof described herein that may be linked to or coexpressed with another functional molecule (e.g., another peptide or protein). For example, an antibody or fragment thereof may be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent bonding, or otherwise) to one or more other molecular entities, such as a protein or fragment thereof, to generate a bispecific or multispecific antigen-binding molecule having a second binding specificity.

[0157] The CACNG1-binding proteins described herein may be antigen-binding fragments of antibodies (which may optionally be conjugated to a molecular cargo). The terms "antigen-binding portion" or "antigen-binding fragment" of an antibody, as used herein, refer to an immunoglobulin molecule that binds to an antigen but does not contain all of the sequence of a complete antibody (preferably, the complete antibody is an IgG). Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments (Ward et al. (1989) Nature 241:544-546), which consist of the hypervariable regions of an antibody (e.g., isolated complementarity-determining regions (CDRs) such as CDR3 peptides) or constrained FR3-CDR3-FR4 peptides, and (vi) amino acid residues mimicking isolated CDRs. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, one-arm antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, single-chain antibodies such as diabodies (see, e.g., Holliger et al. (1993) PNAS USA 90:6444-6448; Poljak et al. (1994) Structure 2:1121-1123), triabodies, tetrabodies, minibodies, and small modular immunopharmaceuticals (SMIPs), are also encompassed by the term "antigen-binding fragment" as used herein.

[0158] Antigen-binding proteins or antigen-binding fragments of antibodies, etc., described herein can include any naturally occurring, enzymatically derived, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived from intact antibody molecules using any suitable standard techniques, such as, for example, proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable domains and, optionally, constant domains. Such DNA is known and / or readily available, for example, from commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. DNA can be sequenced and manipulated chemically or by using molecular biology techniques to, for example, arrange one or more variable and / or constant domains in a suitable configuration, or to introduce codons, create cysteine ​​residues, modify, add, or delete amino acids.

[0159] As noted, the CACNG1-binding proteins described herein may be scFvs that can be conjugated to molecular cargo. scFvs (single-chain fragment variable) comprise variable regions, heavy (VH) and light (VL) domains (in either order), preferably linked together by a flexible linker (e.g., a peptide linker). The length of the flexible linker used to link both V domains can be important for ensuring correct folding of the polypeptide chain. Previously, it has been estimated that a peptide linker must span 3.5 nm (35 Å) between the carboxy terminus of one variable domain and the amino terminus of the other domain without affecting the ability of the domains to fold and form an intact antigen-binding site (Huston et al., Protein engineering of single-chain Fv analogs and fusion proteins. Methods in Enzymology. 1991;203:46-88). In one embodiment, the linker comprises an amino acid sequence long enough to separate the variable domains by approximately 3.5 nm. In some embodiments, the VH and VL are connected by a linker sequence of 10 to 25 amino acids.

[0160] The scFv polypeptide may also contain other amino acid sequences (e.g., CL or CH1 regions). scFv molecules can be produced by phage display or by directly subcloning heavy and light chains from hybridomas or B cells. Ahmad et al., Clinical and Developmental Immunology, volume 2012, article ID 98025, is incorporated herein by reference for methods of generating scFv fragments by phage display and antibody domain cloning.

[0161] In some embodiments, an antigen binding protein that specifically binds to CACNG1 comprises a heavy chain variable region (HCVR or V H ) and / or light chain variable region (LCVR or V L) is included.

[0162] In one embodiment, an antigen binding protein that specifically binds to CACNG1 comprises an anti-CACNG1 scFv comprising the following variable region arrangement: LCVR-HCVR or HCVR-LCVR, wherein the HCVR and LCVR are optionally connected by a linker.

[0163] In some embodiments, the CACNG1 binding protein-drug conjugate comprises a heavy chain variable region HCVR or V H ) and / or light chain variable region (LCVR or V L ) is included.

[0164] In one embodiment, the CACNG1-binding protein-drug conjugate comprises an anti-CACNG1 scFv comprising a variable region arrangement such as the following: LCVR-HCVR or HCVR-LCVR, where the HCVR and LCVR are optionally connected by a linker, and the scFv is optionally connected by a linker to a molecular cargo (e.g., LCVR-(Gly4Ser)3-HCVR-molecular cargo ("GGGGSGGGGSGGGGS" disclosed as SEQ ID NO: 423), or LCVR-(Gly4Ser)3-HCVR-molecular cargo ("GGGGSGGGGSGGGGS" disclosed as SEQ ID NO: 423)).

[0165] The term "domain" refers to any portion of a protein or polypeptide that has a specific function or structure. Preferably, the domains described herein bind to a cell-specific antigen or target antigen. Cell-specific antigen or target antigen binding domain, etc., as used herein, includes any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen.

[0166] In some embodiments, the CACNG1-binding proteins described herein comprise half bodies. The terms "half body" or "half antibody," used interchangeably, refer to half of an antibody essentially containing one heavy chain and one light chain. Antibody heavy chains can form dimers; thus, the heavy chain of one half body can associate with a heavy chain associated with a different molecule (e.g., another half body) or another Fc-containing polypeptide. Two slightly different Fc domains can "heterodimerize," as in the formation of bispecific antibodies or other heterodimers, trimers, tetramers, etc. See Vincent and Murini, "Current strategies in antibody engineering: Fc engineering and pH-dependent antigen binding, bispecific anti-bodies and antibody drug conjugates," 7 Biotechnol. J. 1444-1450 (2012), and Shimamoto et al., "Peptibodies: A flexible alternative format to antibodies," 4(5) Mabs 586-91 (2012).

[0167] In some embodiments, the anti-CACNG1 protein-drug conjugates described herein may comprise a Fab conjugated to a molecular cargo.

[0168] In some embodiments, the anti-CACNG1 protein-drug conjugates described herein comprise a bivalent antibody conjugated to a molecular cargo.

[0169] In some embodiments, the anti-CACNG1 binding proteins described herein comprise monovalent or "one-arm" antibodies. As used herein, a monovalent or "one-arm" antibody refers to an immunoglobulin protein that comprises a single variable domain. For example, a one-arm antibody may comprise a Fab may comprise a single variable domain within the Fab linked to at least one Fc fragment. In certain embodiments, a one-armed antibody comprises a polypeptide comprising: (i) a heavy chain comprising a heavy chain constant region and a heavy chain variable region; (ii) a light chain comprising a light chain constant region and a light chain variable region; and (iii) an Fc fragment or truncated heavy chain. In certain embodiments, the Fc fragment or truncated heavy chain comprised in a separate polypeptide is a "dummy Fc," which refers to an Fc fragment that is not linked to an antigen-binding domain. One-armed antibodies of the present disclosure may comprise any of the HCVR / LCVR pairs or CDR amino acid sequences set forth in Table 1-1 herein. One-arm antibodies comprising a full-length heavy chain, a full-length light chain, and an additional Fc domain polypeptide can be constructed using standard methodology (see, e.g., WO2010151792, incorporated herein by reference in its entirety), where the heavy chain constant region differs from the Fc domain polypeptide by at least two amino acids (e.g., H95R and Y96F according to the IMGT exon numbering system; or H435R and Y436F according to the EU numbering system). Such modifications are useful for purifying monovalent antibodies (see, e.g., WO2010151792).

[0170] In one embodiment, an antigen-binding fragment of an antibody comprises at least one variable domain. The variable domain may be of any size or amino acid composition and generally comprises at least one CDR adjacent to or in-frame with one or more framework sequences. In an antigen-binding fragment having a VH domain associated with a VL domain, the VH and VL domains may be positioned relative to each other in any suitable arrangement. For example, the variable region may be dimeric, comprising VH-VH, VH-VL, or VL-VL dimers. Alternatively, an antigen-binding fragment of an antibody may comprise non-covalently bound monomeric VH and / or VL domains.

[0171] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found in the antigen-binding fragments of antibodies described herein include: (i) VH-CH1, (ii) VH-CH2, (iii) VH-CH3, (iv) VH-CH1-CH2, (v) VH-CH1-CH2-CH3, (vi) VH-CH2-CH3, (vii) VH-CL, (viii) VL-CH1, (ix) VL-CH2, (x) VL-CH3, (xi) VL-CH1-CH2, (xii) VL-CH1-CH2-CH3, (xiii) VL-CH2-CH3, and (xiv) VL-CL. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be directly linked to each other or may be linked by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids and provide a flexible or semi-flexible link between adjacent variable and / or constant domains within a single polypeptide molecule. Furthermore, antigen-binding fragments of antibodies described herein may comprise homodimers or heterodimers (or other multimers) of any of the above-listed variable and constant domain configurations non-covalently associated (e.g., by disulfide bonds) with each other and / or with one or more monomeric VH or VL domains. The present disclosure includes antigen-binding fragments of antigen-binding proteins such as the antibodies set forth herein.

[0172] Antigen-binding proteins (e.g., antibodies and antigen-binding fragments) can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding proteins are discussed further herein. The present disclosure includes monospecific and multispecific (e.g., bispecific) antigen-binding fragments comprising one or more variable domains from the antigen-binding proteins specifically provided herein. In some embodiments, multispecific antigen-binding fragments of the antibodies described herein can comprise at least two different variable domains, each capable of specifically binding to a distinct antigen or a different epitope on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, can be adapted for use in the context of the antigen-binding fragments of the antibodies described herein using routine techniques available in the art.

[0173] The anti-CACNG1 (e.g., anti-hCACNG1) and antigen-binding fragments thereof described herein can be monospecific or multispecific (e.g., bispecific). Multispecific antibodies may be specific for different epitopes of a single target polypeptide or may contain antigen-binding domains specific for two or more target polypeptides. See, for example, Tutt et al., 1991, J. Immunol. 147:60-69; Kufer et al., 2004, Trends Biotechnol. 22:238-244. The anti-CACNG1 antibodies (e.g., anti-hCACNG1 antibodies) and antigen-binding fragments thereof described herein can be linked to or co-expressed with another functional molecule, such as another peptide or protein. For example, an antibody or fragment thereof can be operatively linked (e.g., by chemical coupling, genetic fusion, non-covalent bonding, or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment, to generate a multispecific antibody having second or additional binding specificities.

[0174] The use of the phrase "anti-CACNG1 antibody" or "anti-hCACNG1 antibody" herein is intended to include both monospecific anti-CACNG1 antibodies, e.g., anti-hCACNG1 antibodies, and multispecific antibodies, e.g., bispecific antibodies, comprising a CACNG1-binding arm and a "target"-binding arm. Thus, bispecific antibodies are described herein, in which one immunoglobulin arm binds to CANG1, e.g., hCACNG1, and the other immunoglobulin arm is specific for another target molecule. The CACNG1-binding arm can comprise any of the HCVR / LCVR or CDR amino acid sequences shown in Table 1-1 herein.

[0175] In certain embodiments, the CACNG1-binding arm binds to CACNG1, e.g., hCACNG1, and induces internalization of CACNG1 and antibodies bound thereto. In certain embodiments, the CACNG1-binding arm binds weakly to CACNG1, e.g., hCACNG1, and induces internalization of CACNG1 and antibodies bound thereto.

[0176] In certain embodiments, the bispecific antigen-binding molecules described herein are bispecific antibodies. The term "bispecific antibody" includes antibodies that can selectively bind to two or more epitopes. Bispecific antibodies generally comprise two different heavy chains, each of which specifically binds to a different epitope on two different molecules (e.g., antigens) or on the same molecule (e.g., the same antigen). When a bispecific antibody can selectively bind to two different epitopes (a first epitope and a second epitope), the affinity of the first heavy chain for the first epitope is generally at least one to two, three, or four orders of magnitude lower than the affinity of the first heavy chain for the second epitope, or vice versa. The epitopes recognized by bispecific antibodies can be on the same or different targets (e.g., on the same or different proteins). Bispecific antibodies can be generated, for example, by combining heavy chains that recognize different epitopes of the same antigen. For example, nucleic acid sequences encoding heavy chain variable sequences that recognize different epitopes of the same antigen can be fused to nucleic acid sequences encoding different heavy chain constant regions, and such sequences can be expressed in cells that express immunoglobulin light chains. A typical bispecific antibody has two heavy chains, each having three heavy chain CDRs followed (from N- to C-terminus) by a CH1 domain, a hinge, a CH2 domain, and a CH3 domain, and an immunoglobulin light chain that does not confer antigen binding specificity but can associate with each heavy chain, or that can associate with each heavy chain and bind to one or more of the epitopes bound by the heavy chain antigen-binding region, or that can associate with each heavy chain and enable one or both heavy chains to bind to one or both epitopes.

[0177] Each antigen-binding domain of a bispecific antibody comprises a heavy chain variable domain (HCVR) and a light chain variable domain (LCVR). In the context of a bispecific antigen-binding molecule (e.g., a bispecific antibody) comprising a first and a second antigen-binding domain, the CDRs of the first antigen-binding domain may be designated with the prefix "A1", and the CDRs of the second antigen-binding domain may be designated with the prefix "A2". Accordingly, the CDRs of the first antigen-binding domain may be referred to herein as A1-HCDR1, A1-HCDR2, and A1-HCDR3, and the CDRs of the second antigen-binding domain may be referred to herein as A2-HCDR1, A2-HCDR2, and A2-HCDR3.

[0178] The first antigen-binding domain and the second antigen-binding domain may be directly or indirectly connected to each other to form the bispecific antigen-binding molecule described herein. Alternatively, the first antigen-binding domain and the second antigen-binding domain may each be connected to a separate multimerization domain. The association of one multimerization domain with another multimerization domain promotes the association between the two antigen-binding domains, thereby forming the bispecific antigen-binding molecule. A "multimerization domain" is any macromolecule, protein, polypeptide, peptide, or amino acid that has the ability to associate with a second multimerization domain of the same or similar structure or configuration. For example, a multimerization domain may be connected to a second multimerization domain of the same or similar structure or configuration. H A non-limiting example of a multimerization component can be a polypeptide comprising three domains. H 2-C H 3 domains), for example, the Fc domain of IgG selected from the isotypes IgG1, IgG2, IgG3, and IgG4, as well as any allotype within each isotype group.

[0179] The bispecific antigen-binding molecules described herein typically comprise two multimerization domains, e.g., two Fc domains that are each part of a separate antibody heavy chain. The first and second multimerization domains may be of the same IgG isotype, e.g., IgG1 / IgG1, IgG2 / IgG2, or IgG4 / IgG4. Alternatively, the first and second multimerization domains may be of different IgG isotypes, e.g., IgG1 / IgG2, IgG1 / IgG4, or IgG2 / IgG4.

[0180] In certain embodiments, the multimerization domain can be an Fc fragment or an amino acid sequence of 1 to about 200 amino acids in length containing at least one cysteine ​​residue. In other embodiments, the multimerization domain can be a cysteine ​​residue or a short cysteine-containing peptide. Other multimerization domains include peptides or polypeptides comprising or consisting of a leucine zipper, a helix-loop motif, or a coiled-coil motif.

[0181] Any bispecific antibody format or technology can be used to generate the bispecific antigen-binding molecules described herein. For example, an antibody or fragment thereof with a first antigen-binding specificity can be operatively linked (e.g., by chemical coupling, genetic fusion, noncovalent association, or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment with a second antigen-binding specificity, to produce the bispecific antigen-binding molecule. Specific exemplary bispecific formats include, but are not limited to, scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (DVD)-Ig, quadroma, knobs-into-holes, common light chain (e.g., common light chain with knobs-into-holes), CrossMab, CrossFab, (SEED) body, leucine zipper, duobody, IgG1 / IgG2, dual acting Fab (DAF)-IgG, and Mab2 bispecific formats (see, e.g., Klein et al. 2012, mAbs 4:6, 1-11 and references cited therein for a review of the aforementioned formats).

[0182] In the context of the bispecific antigen-binding molecules described herein, the multimerization domain, e.g., the Fc domain, may contain one or more amino acid changes (e.g., insertions, deletions, or substitutions) compared to a wild-type, naturally occurring version of the Fc domain. For example, the bispecific antigen-binding molecule may contain one or more modifications in the Fc domain that result in a modified Fc domain with modified (e.g., enhanced or decreased) binding interactions between Fc and FcRn. In one embodiment, the bispecific antigen-binding molecule comprises a C H 2 or C HThe FcRn comprises modifications in three regions that increase the affinity of the Fc domain for FcRn in acidic environments (e.g., endosomes with a pH ranging from about 5.5 to about 6.0). Non-limiting examples of such Fc modifications include modifications at positions 250 (e.g., E or Q), 250 and 428 (e.g., L or F), 252 (e.g., L / Y / F / W, or T), 254 (e.g., S or T), and 256 (e.g., S / R / Q / E / D, or T), or at positions 428 and / or 433 (e.g., L / R / S / P / Q, or K) and / or 434 (e.g., H / F, or Y), or at positions 250 and / or 428, or at positions 307 or 308 (e.g., 308F, V308F), and 434. In one embodiment, the modifications include a 428L (e.g., M428L) and a 434S (e.g., N434S) modification, a 428L, 259I (e.g., V259I), and 308F (e.g., V308F) modification, a 433K (e.g., H433K) and a 434 (e.g., 434Y) modification, a 252, 254, and 256 (e.g., 252Y, 254T, and 256E) modification, a 250Q and 428L modification (e.g., T250Q and M428L), and a 307 and / or 308 modification (e.g., 308F or 308P). It should be understood that the Fc domain of the antigen binding molecules disclosed herein, including but not limited to bispecific antigen binding molecules, can include any Fc domain described herein, for example, an Fc domain comprising any of the various modifications described herein.

[0183] Also, the first C H 3 domain and second Ig C H A bispecific antigen-binding molecule comprising three domains, a first and a second Ig C H Also described herein are bispecific antigen-binding molecules in which the three domains differ from each other by at least one amino acid, and the at least one amino acid difference reduces binding of the bispecific antibody to Protein A compared to a bispecific antibody lacking the amino acid difference. In one embodiment, the first Ig C H The 3 domain binds to protein A and the second Ig CH The 3 domain contains mutations that reduce or abolish Protein A binding, such as the H95R modification (according to the IMGT exon numbering, H435R according to the EU numbering). H 3 may further comprise a Y96F modification (Y436F according to IMGT and Y436F according to EU). See, e.g., U.S. Patent No. 8,586,713. H Further modifications that may be found within 3 include D16E, L18M, N44S, K52N, V57M, and V82I for IgG1 antibodies (D356E, L358M, N384S, K392N, V397M, and V422I by IMGT and by EU), N44S, K52N, and V82I for IgG2 antibodies (N384S, K392N, and V422I by IMGT and by EU), and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I for IgG4 antibodies (Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I by IMGT and by EU).

[0184] In certain embodiments, the Fc domain may be chimeric, combining Fc sequences from two or more immunoglobulin isotypes. For example, a chimeric Fc domain may be a human IgG1, human IgG2, or human IgG4 C H C derived from 2 regions H 2 sequences, and C derived from human IgG1, human IgG2, or human IgG4 H The chimeric Fc domain may comprise some or all of the three sequences. The chimeric Fc domain may also contain a chimeric hinge region. For example, the chimeric hinge may comprise an "upper hinge" sequence derived from a human IgG1, human IgG2, or human IgG4 hinge region combined with a "lower hinge" sequence derived from a human IgG1, human IgG2, or human IgG4 hinge region. A specific example of a chimeric Fc domain that may be included in any of the antigen-binding molecules presented herein is, from the N-terminus to the C-terminus, a chimeric Fc domain comprising: [IgG4 C H 1]-[IgG4 upper hinge]-[IgG2 lower hinge]-[IgG4 C H2]-[IgG4 C H Another example of a chimeric Fc domain that may be included in any of the antigen-binding molecules described herein includes, from the N-terminus to the C-terminus, [IgG1 C H 1]-[IgG1 upper hinge]-[IgG2 lower hinge]-[IgG4 C H 2]-[IgG1 C H 3]. These and other examples of chimeric Fc domains that may be included in any of the antigen-binding molecules described herein are described in U.S. Patent Application Publication No. 2014 / 0243504, published August 28, 2014, which is incorporated herein in its entirety. Chimeric Fc domains having these general structural arrangements and variants thereof can alter Fc receptor binding, which in turn affects Fc effector function.

[0185] The terms "antibody that binds CACNG1," or "anti-CACNG1 antibody," or "anti-hCACNG1 antibody" include antibodies and antigen-binding fragments thereof that specifically recognize a single CACNG1 molecule. The antibodies and antigen-binding fragments thereof described herein can bind to soluble CACNG1 and / or cell surface-expressed CACNG1. Soluble CACNG1 includes native CACNG1 protein as well as recombinant CACNG1 protein variants that lack the transmembrane domain or are not otherwise associated with the cell membrane.

[0186] The terms "specifically binds" or "binds specifically" mean a specific affinity of at least about 10 as measured by a real-time label-free biolayer interferometry assay, e.g., at 25°C or 37°C, e.g., an Octet® HTX biosensor, or by surface plasmon resonance, e.g., BIACORE™, or by solution affinity ELISA. -9 K of M (e.g., 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0 nM) D"Anti-CACNG1" refers to an antigen binding protein (e.g., an antibody or antigen-binding fragment thereof) that has binding affinity to an antigen, such as human CACNG1, mouse CACNG1, or monkey CACNG1, which is represented as

[0187] In some embodiments, the antigen binding proteins (e.g., antibodies or antigen-binding fragments thereof) described herein have high affinity for CACNG1, e.g., at least 10, as measured by surface plasmon resonance, e.g., BIACORE™, or solution affinity ELISA. -9 M, at least 10 -10 M, at least 10 -11 M, or at least 10 -12 I am M.

[0188] Cell-based binding strategies, such as fluorescent-activated cell sorting (FACS) binding assays, are also routinely used to provide binding characterization data for cell surface-expressed proteins. FACS data correlate well with other methods, such as radioligand competitive binding and SPR (Benedict, CA, J Immunol Methods. 1997, 201(2):223-31; Geuijen, CA, et al. J Immunol Methods. 2005, 302(1-2):68-77).

[0189] Thus, the anti-CACNG1 antibodies and antigen-binding fragments thereof described herein have a K that is at least 10-fold lower than their affinity for binding to non-specific antigens (e.g., BSA, casein). D binds to a given antigen or cell surface molecule (receptor) with an affinity corresponding to a K value that is 1 / 10 or less than that of a nonspecific antigen DAn antibody affinity corresponding to a value may be considered undetectable binding, but such an antibody may be paired with a second antigen-binding arm to produce a bispecific antibody as described herein.

[0190] "K" in mole (M) D The term K refers to the dissociation equilibrium constant of a particular antibody-antigen interaction or the dissociation equilibrium constant of an antibody or antibody-binding fragment that binds to an antigen. D There is an inverse relationship between K and binding affinity, and therefore, K D The smaller the value, the higher or stronger the affinity. Thus, the terms "higher affinity" or "stronger affinity" refer to a higher ability to form an interaction and therefore a smaller K D Conversely, the terms "lower affinity" or "weaker affinity" refer to a lower ability to form an interaction and therefore a larger K D In some situations, a higher binding affinity (or K ) of a particular molecule (e.g., an antibody) to its interaction partner molecule (e.g., antigen X) compared to the binding affinity of the molecule (e.g., an antibody) to another interaction partner molecule (e.g., antigen Y) may be involved. D ) is larger than K D A smaller K value (lower or weaker affinity) D The binding affinity may be expressed as a binding ratio determined by dividing by the value (higher or stronger affinity), for example, 5-fold or 10-fold greater binding affinity, as the case may be.

[0191] Also described herein are antibodies and antigen-binding fragments thereof that bind to CACNG1, e.g., hCACNG1, with high, moderate, or low affinity, depending on the therapeutic situation and the specific target characteristics desired. For example, in the context of a bispecific antigen-binding molecule in which one arm binds to CACNG1 and another arm binds to a target antigen (e.g., a tumor-associated antibody), it may be desirable for the target antigen-binding arm to bind to the target antigen with high affinity, while the anti-CACNG1 arm, e.g., anti-hCACNG1, binds to CACNG1 with only moderate or low affinity. In this way, preferential targeting of the antigen-binding molecule to cells expressing the target antigen can be achieved while avoiding general / non-targeted CACNG1 binding and the resulting adverse side effects associated therewith.

[0192] Also described herein are antibodies, antigen-binding fragments thereof, and bispecific antibodies thereof that bind to CACNG1, e.g., hCACNG1, with weak (i.e., low) or undetectable affinity. In some embodiments, the antibodies and antigen-binding fragments thereof described herein bind to CACNG1, e.g., hCACNG1, with a K of greater than about 100 nM as measured by surface plasmon resonance (e.g., at 37°C). D In some embodiments, the antibodies or antigen-binding fragments described herein have a K of greater than about 110 nM, at least 120 nM, greater than about 130 nM, greater than about 140 nM, greater than about 150 nM, at least 160 nM, greater than about 170 nM, greater than about 180 nM, greater than about 190 nM, greater than about 200 nM, greater than about 250 nM, greater than about 300 nM, greater than about 400 nM, greater than about 500 nM, greater than about 600 nM, greater than about 700 nM, greater than about 800 nM, greater than about 900 nM, or greater than about 1 μM, as measured by surface plasmon resonance (e.g., mAb capture or antigen capture format) or a substantially similar assay. D It binds to CACNG1 with or without detectable affinity.

[0193] "k dThe term "(sec-1 or 1 / sec)" refers to the dissociation rate constant of a particular antibody-antigen interaction, or the dissociation rate constant of an antibody or antibody-binding fragment. off Also called value.

[0194] "k a The term "(M-1 x sec-1 or 1 / M) refers to the association rate constant of a particular antibody-antigen interaction, or the association rate constant of an antibody or antibody binding fragment.

[0195] "K A The term "(M-1 or 1 / M)" refers to the association equilibrium constant of a particular antibody-antigen interaction, or the association equilibrium constant of an antibody or antibody-binding fragment. The association equilibrium constant is k a k d It is obtained by dividing by

[0196] "EC 50 " or "EC 50 The term "half maximal effective concentration" refers to the concentration of antibody that elicits a response halfway between baseline and maximum after a specific exposure time. 50 essentially represents the concentration of an antibody at which 50% of its maximal effect is observed. In certain embodiments, the EC 50 The EC value is equal to the concentration of an antibody described herein that gives half-maximal binding to cells expressing CACNG1, as determined, for example, by a FACS binding assay or an androgen receptor-activated luciferase assay. 50 Alternatively, decreased or weakened binding is observed with increasing half-maximal effective concentration values.

[0197] In one embodiment, the decreased binding is an increased EC2 that allows binding to half-maximal amounts of target cells. 50 It can be defined as the antibody concentration.

[0198] "Isolated" antigen binding proteins (e.g., antibodies or antigen-binding fragments thereof), polypeptides, polynucleotides, and vectors are at least partially free from other biological molecules from the cell or cell culture in which they are produced. Such biological molecules include nucleic acids, proteins, other antibodies or antigen-binding fragments, lipids, carbohydrates, or other materials such as cell debris and growth medium. Isolated antigen binding proteins may also be at least partially free from expression system components such as biological molecules from the host cell or its growth medium. In general, the term "isolated" is not intended to refer to the complete absence of such biological molecules (e.g., trace or insignificant amounts of impurities may remain), or the absence of water, buffers, or salts, or components of a pharmaceutical formulation that comprises the antigen binding protein (e.g., antibody or antigen-binding fragment).

[0199] In some embodiments, an isolated antibody described herein may be an antibody that has been identified, separated, and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which it naturally occurs or is naturally produced, may be considered an "isolated antibody." Isolated antibodies also include in situ antibodies within recombinant cells. An isolated antibody is an antibody that has been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0200] The present disclosure includes antigen binding proteins, such as antibodies or antigen-binding fragments, that bind to the same epitope as the antigen binding proteins described herein.

[0201] An antigen is a molecule, such as a peptide (e.g., CACNG1 or a fragment thereof (antigenic fragment)) to which an antibody or antigen-binding fragment thereof binds. The specific region on an antigen that an antibody recognizes and binds to is called an epitope. Antigen-binding proteins (e.g., antibodies) described herein that specifically bind to such antigens are part of the present disclosure.

[0202] The term "epitope" refers to a specific antigen-binding site of an antigen-binding protein, e.g., an antigenic determinant (e.g., on CACNG1) that interacts with the variable region of an antibody known as the paratope. A single antigen may have two or more epitopes. Thus, different antibodies may bind to different regions on an antigen and have different biological effects. The term "epitope" may also refer to the site on an antigen to which B cells and / or T cells respond and / or the region of an antigen bound by an antibody. Epitopes may be defined as structural or functional. Functional epitopes are generally a subset of structural epitopes and contain residues that directly contribute to the affinity of the interaction. Epitopes may be linear or conformational, i.e., composed of non-linear amino acids. In certain embodiments, epitopes may include determinants that are chemically active surface groups of molecules, such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three-dimensional structural characteristics and / or specific charge characteristics. The epitopes to which the antigen-binding proteins described herein bind may be contained in a fragment of CACNG1, such as its extracellular domain. Antigen-binding proteins (e.g., antibodies) described herein that bind to such epitopes are part of the present disclosure.

[0203] The epitope on CACNG1 to which the anti-CACNG1 antibodies described herein, e.g., anti-hCACNG1 antibodies and antigen-binding fragments thereof, bind can consist of a single contiguous sequence of three or more amino acids of the CACNG1 protein (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more). Alternatively, the epitope can consist of multiple non-contiguous amino acids (or amino acid sequences) of CACNG1. The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule, known as a paratope. A single antigen can have two or more epitopes. Thus, different antibodies may bind to different regions on an antigen and have different biological effects. Epitopes can be either conformational or linear. Conformational epitopes are produced by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. In certain circumstances, an epitope may include a carbohydrate, phosphoryl, or sulfonyl moiety on an antigen.

[0204] Methods for determining the epitope of an antigen-binding protein, such as an antibody or fragment or polypeptide, include alanine scanning mutation analysis, peptide blot analysis (Reineke (2004) Methods Mol. Biol. 248:443-63), peptide truncation analysis, crystallographic studies, and NMR analysis. Additionally, methods such as epitope excision, epitope extraction, and chemical modification of antigens can be used (Tomer (2000) Prot. Sci. 9:487-496). Another method that can be used to identify amino acids within a polypeptide with which an antigen-binding protein (e.g., an antibody or fragment or polypeptide) interacts is hydrogen / deuterium exchange as detected by mass spectrometry. See, e.g., Ehring (1999) Analytical Biochemistry 267:252-259; Engen and Smith (2001) Anal. Chem. 73:256A-265A. Generally, hydrogen / deuterium exchange methods involve deuterium-labeling a protein of interest and then binding an antibody to the deuterium-labeled protein. The protein / antibody complex is then transferred to water, allowing hydrogen-deuterium exchange to occur at all residues except those protected by the antibody (which remain deuterium-labeled). After dissociation of the antibody, the target protein is subjected to protease cleavage and mass spectrometry, thereby revealing deuterium-labeled residues corresponding to the specific amino acids with which the antibody interacts. See, for example, Ehring (1999) Analytical Biochemistry 267(2):252-259; Engen and Smith (2001) Anal. Chem. 73:256A-265A. X-ray crystallography of antigen / antibody complexes can also be used for epitope mapping purposes.

[0205] The present disclosure includes antigen binding proteins that compete with the antigen binding proteins described herein for binding to the CACNG1 epitope as discussed herein. As used herein, the term "compete" refers to an antigen binding protein (e.g., an antibody or antigen-binding fragment thereof) that binds to an antigen (e.g., CACNG1) and inhibits or blocks the binding of another antigen binding protein (e.g., an antibody or antigen-binding fragment thereof) to the antigen. Unless otherwise specified, the term also includes competition between two antigen binding proteins, e.g., antibodies, in both orientations, i.e., a first antibody that binds to an antigen and blocks binding by a second antibody, and vice versa. Thus, in one embodiment, competition occurs in one such orientation. In certain embodiments, a first antigen binding protein (e.g., an antibody) and a second antigen binding protein (e.g., an antibody) may bind to the same epitope. Alternatively, the first and second antigen-binding proteins (e.g., antibodies) can bind to different, but overlapping or non-overlapping, epitopes, such that the binding of one inhibits or blocks the binding of the second antibody, for example, through steric hindrance. Competition between antigen-binding proteins (e.g., antibodies) can be measured by methods known in the art, such as real-time label-free biolayer interferometry assays. Binding competition between CACNG1-binding proteins (e.g., monoclonal antibodies (mAbs)) can also be determined using real-time label-free biolayer interferometry assays on an Octet RED384 biosensor (Pall ForteBio Corp.).

[0206] Those skilled in the art can easily determine whether a particular antigen-binding molecule (e.g., an antibody) or its antigen-binding domain binds to the same epitope as a reference antigen-binding molecule described herein, or competes for binding, using routine methods known in the art. For example, to determine whether a test antibody binds to the same epitope on CACNG1 as a reference bispecific antigen-binding molecule described herein, the reference bispecific molecule is first bound to the CACNG1 protein. The ability of the test antibody to bind to the CACNG1 molecule is then evaluated. If the test antibody can bind to CACNG1 after saturation binding with the reference bispecific antigen-binding molecule, it can be concluded that the test antibody binds to a different epitope on CACNG1 than the reference bispecific antigen-binding molecule. On the other hand, if the test antibody cannot bind to the CACNG1 molecule after saturation binding with the reference bispecific antigen-binding molecule, the test antibody may bind to the same epitope on CACNG1 as the epitope bound by the reference bispecific antigen-binding molecule described herein. Further routine experiments (e.g., peptide mutations and binding analysis) can then be performed to confirm whether the observed lack of binding of the test antibody is indeed due to binding to the same epitope as the reference bispecific antigen-binding molecule, or whether steric blocking (or another phenomenon) is responsible for the observed lack of binding. This type of experiment can be performed using ELISA, RIA, Biacore, flow cytometry, or any other quantitative or qualitative antibody binding assay available in the art. According to some embodiments described herein, two antigen-binding proteins bind to the same (or overlapping) epitope if, for example, a 1-fold, 5-fold, 10-fold, 20-fold, or 100-fold excess of one antigen-binding protein inhibits binding of the other by at least 50%, preferably 75%, 90%, or even 99%, as measured in a competitive binding assay (see, e.g., Junghans et al., Cancer Res. 1990:50:1495-1502).Alternatively, two antigen-binding proteins are considered to bind to the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antigen-binding protein also reduce or eliminate binding of the other. Two antigen-binding proteins are considered to have "overlapping epitopes" if only a subset of amino acid mutations that reduce or eliminate binding of one antigen-binding protein also reduce or eliminate binding of the other.

[0207] To determine whether an antibody or its antigen-binding domain competes for binding with a reference antigen-binding molecule, the above-described binding methodology is carried out in two ways: in the first way, the reference antigen-binding molecule is bound to the CACNG1 protein under saturating conditions, followed by assessing the binding of the test antibody to the CACNG1 molecule. In the second way, the test antibody is bound to the CACNG1 molecule under saturating conditions, followed by assessing the binding of the reference antigen-binding molecule to the CACNG1 molecule. In both ways, if only the first (saturating) antigen-binding molecule can bind to the CACNG1 molecule, it is concluded that the test antibody and the reference antigen-binding molecule compete for binding to CACNG1. As will be understood by those skilled in the art, an antibody that competes for binding with a reference antigen-binding molecule does not necessarily bind to the same epitope as the reference antibody, but may sterically block the binding of the reference antibody by binding to an overlapping or adjacent epitope.

[0208] Typically, antibodies or antigen-binding fragments described herein that have been modified in some way retain the ability to specifically bind to CACNG1, e.g., retain at least 10% of their CACNG1-binding activity (compared to the parent antibody) when that activity is expressed on a molar basis. Preferably, antibodies or antigen-binding fragments described herein retain at least 20%, 50%, 70%, 80%, 90%, 95%, or 100% or more of the CACNG1-binding affinity of the parent antibody. It is also intended that the antibodies or antigen-binding fragments described herein may include conservative or non-conservative amino acid substitutions (referred to as "conservative variants" or "function-conservative variants" of antibodies) that do not substantially alter their biological activity.

[0209] The CACNG1-binding proteins described herein can be monoclonal antibodies or CACNG1-binding fragments of monoclonal antibodies that can be conjugated to molecular cargo. The present disclosure includes monoclonal CACNG1-binding proteins, such as antibodies and antigen-binding fragments thereof, as well as monoclonal compositions comprising a plurality of isolated monoclonal antigen-binding proteins. As used herein, the term "monoclonal antibody" or "mAb" refers to an antibody from a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts. A "plurality" of such monoclonal antibodies and fragments in a composition refers to a concentration of identical (i.e., in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts, as described above) antibodies and fragments that exceeds the concentration normally present in nature in the blood of a host organism, such as a mouse or human.

[0210] In one embodiment, the CACNG1-binding protein, e.g., an antibody or antigen-binding fragment (optionally conjugated to a molecular cargo), comprises a heavy chain constant domain, e.g., of the IgA (e.g., IgA1 or IgA2), IgD, IgE, IgG (e.g., IgG1, IgG2, IgG3 and IgG4) or IgM type. In one embodiment, the antigen-binding protein, e.g., an antibody or antigen-binding fragment, comprises a light chain constant domain, e.g., of the kappa or lambda type. In one embodiment, the VH shown herein is linked to a human heavy chain constant domain (e.g., IgG) and the VL shown herein is linked to a human light chain constant domain (e.g., kappa). The present disclosure includes antigen-binding proteins comprising the variable domains described herein linked to heavy and / or light chain constant domains, e.g., as described herein.

[0211] The present disclosure includes human CACNG1-binding proteins that can be conjugated to molecular cargoes. The term "human" antigen-binding protein (e.g., antibody or antigen-binding fragment), as used herein, includes antibodies and fragments having variable and constant regions derived from human germline immunoglobulin sequences, whether in a human cell or grafted into a non-human cell (e.g., a mouse cell). See, e.g., U.S. Patent Nos. 8,502,018, 6,596,541, or 5,789,215. The anti-CACNG1 human mAbs described herein may contain amino acid residues, e.g., in the CDRs, particularly CDR3, that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or somatic mutation in vivo). However, the term "human antibody," as used herein, is not intended to include mAbs in which CDR sequences derived from the germline of another mammalian species (e.g., a mouse) are grafted onto human FR sequences. The term includes antibodies recombinantly produced in a non-human mammal or in the cells of a non-human mammal. The term is not intended to include natural antibodies isolated directly from a human subject. The present disclosure includes human antigen-binding proteins (e.g., antibodies or antigen-binding fragments thereof described herein).

[0212] The antibodies described herein may, in some embodiments, be recombinant human antibodies. The term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, generated, or isolated by recombinant means, e.g., antibodies expressed using a recombinant expression vector transfected into a host cell, antibodies isolated from a recombinant combinatorial human antibody library, antibodies isolated from an animal (e.g., a mouse) transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, generated, or isolated by any other means, including splicing of human immunoglobulin gene sequences into other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when animals transgenic for human Ig sequences are used, to in vivo somatic mutagenesis) such that the amino acid sequences of the VH and VL regions of the recombinant antibodies are derived from and related to human germline VH and VL sequences, but are sequences that may not naturally occur within the human antibody germline repertoire in vivo.

[0213] Human antibodies can exist in two general forms related to hinge heterogeneity. In one general form, the immunoglobulin molecule contains a stable four-chain construct of approximately 150-160 kDa, in which dimers are held together by interchain heavy chain disulfide bonds. In the second general form, the dimers are not linked via interchain disulfide bonds, resulting in approximately 75-80 kDa molecules composed of covalently linked light and heavy chains (half antibodies). These forms have been extremely difficult to separate, even after affinity purification.

[0214] The frequency of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the antibody hinge region isotype. A single amino acid substitution in the hinge region of a human IgG4 hinge can significantly reduce the occurrence of the second form to the level typically observed using a human IgG1 hinge (Angal et al. (1993) Molecular Immunology 30:105). The antibodies described herein may be modified to incorporate a hinge, C, or C-terminal fragment, which may be desirable, for example, in production to improve the yield of the desired antibody form. H 2 or C H It may have one or more mutations in the three regions.

[0215] The present disclosure includes anti-CACNG1 chimeric antigen-binding proteins, such as antibodies and antigen-binding fragments thereof (which may be conjugated to molecular cargo), and methods of use thereof. As used herein, a "chimeric antibody" is an antibody having a variable domain derived from a first antibody and a constant domain derived from a second antibody, where the first antibody and the second antibody are from different species. (See, e.g., U.S. Pat. No. 4,816,567 and Morrison et al., (1984) Proc. Natl. Acad. Sci. USA 81:6851-6855.) The present disclosure includes chimeric antibodies comprising the variable domains described herein and non-human constant domains.

[0216] The term "recombinant" CACNG1-binding protein, e.g., an antibody or antigen-binding fragment thereof (which may be conjugated to a molecular cargo), refers to such molecules made, expressed, isolated, or obtained by techniques or methods known in the art, such as recombinant DNA technology, including DNA splicing and transgenic expression. This term includes antibodies expressed in a non-human mammal (including a transgenic non-human mammal, e.g., a transgenic mouse), or in a host cell (e.g., a Chinese hamster ovary (CHO) cell) or cell expression system, or antibodies isolated from a recombinant combinatorial human antibody library. The present disclosure includes recombinant antigen-binding proteins, such as the antibodies and antigen-binding fragments described herein.

[0217] A "variant" of a polypeptide, e.g., an immunoglobulin chain, refers to a polynucleotide comprising an amino acid sequence that is at least about 70 to 99.9% (e.g., at least 70, 72, 74, 75, 76, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, or 99.9%) identical or similar to a reference amino acid sequence set forth herein (e.g., any of SEQ ID NOS: 1-180) when the comparison is performed by the BLAST algorithm, where the algorithm parameters are selected to give the largest match between the respective sequences over the entire length of the respective reference sequence (e.g., expected threshold: 10, word size: 3; maximum match within query range: 0; BLOSUM 62 matrix; gap costs: presence 11, extension 1; conditional composition score matrix adjustment), and / or refers to a polypeptide comprising that amino acid sequence but having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) mutations (e.g., point mutations, insertions, truncations, and / or deletions).

[0218] Furthermore, a variant of a polypeptide can include a polypeptide such as an immunoglobulin chain that can comprise the amino acid sequence of a reference polypeptide, which amino acid sequence is specifically set forth herein, but with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) mutations, such as one or more missense mutations (e.g., conservative substitutions), non-sense mutations, deletions, or insertions. For example, the present disclosure provides immunoglobulin light chain (or VL) variants that include the amino acid sequences set forth in SEQ ID NOs: 5, 13, 21, 29, 37, 45, 53, 61, 69, 77, 85, 93, 101, 109, 117, 125, 133, 141, 437, 459, but have one or more of such mutations, and / or immunoglobulin heavy chain (or VL) variants that include the amino acid sequences set forth in SEQ ID NOs: 1, 9, 17, 25, 33, 41, 49, 57, 65, 73, 81, 89, 97, 105, 113, 121, 129, 137, 429, 451, but have one or more of such mutations. H In one embodiment, the CACNG1-binding protein comprises an immunoglobulin light chain variant comprising CDR-L1, CDR-L2, and CDR-L3, in which one or more (e.g., one, or two, or three) of such CDRs have one or more of such mutations (e.g., conservative substitutions), and / or an immunoglobulin heavy chain variant comprising CDR-H1, CDR-H2, and CDR-H3, in which one or more (e.g., one, or two, or three) of such CDRs have one or more of such mutations (e.g., conservative substitutions).

[0219] The following references relate to the BLAST algorithm, which is often used for sequence analysis: BLAST ALGORITHMS: Altschul et al. (2005) FEBS J. 272(20):5101-5109, Altschul, SF, et al., (1990) J. Mol. Biol. 215:403-410, Gish, W., et al., (1993) Nature Genet. 3:266-272, Madden, TL, et al., (1996) Meth. Enzymol. 266:131-141, Altschul, SF, et al., (1997) Nucleic Acids Res. 25:3389-3402, Zhang, J., et al., (1997) Genome Res. 7:649-656, Wootton, JC, et al. al., (1993) Comput.Chem.17:149-163, Hancock, JMet al., (1994) Comput.Appl.Biosci.10:67-70, ALIGNMENT SCORING SYSTEMS: Dayhoff, MO, et al., "A model of evolutionary change in proteins" in Atlas of Protein Sequence and Structure, (1978) vol. 5, sup. Structure,(1978)vol.5,suppl.3."MODayhoff(ed.),pp.353-358,Natl.Biomed.Res.Found.,Washington,DC,Altschul,SF,(1991)J.Mol.Biol.219:555-565,States,DJ,et al.,(1991)Methods 3:66-70, Henikoff, S., et al., (1992) Proc. Natl. Acad. Sci.USA 89:10915-10919, Altschul,SF,et al.,(1993)J.Mol.Evol.36:290-300,ALIGNMENT STATISTICS:Karlin,S.,et al.,(1990)Proc.Natl.Acad.Sci.USA 87:2264-2268,Karlin,S.,et al., (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877, Dembo, A., et al., (1994) Ann. Prob.22:2022-2039, and Altschul, SF "Evaluating the statistical significance of multiple distinct local alignments" in Theoretical and Computational Methods in Genome Research (S. Suhai, ed.), (1997) pp.1-14, Plenum, NY. .

[0220] The anti-hCACNG1 antibodies disclosed herein may contain one or more amino acid substitutions, insertions, and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences from which the antibody is derived. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. Also described herein are antibodies and antigen-binding fragments thereof derived from any of the amino acid sequences disclosed herein, in which one or more amino acids in one or more framework and / or CDR regions are mutated to the corresponding residue in the germline sequence from which the antibody is derived, or to the corresponding residue in another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue (such sequence changes are collectively referred to herein as "germline mutations").

[0221] Starting with the heavy and light chain variable region sequences disclosed herein, one of skill in the art can readily produce numerous antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof. In certain embodiments, all of the framework and / or CDR residues in the VH and / or VL domains are mutated back to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are mutated back to the original germline sequence, e.g., only mutated residues found within the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only mutated residues found in CDR1, CDR2, or CDR3. In other embodiments, one or more of the framework and / or CDR residues are mutated to the corresponding residue in a different germline sequence (i.e., a different germline sequence from the germline sequence from which the antibody was originally derived). Furthermore, the antibodies described herein may contain any combination of two or more germline mutations within the framework and / or CDR regions, e.g., certain individual residues are mutated to the corresponding residue in a particular germline sequence, while certain other residues that differ from the original germline sequence are either maintained or mutated to the corresponding residue in a different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be readily tested for one or more desired properties (e.g., improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc.). In some embodiments, the antibodies or antigen-binding fragments described herein are obtained by this general method.

[0222] Also described herein are anti-CACNG1 antibodies comprising variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein with one or more conservative substitutions. For example, some embodiments include anti-CACNG1 antibodies with HCVR, LCVR, and / or CDR amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc., conservative amino acid substitutions compared to any of the HCVR, LCVR, and / or CDR amino acid sequences shown in Table 1-1 herein. The antibodies and antigen-binding fragments thereof described herein can include one or more amino acid substitutions, insertions, and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences from which the individual antigen-binding domains are derived, e.g., while maintaining or improving the desired weak to undetectable binding to CACNG1.

[0223] For example, "conservatively modified variants," or "conservative substitutions," or "conservative amino acid substitutions" of immunoglobulin chains as set forth herein refer to variants in which there is a substitution of one or more amino acids in a polypeptide with other amino acids having similar characteristics (e.g., charge, side chain size, hydrophobicity / hydrophilicity, main-chain conformation and rigidity, etc.). Such changes can frequently be made without significantly destroying the biological activity of the antibody or fragment. In some embodiments, conservative amino acid substitutions can maintain or improve the desired weak to undetectable binding affinity in the case of the anti-CACNG1 binding molecules (e.g., anti-hCACNG1 binding molecules) described herein. Those skilled in the art will generally recognize that single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. (1987) Molecular Biology of the Gene, The Benjamin / Cummings Pub. Co., p. 224(4)). th (See, e.g., J. Am. Chem. Soc. 1999, 14:131-132, 1999). Furthermore, substitutions of structurally or functionally similar amino acids are unlikely to significantly disrupt biological activity. The present disclosure includes CACNG1-binding proteins comprising such conservatively modified variant immunoglobulin chains.

[0224] Examples of groups of amino acids with side chains having similar chemical properties include: 1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; 2) aliphatic-hydroxyl side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; 6) acidic side chains: aspartate and glutamate; and 7) sulfur-containing side chains: cysteine ​​and methionine. Alternatively, a conservative substitution is any change that has a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256:1443-45. Preferred conservative amino acid substitution groups are valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic acid-aspartic acid, and asparagine-glutamine. Alternatively, a conservative substitution is any change that has a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256:1443-1445 (incorporated herein by reference). A "moderately conservative" substitution is any change that has a positive value in the PAM250 log-likelihood matrix.

[0225] Once obtained, antigen-binding domains containing one or more germline mutations can be tested for reduced binding affinity using one or more in vitro assays. In general, antibodies that recognize a particular antigen are typically screened for this purpose by testing for high (i.e., strong) binding affinity to the antigen.

[0226] Unexpected benefits, such as improved pharmacokinetic properties and reduced toxicity to patients, may be realized from further modifying the antibodies described herein by the methods described herein.

[0227] Also described herein are anti-CACNG1 antibodies and antigen-binding fragments thereof comprising an antigen-binding domain having an HCVR and / or CDR amino acid sequence substantially identical to any of the HCVR and / or CDR amino acid sequences disclosed herein, while maintaining or improving a desired weak affinity for the CACNG1 antigen. When referring to amino acid sequences, the term "substantial identity" or "substantially identical" means that two amino acid sequences share at least 95% sequence identity, and even more preferably at least 98% or 99% sequence identity, when optimally aligned, such as by the programs GAP or BEST-FIT, using default gap weights. Preferably, residue positions that are not identical differ by conservative amino acid substitutions. When two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity may be adjusted upward to correct for the conservative nature of the substitutions. Means for making this adjustment are well known to those of skill in the art. See, e.g., Pearson (1994) Methods Mol. Biol. 24:307-331 (incorporated herein by reference).

[0228] Sequence similarity of polypeptides, also referred to as sequence identity, is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions, and other modifications, including conservative amino acid substitutions. For example, GCG software includes programs such as GAP and BEST-FIT, which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms, or between a wild-type protein and its mutein. See, for example, GCG version 6.1. Polypeptide sequences can also be compared using FASTA (a program in GCG version 6.1) using default or recommended parameters. FASTA (e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the best regions of overlap between the query and search sequences (Pearson (2000) supra). Another preferred algorithm for comparing the sequences described herein to databases containing a large number of sequences from different organisms is the computer program BLAST, particularly BLASTP or TBLASTN, using default parameters. See, for example, Altschul et al. (1990) J. Mol. Biol. 215:403-410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389-402, each of which is incorporated herein by reference.

[0229] Also described herein are anti-CACNG1 antibodies and antigen-binding fragments thereof having pH-dependent binding properties. For example, the anti-CACNG1 antibodies described herein may exhibit reduced binding to CACNG1 at acidic pH compared to neutral pH. Alternatively, the anti-CACNG1 antibodies described herein may exhibit enhanced binding to CACNG1 at acidic pH compared to neutral pH. The term "acidic pH" includes pH values ​​less than about 6.2, such as about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0, or less. The term "neutral pH" refers to a pH of about 7.0 to about 7.4. The expression "neutral pH" includes pH values ​​of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.

[0230] In certain cases, "reduced binding at acidic pH compared to neutral pH" refers to the K of antibody binding to its antigen at neutral pH. D K value for antibody binding to its antigen at acidic pH D For example, an antibody or antigen-binding fragment thereof may be expressed in terms of a ratio of values ​​such that the antibody or antigen-binding fragment thereof has an acidic / neutral K of about 3.0 or greater. D When a ratio is presented, it can be considered to indicate "reduced binding to CACNG1 at acidic pH compared to neutral pH" for purposes of the description herein. In certain exemplary embodiments, the acidic / neutral K D The ratio can be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0, or more.

[0231] Antibodies with pH-dependent binding properties can be obtained, for example, by screening a population of antibodies for reduced (or enhanced) binding to a specific antigen at acidic pH compared to neutral pH. In addition, modification of the antigen-binding domain at the amino acid level can result in antibodies with pH-dependent characteristics. For example, by substituting one or more amino acids in the antigen-binding domain (e.g., within the CDR) with histidine residues, an antibody can be obtained that has reduced antigen binding at acidic pH compared to neutral pH.

[0232] The antibodies and antigen-binding fragments described herein include immunoglobulin chains comprising the amino acid sequences specifically set forth herein (and variants thereof), as well as cellular and in vitro post-translational modifications to the antibodies or fragments. For example, the present disclosure includes antibodies and antigen-binding fragments thereof that specifically bind to CACNG1 comprising the heavy chain amino acid sequences and / or light chain amino acid sequences set forth herein, as well as antibodies and fragments in which one or more asparagine, serine, and / or threonine residues are glycosylated, one or more asparagine residues are deamidated, one or more residues (e.g., Met, Trp, and / or His) are oxidized, the N-terminal glutamine is pyroglutamate (pyroE), and / or the C-terminal lysine or other amino acid is missing.

[0233] The amino acid sequences of domains in the CACNG1-binding proteins of the conjugates of the present disclosure are summarized in Table 1-1 below. For example, anti-CACNG1 antibodies and antigen-binding fragments thereof (e.g., scFv and Fab) comprising the HCVR and LCVR of the molecules in Table 1-1, or comprising their CDRs conjugated to molecular cargo, form part of the present disclosure.

[0234] [Table 1-1]

[0235] The sequences of the domains in the antibodies or antigen-binding fragments (e.g., Fab or scFv molecules) in the protein-drug conjugates described herein are shown below.

[0236] H2aM31929N / REGN10728 HCVR DNA sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTACAGCGTCTGGAATCACCTTCAGAAATTATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAAT AAGTACTATGCAGACTCCGTGAAGGGCCGTTTCACCATCTCCGGAGACAATTCCAAGG TGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAG AAGGGGCACTATAAGAACAGCTGCCCCTTTTGACTACTGGGGTCAGGGAACCCTGGT CACCGTCTCCTCA (SEQ ID NO: 181) HCVR amino acid sequence: QVQLVESGGGVVQPGRSLRLSCTASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSN KYYADSVKGRFTISGDNSKVYLQMNSLRAEDTAVYYCARRGTIRTAAPFDYWGQGTLVTV SS (SEQ ID NO: 1) HCDR1 DNA sequence GGAATCACCTTCAGAAATTATGGC (SEQ ID NO: 182) HCDR1 amino acid sequence GITFRNYG (SEQ ID NO: 2) HCDR2 DNA sequence ATGTGGTATGATGGAAGTAATAAG (SEQ ID NO: 183) HCDR2 amino acid sequence MWYDGSNK (SEQ ID NO: 3) HCDR3 DNA sequence GCGAGAAGGGGCACTATAAGAACAGCTGCCCCTTTTGACTAC (SEQ ID NO: 184) HCDR3 amino acid sequence ARRGTIRTAAPFDY (SEQ ID NO: 4) LCVR DNA sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAA ACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTC CCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTC TGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATC ACCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 185) LCVR amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 5) LCDR1 DNA sequence CAGAGCATTAGCAGCTAT (SEQ ID NO: 186) LCDR1 amino acid sequence QSISSY (SEQ ID NO: 6) LCDR2 DNA sequence GCTGCATCC (SEQ ID NO: 187) LCDR2 amino acid sequence AAS (SEQ ID NO: 7) LCDR3 DNA sequence CAACAGAGTTACAGTACCCCTCCGATCACC (SEQ ID NO: 188) LCDR3 amino acid sequence QQSYSTPPIT (SEQ ID NO: 8) HC DNA sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTACAGCGTCTGGAATCACCTTCAGAAATTATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAAT AAGTACTATGCAGACTCCGTGAAGGGCCGTTTCACCATCTCCGGAGACAATTCCAAGG TGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAG AAGGGGCACTATAAGAACAGCTGCCCCTTTTGACTACTGGGGTCAGGGAACCCTGGT CACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTC CAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC CGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCC CTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAA CACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCGTGCCC AGCACCAGGCGGTGGCGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACAC TCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGA AGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAA GACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCAC CGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGA GCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAG CCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAG CAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGG CTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAA TGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCC CTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 189) HC amino acid sequence QVQLVESGGGVVQPGRSLRLSCTASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSN KYYADSVKGRFTISGDNSKVYLQMNSLRAEDTAVYYCARRGTIRTAAPFDYWGQGTLVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPGGGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 145) LC DNA sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAA ACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTC CCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTC TGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATC ACCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCT TCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCT GCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTAC AGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGG GGAGAGTGTTAG (SEQ ID NO: 190) LC amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 146) H2aM31944N HCVR DNA sequence CAGGTGCAGTTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTGAAGCGTCTGGAATCACCTTCAGAAACTATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAAT AAATACTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGA ACACGGTGTATCTGCAAATGAACAGCCTGAGAGCCGAAGACACGGCTGTGTATTACTG TGCGAGACGGGGTCATATAGCAACAGCTGCTCCCTTTGACTACTGGGCCAGGGAAC CCTGGTCACCGTCTCCTCA (SEQ ID NO: 191) HCVR amino acid sequence QVQLVESGGGVVQPGRSLRLSCEASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSN KYYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCARRGHIATAAPFDYWGQGTLV TVSS (SEQ ID NO: 9) HCDR1 DNA sequence GGAATCACCTTCAGAAACTATGGC (SEQ ID NO: 192) HCDR1 amino acid sequence GITFRNYG (SEQ ID NO: 10) HCDR2 DNA sequence ATGTGGTATGATGGAAGTAATAAA (SEQ ID NO: 193) HCDR2 amino acid sequence MWYDGSNK (SEQ ID NO: 11) HCDR3 DNA sequence GCGAGACGGGGTCATATAGCAACAGCTGCTCCCTTTGACTAC (SEQ ID NO: 194) HCDR3 amino acid sequence ARRGHIATAAPFDY (SEQ ID NO: 12) LCVR DNA sequence GACATCCAGATGACCCAGTCTCCATCCCCTGTCTGCATCCGTAGGAGACAGAGTCA CCATCAGTTGCCGGGCAAGTCAGAGCATTAGTAGTTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGGTCCTGATGTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAGGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 195) LCVR amino acid sequence DIQMTQSPSSLSASVGDRVTISCRASQSISSYLNWYQQKPGKAPKVLMYAASSLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 13) LCDR1 DNA sequence CAGAGCATTAGTAGTTAT (SEQ ID NO: 196) LCDR1 amino acid sequence QSISSY (SEQ ID NO: 14) LCDR2 DNA sequence GCTGCATCC (SEQ ID NO: 197) LCDR2 amino acid sequence AAS (SEQ ID NO: 15) LCDR3 DNA sequence CAACAGAGTTACAGTACCCCTCCGATCACC (SEQ ID NO: 198) LCDR3 amino acid sequence QQSYSTPPIT (SEQ ID NO: 16) HC DNA sequence CAGGTGCAGTTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTGAAGCGTCTGGAATCACCTTCAGAAACTATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAAT AAATACTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGA ACACGGTGTATCTGCAAATGAACAGCCTGAGAGCCGAAGACACGGCTGTGTATTACTG TGCGAGACGGGGTCATATAGCAACAGCTGCTCCCTTTGACTACTGGGGCCAGGGAAC CCTGGTCACCGTCTCCTCAGCCAAAACAACAGCCCCATCGGTCTATCCACTGGCCCCT GTGTGTGGAGATACAACTGGCTCCTCGGTGACTCTAGGATGCCTGGTCAAGGGTTATT TCCCTGAGCCAGTGACCTTGACCTGGAACTCTGGATCCCTGTCCAGTGGTGTGCACAC CTTCCCAGCTGTCCTGCAGTCTGACCTCTACACCCTCAGCAGCTCAGTGACTGTAACC TCGAGCACCTGGCCCAGCCAGTCCATCACCTGCAATGTGGCCCACCCGGCAAGCAGC ACCAAGGTGGACAAGAAAATTGAGCCCAGAGGGCCCACAATCAAGCCCTGTCCTCCAT GCAAATGCCCAGCACCTAACCTCTTGGGTGGACCATCCGTCTTCATCTTCCCTCCAAA GATCAAGGATGTACTCATGATCTCCCTGAGCCCCATAGTCACATGTGTGGTGGTGGAT GTGAGCGAGGATGACCCAGATGTCCAGATCAGCTGGTTTGTGAACAACGTGGAAGTA CACACAGCTCAGACACAAACCCATAGAGAGGATTACAACAGTACTCTCCGGGTGGTCA GTGCCCTCCCCATCCAGCACCAGGACTGGATGAGTGGCAAGGAGTTCAAATGCAAGGTCAACAACAAAGACCTCCCAGCGCCCATCGAGAGAACCATCTCAAAACCCAAAGGGTC AGTAAGAGCTCCACAGGTATATGTCTTGCCTCCACCAGAAGAAGAGATGACTAAGAAA CAGGTCACTCTGACCTGCATGGTCACAGACTTCATGCCTGAAGACATTTACGTGGAGT GGACCAAACAACGGGAAAACAGAGCTAAACTACAAGACACTGAACCAGTCCTGGACTC TGATGGTTCTTACTTCATGTACAGCAAGCTGAGAGTGGAAAAGAAGAACTGGGTGGAAAGAAATAGCTACTCCTGTTCAGTGGTCCACGAGGGTCTGCACAATCACCACACGACTA AGAGCTTCTCCCGGACTCCGGGTAAATGA (SEQ ID NO: 199) HC amino acid sequence QVQLVESGGGVVQPGRSLRLSCEASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSN KYYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCARRGHIATAAPFDYWGQGTLV TVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVL QSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLG GPSVFIFPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNS TLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMT KKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWV ERNSYSCSVVHEGLHNHHTTKSFSRTPGK (SEQ ID NO: 147) LC DNA sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCCGTAGGAGACAGAGTCA CCATCAGTTGCCGGGCAAGTCAGAGCATTAGTAGTTATTTAAATTGGTATCAGCAGAAA CCAGGGAAAGCCCCTAAGGTCCTGATGTATGCTGCATCCAGTTTGCAAAGTGGGGTCC CATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCT GCAACCTGAGGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATCA CCTTCGGCCAAGGGACACGACTGGAGATTAAACGAGCTGATGCTGCACCAACTGTATC CATCTTCCCACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGTGCTTC TTGAACAACTTCTACCCCAAAGACATCAATGTCAAGTGGAAGATTGATGGCAGTGAAC GACAAAATGGCGTCCTGAACAGTTGGACTGATCAGGACAGCAAAGACAGCACCTACAG CATGAGCAGCACCCTCACGTTGACCAAGGACGAGTATGAACGACATAACAGCTATACC TGTGAGGCCACTCACAAGACATCAACTTCACCCATTGTCAAGAGCTTCAACAGGGGAG AGTGTTGA (SEQ ID NO: 200) LC amino acid sequence DIQMTQSPSSLSASVGDRVTISCRASQSISSYLNWYQQKPGKAPKVLMYAASSLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRADAAPTVSIFPPS SEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTL TKDEYERHNSYTCEATHKTSTSPIVKSFNRGEC (SEQ ID NO: 148) H4H31265P2 / REGN5972 HCVR DNA sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCCTGTACAGCGTCTGGATTCACCTTCCGTTCCTATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGTCAGTTATTTGGATTGATGGAAATAATA TATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAA CACGCTGTATCTGCAAATGGACAGCCTGAGAGCCGAGGACACGGCTGTTTATTACTGT GCGAGAAGACTGGCTATAACATCAGCTGCCCCCTTTGACTACTGGGGCCAGGGAACC CTGGTCACCGTCTCCTCA (SEQ ID NO: 201) HCVR amino acid sequence QVQLVESGGGVVQPGRSLRLSCTASGFTFRSYGMHWVRQAPGKGLEWVSVIWIDGNNIY YADSVKGRFTISRDNSKNTLYLQMDSLRAEDTAVYYCARRLAITSAAPFDYWGQGTLVTVSS (SEQ ID NO: 17) HCDR1 DNA sequence GGATTCACCTTCCGTTCCTATGGC (SEQ ID NO: 202) HCDR1 amino acid sequence GFTFRSYG (SEQ ID NO: 18) HCDR2 DNA sequence ATTTGGATTGATGGAAATAATATA (SEQ ID NO: 203) HCDR2 amino acid sequence IWIDGNNI (SEQ ID NO: 19) HCDR3 DNA sequence GCGAGAAGACTGGCTATAACATCAGCTGCCCCCTTTGACTAC (SEQ ID NO: 204) HCDR3 amino acid sequence ARRLAITSAAPFDY (SEQ ID NO: 20) LCVR DNA sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAA ACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTC CCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTC TGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATC ACCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 205) LCVR amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 21) LCDR1 DNA sequence CAGAGCATTAGCAGCTAT (SEQ ID NO: 206) LCDR1 amino acid sequence QSISSY (SEQ ID NO: 22) LCDR2 DNA sequence GCTGCATCC (SEQ ID NO: 207) LCDR2 amino acid sequence AAS (SEQ ID NO: 23) LCDR3 DNA sequence CAACAGAGTTACAGTACCCCTCCGATCACC (SEQ ID NO: 208) LCDR3 amino acid sequence QQSYSTPPIT (SEQ ID NO: 24) HC DNA sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTACAGCGTCTGGATTCACCTTCCGTTCCTATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGTCAGTTATTTGGATTGATGGAAATAATA TATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAA CACGCTGTATCTGCAAATGGACAGCCTGAGAGCCGAGGACACGGCTGTTTATTACTGT GCGAGAAGACTGGCTATAACATCAGCTGCCCCCTTTGACTACTGGGGCCAGGGAACC CTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCC TGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTAC TTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCA CACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACC GTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCC AGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCT GCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAA GGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAG CCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAA TGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCC CCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCA GGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTG GGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTC CGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGA GGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAG AAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 209) HC amino acid sequence QVQLVESGGGVVQPGRSLRLSCTASGTFRSYGMHWVRQAPGKGLEWVSVIWIDGNNIY YADSVKGRFTISRDNSKNTLYLQMDSLRAEDTAVYYCARRLAITSAAPFDYWGQGTLVTVS SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK * (SEQ ID NO: 149) LC DNA sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAA ACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTC CCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTC TGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATC ACCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCT TCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTAC AGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGG GGAGAGTGTTAG (SEQ ID NO: 210) LC amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC * (SEQ ID NO: 150) H2aM31941N HCVR DNA sequence CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAG GTCTCCTGCAAGGCTTCTGGTTACGCCTTCACCACCTATGGTATCACCTGGGTGCGAC AGGCCCCTGGACAAGGACTTGAGTGGATGGGATGGATCAGCGCTTACAATGGAAATA CAAACTATGCAGAGAAGGTCCAGGGCAGATTCACCATGACCACAGACACATCCACGAA TACAGCCTACATGGAGCTGAGGAGCCTGAGATCCGACGACACGGCCGTGTATTTCTGT GCGAGAAAGGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTTTG GGGCCAAGGGACAATGGTCACCGTCTCTTCA (SEQ ID NO: 211) HCVR amino acid sequence QVQLVQSGAEVKKPGASVKVSCKASGYAFTTYGITWVRQAPGQGLEWMGWISAYNGNT NYAEKVQGRFTMTTDTSTNTAYMELRSLRSDDTAVYFCARKGHYGSGTYYNPFGFDFWG QGTMVTVSS (SEQ ID NO: 25) HCDR1 DNA sequence GGTTACGCCTTCACCACCTATGGT (SEQ ID NO: 212) HCDR1 amino acid sequence GYAFTTYG (SEQ ID NO: 26) HCDR2 DNA sequence ATCAGCGCTTACAATGGAAATACA (SEQ ID NO: 213) HCDR2 amino acid sequence ISAYNGNT (SEQ ID NO: 27) HCDR3 DNA sequence GCGAGAAAGGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTT (SEQ ID NO: 214) HCDR3 amino acid sequence ARKGHYGSGTYYNPFGFDF (SEQ ID NO: 28) LCVR DNA sequence GAAATTATGTTGATGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAACA GAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGA CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGC AGACTGGAGCCTGAAGATTTTGCAGTTTATTTCTGTCAGCAGTATTATGGCTCACCTTG GACGTTCGGCCAAGGGACCAAGGTGGAAATCAAGCG (SEQ ID NO: 215) LCVR amino acid sequence EIMLMQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATDIPD RFSGSGSGTDFTLTISRLEPEDFAVYFCQQYYGSPWTFGQGTKVEIK (SEQ ID NO: 29) LCDR1 DNA sequence CAGAGTGTTAGCAGCAGCTAC (SEQ ID NO: 216) LCDR1 amino acid sequence QSVSSSY (SEQ ID NO: 30) LCDR2 DNA sequence GGTGCATCC (SEQ ID NO: 217) LCDR2 amino acid sequence GAS (SEQ ID NO: 31) LCDR3 DNA sequence CAGCAGTATTATGGCTCACCTTGGACG (SEQ ID NO: 218) LCDR3 amino acid sequence QQYYGSPWT (SEQ ID NO: 32) HC DNA sequence CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAG GTCTCCTGCAAGGCTTCTGGTTACGCCTTCACCACCTATGGTATCACCTGGGTGCGAC AGGCCCCTGGACAAGGACTTGAGTGGATGGGATGGATCAGCGCTTACAATGGAAATA CAAACTATGCAGAGAAGGTCCAGGGCAGATTCACCATGACCACAGACACATCCACGAA TACAGCCTACATGGAGCTGAGGAGCCTGAGATCCGACGACACGGCCGTGTATTTCTGT GCGAGAAAGGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTTTG GGGCCAAGGGACAATGGTCACCGTCTCTTCAGCCAAAACGACACCCCCATCTGTCTAT CCACTGGCCCCTGGATCTGCTGCCCAAACTAACTCCATGGTGACCCTGGGATGCCTG GTCAAGGGCTATTTCCCTGAGCCAGTGACAGTGACCTGGAACTCTGGATCCCTGTCCA GCGGTGTGCACACCTTCCCAGCTGTCCTGCAGTCTGACCTCTACACTCTGAGCAGCTC AGTGACTGTCCCCTCCAGCACCTGGCCCAGCGAGACCGTCACCTGCAACGTTGCCCACCCGGCCAGCAGCACCAAGGTGGACAAGAAAATTGTGCCCAGGGATTGTGGTTGTAA GCCTTGCATATGTACAGTCCCAGAAGTATCATCTGTCTTCATCTTCCCCCCAAAGCCCA AGGATGTGCTCACCATTACTCTGACTCCTAAGGTCACGTGTGTTGTGGTAGACATCAG CAAGGATGATCCCGAGGTCCAGTTCAGCTGGTTTGTAGATGATGTGGAGGTGCACACA GCTCAGACGCAACCCCGGGAGGAGCAGTTCAACAGCACTTTCCGCTCAGTCAGTGAA CTTCCCATCATGCACCAGGACTGGCTCAATGGCAAGGAGTTCAAATGCAGGGTCAACAGTGCAGCTTTCCCTGCCCCCATCGAGAAAACCATCTCCAAAACCAAAGGCAGACCGAA GGCTCCACAGGTGTACACCATTCCACCTCCCAAGGAGCAGATGGCCAAGGATAAAGT CAGTCTGACCTGCATGATAACAGACTTCTTCCCTGAAGACATTACTGTGGAGTGGCAG TGGAATGGGCAGCCAGCGGAGAACTACAAGAACACTCAGCCCATCATGGACACAGAT GGCTCTTACTTCGTCTACAGCAAGCTCAATGTGCAGAAGTCCAACTGGGAGGCAGGAA ATACTTTCACCTGCTCTGTGTTACATGAGGGCCTGCACAACCACCATACTGAGAAGTC CCTCTCCCACTCTCCTGGTAAATGA (SEQ ID NO: 219) HC amino acid sequence QVQLVQSGAEVKKPGASVKVSCKASGYAFTTYGITWVRQAPGQGLEWMGWISAYNGNT NYAEKVQGRFTMTTDTSTNTAYMELRSLRSDDTAVYFCARKGHYGSGTYYNPFGFDFWG QGTMVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGV HTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTV PEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQF NSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQ MAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSN WEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK (SEQ ID NO: 151) LC DNA sequence GAAATTATGTTGATGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGA CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGC AGACTGGAGCCTGAAGATTTTGCAGTTTATTTCTGTCAGCAGTATTATGGCTCACCTTG GACGTTCGGCCAAGGGACCAAGGTGGAAATCAAGCGAGCTGATGCTGCACCAACTGT ATCCATCTTCCCACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGTCGTGTGC TTCTTGAACAACTTCTACCCCAAAGACATCAATGTCAAGTGGAAGATTGATGGCAGTGA ACGACAAAATGGCGTCCTGAACAGTTGGACTGATCAGGACAGCAAAGACAGCACCTAC AGCATGAGCAGCACCCTCACGTTGACCAAGGACGAGTATGAACGACATAACAGCTATA CCTGTGAGGCCACTCACAAGACATCAACTTCACCCATTGTCAAGAGCTTCAACAGGGG AGAGTGTTGA (SEQ ID NO: 220) LC amino acid sequence EIMLMQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATDIPD RFSGSGSGTDFTLTISRLEPEDFAVYFCQQYYGSPWTFGQGTKVEIKRADAAPTVSIFPPS SEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTL TKDEYERHNSYTCEATHKTSTSPIVKSFNRGEC (SEQ ID NO: 152) REGN7660 HCVR DNA sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCGGGGGGGTCCCTGAA ACTCCTGTACAGCCTCTGGGTTGACCCTCAGTGACTCTGCTATGCACTGGGTCCGC CAGGCTTCCGGGAAAGGGCTGGAGTGGGTTGGCCGTATAAGAAATAAGGCTAATAGG TACGCGACAGAATATGCTGCGTCGGTGAAAGGCAGGTTCACCATTTCAAGAGATGATT CAAAGAACACGGCGTATCTACAAATGAACAGCCTGAAAACCGAGGACACGGCCGTGTA TTATTGTACTAGAAAACTGGAAGATTTTCCTCTTTGACTACTGGGGCCAGGGAACCCTGG TCACCGTCTCCTCA (SEQ ID NO: 221) HCVR amino acid sequence EVQLVESGGGLVQPGGSLKLSCTASGLTLSDSAMHWVRQASGKGLEWVGRIRNKANRYA TEYAASVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTRNWKIFLFDYWGQGTLVTVSS (SEQ ID NO: 33) HCDR1 DNA sequence GGGTTGACCCTCAGTGACTCTGCT (SEQ ID NO: 222) HCDR1 amino acid sequence GLTLSDSA (SEQ ID NO: 34) HCDR2 DNA sequence ATAAGAAATAAGGCTAATAGGTACGCGACA (SEQ ID NO: 223) HCDR2 amino acid sequence IRNKANRYAT (SEQ ID NO: 35) HCDR3 DNA sequence ACTAGAAACTGGAAGATTTTCCTCTTTGACTAC (SEQ ID NO: 224) HCDR3 amino acid sequence TRNWKIFLFDY (SEQ ID NO: 36) LCVR DNA sequence GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGACTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGGGCCAGTCAGAGTGTTGGCAGCAAATACTTAGCCTGGTTCCAGCA GAAACGTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGACCAGTGG CATCCCCGACAGGATCAGTGGCAGTGGGTCAGGGACAGACTTCACTCTCACCATCAG CAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGAAGTTCACCC TGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 225) LCVR amino acid sequence EIVLTQSPGTLTLSPGERATLSCRASQSVGSKYLAWFQQKRGQAPRLLIYGASSRTSGIPD RISGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (SEQ ID NO: 37) LCDR1 DNA sequence CAGAGTGTTGGCAGCAAATAC (SEQ ID NO: 226) LCDR1 amino acid sequence QSVGSKY (SEQ ID NO: 38) LCDR2 DNA sequence GGTGCATCC (SEQ ID NO: 227) LCDR2 amino acid sequence GAS (SEQ ID NO: 39) LCDR3 DNA sequence CAGCAGTATGGAAGTTCACCCTGGACG (SEQ ID NO: 228) LCDR3 amino acid sequence QQYGSSPWT (SEQ ID NO: 40) HC DNA sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCGGGGGGGTCCCTGAA ACTCTCCTGTACAGCCTCTGGGTTGACCCTCAGTGACTCTGCTATGCACTGGGTCCGC CAGGCTTCCGGGAAAGGGCTGGAGTGGGTTGGCCGTATAAGAAATAAGGCTAATAGG TACGCGACAGAATATGCTGCGTCGGTGAAAGGCAGGTTCACCATTTCAAGAGATGATT CAAAGAACACGGCGTATCTACAAATGAACAGCCTGAAAACCGAGGACACGGCCGTGTA TTATTGTACTAGAAACTGGAAGATTTTCCTCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCT CCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCC CCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACC TTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC CCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCA ACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCC CAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGA CACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCA GGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCG AGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGT CAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGA CGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGG GAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAG TCCCCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 229) HC amino acid sequence EVQLVESGGGLVQPGGSLKLSCTASGLTLSDSAMHWVRQASGKGLEWVGRIRNKANRYA TEYAASVKGRFTISRDDSKNTAYLQMNSLKTEDTAVYYCTRNWKIFLFDYWGQGTLVTVS SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 153) LC DNA sequence GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGACTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGGGCCAGTCAGAGTGTTGGCAGCAAATACTTAGCCTGGTTCCAGCA GAAACGTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGACCAGTGG CATCCCCGACAGGATCAGTGGCAGTGGGTCAGGGACAGACTTCACTCTCACCATCAG CAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATGGAAGTTCACCC TGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCT GTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTG CCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCC CTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACC TACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCT ACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACA GGGGAGAGTGTTAG (SEQ ID NO: 230) LC amino acid sequence EIVLTQSPGTLTLSPGERATLSCRASQSVGSKYLAWFQQKRGQAPRLLIYGASSRTSGIPD RISGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 154) REGN9909 HCVR DNA sequence GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCGGGGGGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACCTTTAACAACTATGGCATGAGCTGGGTCCGCCAGGGTCCAGGGAAGGGGCTGGAGTGGGTCTCATCTATTAGTGGTAGTGGTGGTACC ACATTCTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGA ACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTG TGGCAAAGGAGGATATTGTAGTAGTAGCGGCTGCCGTCACTACGGTATGGACGTCTG GGGCCAAGGGACCACGGTCACCGTCTCCTCA (SEQ ID NO: 231) HCVR amino acid sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFNNYGMSWVRQGPGKGLEWVSSISGSGGTT FYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGKGGYCSSSGCRHYGMDVWG QGTTVTVSS (SEQ ID NO: 41) HCDR1 DNA sequence GGATTCACCTTTAACAACTATGGC (SEQ ID NO: 232) HCDR1 amino acid sequence GFTFNNYG (SEQ ID NO: 42) HCDR2 DNA sequence ATTAGTGGTAGTGGTGGTACCACA (SEQ ID NO: 233) HCDR2 amino acid sequence ISGSGGTT (SEQ ID NO: 43) HCDR3 DNA sequence GGCAAAGGAGGATATTGTAGTAGTAGCGGCTGCCGTCACTACGGTATGGACGTC (SEQ ID NO: 234) HCDR3 amino acid sequence GKGGYCSSSGCRHYGMDV (SEQ ID NO: 44) LCVR DNA sequence CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGACCCCGGCAGAGGGTCACC ATCTCTTGTTCTGGAAGCAGCTCCAACATCGGAAATAATTATATATACTGGTACCAGCG GCTCCCAGGAACGACCCCCAAACTCCTCATCTATAGGAATAATCAGCGGCCCTCAGGG GTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTG GGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACACCCTGA GTGGGTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA (SEQ ID NO: 235) LCVR amino acid sequence QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNYIYWYQRLPGTTPKLLIYRNNQRPSGVPD RFGSKSGTSASLAISGLRSEDEADYYCAAWDDTLSGYVFGTGTKVTVL (SEQ ID NO: 45) LCDR1 DNA sequence AGCTCCAACATCGGAAATAATTAT (SEQ ID NO: 236) LCDR1 amino acid sequence SSNIGNNY (SEQ ID NO: 46) LCDR2 DNA sequence AGGAATAAT (SEQ ID NO: 237) LCDR2 amino acid sequence RNN (SEQ ID NO: 47) LCDR3 DNA sequence GCAGCATGGGATGACACCCTGAGTGGTATGTC (SEQ ID NO: 238) LCDR3 amino acid sequence AAWDDTLSGYV (SEQ ID NO: 48) HC DNA sequence GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCGGGGGGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACCTTTAACAACTATGGCATGAGCTGGGTCCGC CAGGGTCCAGGGAAGGGGCTGGAGTGGGTCTCATCTATTAGTGGTAGTGGTGGTACC ACATTCTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGA ACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTG TGGCAAAGGAGGATATTGTAGTAGTAGCGGCTGCCGTCACTACGGTATGGACGTCTG GGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCAAAACAACAGCCCCATCGGTCTA TCCACTGGCCCCTGTGTGTGGAGATACAACTGGCTCCTCGGTGACTCTAGGATGCCTG GTCAAGGGTTATTTCCCTGAGCCAGTGACCTTGACCTGGAACTCTGGATCCCTGTCCA GTGGTGTGCACACCTTCCCAGCTGTCCTGCAGTCTGACCTCTACACCCTCAGCAGCTC AGTGACTGTAACCTCGAGCACCTGGCCCAGCCAGTCCATCACCTGCAATGTGGCCCA CCCGGCAAGCAGCACCAAGGTGGACAAGAAAATTGAGCCCAGAGGGCCCACAATCAA GCCCTGTCCTCCATGCAAATGCCCAGCACCTAACCTCTTGGGTGGACCATCCGTCTTC ATCTTCCCTCCAAAGATCAAGGATGTACTCATGATCTCCCTGAGCCCCATAGTCACATG TGTGGTGGTGGATGTGAGCGAGGATGACCCAGATGTCCAGATCAGCTGGTTTGTGAA CAACGTGGAAGTACACACAGCTCAGACACAAACCCATAGAGAGGATTACAACAGTACT CTCCGGGTGGTCAGTGCCCTCCCCATCCAGCACCAGGACTGGATGAGTGGCAAGGAGTTCAAATGCAAGGTCAACAACAAAGACCTCCCAGCGCCCATCGAGAGAACCATCTCAA AACCCAAAGGGTCAGTAAGAGCTCCACAGGTATATGTCTTGCCTCCACCAGAAGAAGA GATGACTAAGAAACAGGTCACTCTGACCTGCATGGTCACAGACTTCATGCCTGAAGAC ATTTACGTGGAGTGGACCAACAACGGGAAAACAGAGCTAAACTACAAGAACACTGAAC CAGTCCTGGACTCTGATGGTTCTTACTTCATGTACAGCAAGCTGAGAGTGGAAAAGAA GAACTGGGTGGAAAGAAATAGCTACTCCTGTTCAGTGGTCCACGAGGGTCTGCACAAT CACCACACGACTAAGAGCTTCTCCCGGACTCCGGGTAAATGA (SEQ ID NO: 239) HC amino acid sequence \EVQLLESGGGLVQPGGSLRLSCAASGFTFNNYGMSWVRQGPGKGLEWVSSISGSGGTT FYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCGKGGYCSSSGCRHYGMDVWG QGTTVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCP APNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTH REDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPP PEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVE KKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK (SEQ ID NO: 155) LC DNA sequence CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACC ATCTCTTGTTCTGGAAGCAGCTCCAACATCGGAAATAATTATATATACTGGTACCAGCG GCTCCCAGGAACGACCCCCAAACTCCTCATCTATAGGAATAATCAGCGGCCCTCAGGG GTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTG GGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACACCCTGA GTGGGTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTACGAGCTGATGCTGCAC CAACTGTATCCATCTTCCCACCATCCAGTGAGCAGTTAACATCTGGAGGTGCCTCAGT CGTGTGCTTCTTGAACAACTTCTACCCCAAAGACATCAATGTCAAGTGGAAGATTGATG GCAGTGAACGACAAAATGGCGTCCTGAACAGTTGGACTGATCAGGACAGCAAAGACA GCACCTACAGCATGAGCAGCACCCTCACGTTGACCAAGGACGAGTATGAACGACATAA CAGCTATACCTGTGAGGCCACTCACAAGACATCAACTTCACCCATTGTCAAGAGCTTCA ACAGGGGAGAGTGTTGA (SEQ ID NO: 240) LC amino acid sequence QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNYIYWYQRLPGTTPKLLIYRNNQRPSGVPD RFSGSKSGTSASLAISGLRSEDEADYYCAAWDDTLSGYVFGTGTKVTVLRADAAPTVSIFP PSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTL TLTKDEYERHNSYTCEATHKTSTSPIVKSFNRGEC (SEQ ID NO: 156) REGN10713 HCVR DNA sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAAACTTGGTACAGCCTGGGGGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACCTTTACCAGCCATGCCATGAACTGGGTCCGC CAGGCTCCAGGGAAGGCTGGAGTGGGTCTCAGTTATTACTGGTAGAGGTTTTGAC ACACACTACGCTGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACATTTCCAAAA ACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTTTATTACTG TGCGAAAGGTCTCTATGATTCGGGGAATTATTATATCGATTACTGGGGCCAGGGAACC CTGGTCACCGTCTCCTCA (SEQ ID NO: 241) HCVR amino acid sequence EVQLVESGGNLVQPGGSLRLSCAASGFTFTSHAMNWVRQAPGKGLEWVSVITGRGFDTH YADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAKGLYDSGNYYIDYWGQGTLVTVSS (SEQ ID NO: 49) HCDR1 DNA sequence GGATTCACCTTTACCAGCCATGCC (SEQ ID NO: 242) HCDR1 amino acid sequence GFTFTSHA (SEQ ID NO: 50) HCDR2 DNA sequence ATTACTGGTAGAGGTTTTGACACA (SEQ ID NO: 243) HCDR2 amino acid sequence ITGRGFDT (SEQ ID NO: 51) HCDR3 DNA sequence GCGAAAGGTCTCTATGATTCGGGGAATTATTATATCGATTAC (SEQ ID NO: 244) HCDR3 amino acid sequence AKGLYDSGNYYIDY (SEQ ID NO: 52) LCVR DNA sequence CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCAGGACAGAAGGTCACC ATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTTTCCTGGTACCAGCA GCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGG ATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCG GACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATCTCAGCCTGA GTTTCAATTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 245) LCVR amino acid sequence QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPD RFSGSKSGTSATLGITGLQTGDEADYYCGTWDLSLSFNWVFGGGTKLTVL (SEQ ID NO: 53) LCDR1 DNA sequence AGCTCCAACATTGGGAATAATTAT (SEQ ID NO: 246) LCDR1 amino acid sequence SSNIGNNY (SEQ ID NO: 54) CDR2 DNA sequence GACAATAAT (SEQ ID NO: 247) LCDR2 amino acid sequence DNN (SEQ ID NO: 55) LCDR3 DNA sequence GGAACATGGGATCTCAGCCTGAGTTTCAATTGGGTG (SEQ ID NO: 248) LCDR3 amino acid sequence GTWDLSLSFNWV (SEQ ID NO: 56) HC DNA sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAAACTTGGTACAGCCTGGGGGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACCTTTACCAGCCATGCCATGAACTGGGTCCGC CAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTACTGGTAGAGGTTTTGAC ACACACTACGCTGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACATTTCCAAAA ACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTTTATTACTG TGCGAAAGGTCTCTATGATTCGGGGAATTATTATATCGATTACTGGGGCCAGGGAACC CTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCC TGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTAC TTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCA CACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACC GTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCC AGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCT GCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAA GGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAG CCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAA TGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGT CCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCC CCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCA GGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTG GGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTC CGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGA GGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAG AAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 249) HC amino acid sequence EVQLVESGGNLVQPGGSLRLSCAASGFTFTSHAMNWVRQAPGKGLEWVSVITGRGFDTH YADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAKGLYDSGNYYIDYWGQGTLVTVS SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK * (SEQ ID NO: 157) LC DNA sequence CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACC ATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTTTCCTGGTACCAGCA GCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGG ATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCG GACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATCTCAGCCTGA GTTTCAATTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGCCAGCCCAAGG CCGCCCCCTCCGTGACCCTGTTCCCCCCCTCCTCCGAGGAGCTGCAGGCCAACAAGG CCACCCTGGTGTGCCTGATCTCCGACTTCTACCCCGGCGCCGTGACCGTGGCCTGGA AGGCCGACTCCTCCCCCGTGAAGGCCGGCGTGGAGACCACCACCCCCTCCAAGCAG TCCAACAACAAGTACGCCGCCTCCTCCTACCTGTCCCTGACCCCCGAGCAGTGGAAGT CCCACCGGTCCTACTCCTGCCAGGTGACCCACGAGGGCTCCACCGTGGAGAAGACCG TGGCCCCCACCGAGTGCTCCTGA (SEQ ID NO: 250) LC amino acid sequence QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPD RFSGSKSGTSATLGITGLQTGDEADYYCGTWDLSLSFNWVFGGGTKLTVLGQPKAAPSVT LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSY LSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS * (SEQ ID NO: 158) REGN10715 HCVR DNA sequence CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGCGACCCTGTCC CGCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTACTGGAACTGGATCCGCC AGTCCCAGGGAAGGGGCTGGAATGGATTGGGGAAATCCTTCATAGTGGAAGAACCA ACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCA GTTCTCCTGAAGCTGACCTCTGTGACCGCCGCGGACACGGCTGTATATTACTGTGCG GGAAGGATAGCAGCTCGTCACGGCTGGTTCGACCCCTGGGGCCAGGGAACCCTGGT CACCGTCTCCTCA (SEQ ID NO: 251) HCVR amino acid sequence QVQLQQWGAGLLKPSATLSRTCAVYGGSFSGYYWNWIRQSPGKGLEWIGEILHSGRTNY NPSLKSRVTISVDTSKNQFSLKLTSVTAADTAVYYCAGRIAARHGWFDPWGQGTLVTVSS (SEQ ID NO: 57) HCDR1 DNA sequence GGTGGGTCCTTCAGTGGTTACTAC (SEQ ID NO: 252) HCDR1 amino acid sequence GGSFSGYY (SEQ ID NO: 58) HCDR2 DNA sequence ATCCTTCATAGTGGAAGAACC (SEQ ID NO: 253) HCDR2 amino acid sequence ILHSGRT (SEQ ID NO: 59) HCDR3 DNA sequence GCGGGAAGGATAGCAGCTCGTCACGGCTGGTTCGACCCC (SEQ ID NO: 254) HCDR3 amino acid sequence AGRIAARHGWFDP (SEQ ID NO: 60) LCVR DNA Sequence GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTACATCTGTAGGAGACAGAGTCA CCATCTCTTGTCGGGCGAGTCAGGATATTCGCAAGTGGTTAGCCTGGTATCAACAGAA ACCAGGAAAAGCCCCTAAACTCCTGATCTATGCTACATCCAGTTTGCAAAGTGGGGTC CCTTCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAGGATTTTGCAACTTACTTTTGTCAACAGGCTAACAGTTTCCCGTTCACT TTTGGCCAGGGGACCAAGCTGGAGATCAAA (SEQ ID NO: 255) LCVR amino acid sequence DIQMTQSPSSVSTSVGDRVTISCRASQDIRKWLAWYQQKPGKAPKLLIYATSSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYFCQQANSFPFTFGQGTKLEIK (SEQ ID NO: 61) LCDR1 DNA sequence CAGGATATTCGCAAGTGG (SEQ ID NO: 256) LCDR1 amino acid sequence QDIRKW (SEQ ID NO: 62) LCDR2 DNA sequence GCTACATCC (SEQ ID NO: 257) LCDR2 amino acid sequence ATS (SEQ ID NO: 63) LCDR3 DNA sequence CAACAGGCTAACAGTTTCCCGTTCACT (SEQ ID NO: 258) LCDR3 amino acid sequence QQANSFPFT (SEQ ID NO: 64) HC DNA sequence CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGCGACCCTGTCC CGCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTACTGGAACTGGATCCGCC AGTCCCCAGGGAAGGGGCTGGAATGGATTGGGGAAATCCTTCATAGTGGAAGAACCA ACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCA GTTCTCCCTGAAGCTGACCTCTGTGACCGCCGCGGACACGGCTGTATATTACTGTGCG GGAAGGATAGCAGCTCGTCACGGCTGGTTCGACCCCTGGGGCCAGGGAACCCTGGT CACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTC CAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC CGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTT CCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCC CTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAA CACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCC AGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGAC ACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAG GAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCC AAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA GAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGG AATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGT CCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 259) HC amino acid sequence QVQLQQWGAGLLKPSATLSRTCAVYGGSFSGYYWNWIRQSPGKGLEWIGEILHSGRTNY NPSLKSRVTISVDTSKNQFSLKLTSVTAADTAVYYCAGRIAARHGWFDPWGQGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK * (SEQ ID NO: 159) LC DNA sequence GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTACATCTGTAGGAGACAGAGTCA CCATCTCTTGTCGGGCGAGTCAGGATATTCGCAAGTGGTTAGCCTGGTATCAACAGAA ACCAGGAAAAGCCCCTAAACTCCTGATCTATGCTACATCCAGTTTGCAAAGTGGGGTC CCTTCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCC TGCAGCCTGAGGATTTTGCAACTTACTTTTGTCAACAGGCTAACAGTTTCCCGTTCACT TTTGGCCAGGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCA TCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAA TCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAG AGTGTTAG (SEQ ID NO: 260) LC amino acid sequence DIQMTQSPSSVSTSVGDRVTISCRASQDIRKWLAWYQQKPGKAPKLLIYATSSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYFCQQANSFPFTFGQGTKLEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC * (SEQ ID NO: 160) REGN10716 HCVR DNA sequence CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTC CCTCACCTGCACTGTCTCTGGTGACTCCATCAAATAATTACTACTGGACCTGGCTCCG AGTTCTCCCTGAAGCTAAATTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGC GAGAGGGGCGGTCAAGTACTTCCGGCATTGGGCCAGGGCACCCTGGTCACCGTCT CCTCA (SEQ ID NO: 261) HCVR amino acid sequence QVQLQESGPGLVKPSETLSLTCTVSGDSINNYYWTWLRQPPGKGLEWIGYIYYSGSANYN PSLKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCARGAVKYFRHWGQGTLVTVSS (SEQ ID NO: 65) HCDR1 DNA sequence GGTGACTCCATCAATAATTACTAC (SEQ ID NO: 262) HCDR1 amino acid sequence GDSINNYY (SEQ ID NO: 66) HCDR2 DNA sequence ATCTATTACAGTGGGAGCGCC (SEQ ID NO: 263) HCDR2 amino acid sequence IYYSGSA (SEQ ID NO: 67) HCDR3 DNA sequence GCGAGAGGGGCGGTCAAGTACTTCCGGCAT (SEQ ID NO: 264) HCDR3 amino acid sequence ARGAVKYFRH (SEQ ID NO: 68) LCVR DNA sequence GAAATTGTGTTGACGCAGTCTCCGGGCACCCTCTCTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGGGCCAGTCAGACTATTAACCACAACAACTTAGCCTGGTACCAGCA GAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAACAGGGCCACTGC CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGC AGACTGGAGCCTGAAGATTTTGAAGTGTATTCTTGTCAGCAGTATGGTAGCTTGCCGC TCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 265) LCVR amino acid sequence EIVLTQSPGTLSLSPGERATLSCRASQTINHNNLAWYQQRPGQAPRLLIYGASNRATAIPD RFSGSGSGTDFTLTISRLEPEDFEVYSCQQYGSLPLTFGGGTKVEIK (SEQ ID NO: 69) LCDR1 DNA sequence CAGACTATTAACCACAACAAC (SEQ ID NO: 266) LCDR1 amino acid sequence QTINHNN (SEQ ID NO: 70) LCDR2 DNA sequence GGTGCATCC (SEQ ID NO: 267) LCDR2 amino acid sequence GAS (SEQ ID NO: 71) LCDR3 DNA sequence CAGCAGTATGGTAGCTTGCCGCTCACT (SEQ ID NO: 268) LCDR3 amino acid sequence QQYGSLPLT (SEQ ID NO: 72) HC DNA sequence CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTC CCTCACCTGCACTGTCTCTGGTGACTCCATCAATAATTACTACTGGACCTGGCTCCGG CAGCCCCCAGGGAAGGGACTGGAGTGGATTGGTTATATCTATTACAGTGGGAGCGCC AACTACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACC AGTTCTCCCTGAAGCTAAATTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGC GAGAGGGGCGGTCAAGTACTTCCGGCATTGGGGCCAGGGCACCCTGGTCACCGTCT CCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCA CCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGG TGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTG TCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCA GCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGG TGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGA GTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATG ATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCC CGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCT GCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACA GGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGAC CTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGG GCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTT CTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTT CTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTCCCTCTCC CTGTCTCTGGGTAAATGA (SEQ ID NO: 269) HC amino acid sequence QVQLQESGPGLVKPSETLSLTTCTVSGDSINNYYWTWLRQPPGKGLEWIGYIYYSGSANYN PSLKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCARGAVKYFRHWGQGTLVTVSSASTK GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS CSVMHEALHNHYTQKSLSLSLGK * (SEQ ID NO: 161) LC DNA sequence GAAATTGTGTTGACGCAGTCTCCGGGCACCCTCTCTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGGGCCAGTCAGACTATTAACCACAACAACTTAGCCTGGTACCAGCA GAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAACAGGGCCACTGC CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGC AGACTGGAGCCTGAAGATTTTGAAGTGTATTCTTGTCAGCAGTATGGTAGCTTGCCGC TCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGC CTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCC TCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCT ACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTA CGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAG GGGAGAGTGTTAG (SEQ ID NO: 270) LC amino acid sequence EIVLTQSPGTLSLSPGERATLSCRASQTINHNNLAWYQQRPGQAPRLLIYGASNRATAIPD RFSGSGSGTDFTLTISRLEPEDFEVYSCQQYGSLPLTFGGGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC * (SEQ ID NO: 162) REGN10717 HCVR DNA sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTACATATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTGGCATGATGGAAGTGAT AAATATTATGTAGACTCCGTGAAGGGCCGATTCTCCATCGCCAGAGACAATTCCAAGA ACACGCTTTATCTGCAAATGAATAGTCTGAGAGTCGAGGACACGGGTATATATTACTGT GCGAGAAGGGGTATACGTGGAACCGTTTTGACCACTGGGGCCTGGGAACCCTGGTC ACCGTCTCCTCA (SEQ ID NO: 271) HCVR amino acid sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS (SEQ ID NO: 73) HCDR1 DNA sequence GGATTCACCTTCAGTACATATGGC (SEQ ID NO: 272) HCDR1 amino acid sequence GFTFSTYG (SEQ ID NO: 74) HCDR2 DNA sequence ATTTGGCATGATGGAAGTGATAAA (SEQ ID NO: 273) HCDR2 amino acid sequence IWHDGSDK (SEQ ID NO: 75) HCDR3 DNA sequence GCGAGAAGGGGTATACGTGGAACCGTTTTTGACCAC (SEQ ID NO: 274) HCDR3 amino acid sequence ARRGIRGTVFDH (SEQ ID NO: 76) LCVR DNA sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCA CCCTCACTTGTCGGGCCAGTCAGAGTATTAGTAACAAGTTGGCCTGGTATCAGCAGAA ACCAGGGAAAGCCCCTAACCTCCTGATCTATAAGGCGTCTAATTTAGAAAGTGGGGTC CCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCC TGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCGTGGACG TTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 275) LCVR amino acid sequence DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIK (SEQ ID NO: 77) LCDR1 DNA sequence CAGAGTATTAGTAACAAG (SEQ ID NO: 276) LCDR1 amino acid sequence QSISNK (SEQ ID NO: 78) LCDR2 DNA sequence AAGGCGTCT (SEQ ID NO: 277) LCDR2 amino acid sequence KAS (SEQ ID NO: 79) LCDR3 DNA sequence CAACAGTATAATAGTTATTCGTGGACG (SEQ ID NO: 278) LCDR3 amino acid sequence QQYNSYSWT (SEQ ID NO: 80) HC DNA sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTACATATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTGGCATGATGGAAGTGAT AAATATTATGTAGACTCCGTGAAGGGCCGATTCTCCATCGCCAGAGACAATTCCAAGA ACACGCTTTATCTGCAAATGAATAGTCTGAGAGTCGAGGACACGGGTATATATTACTGT GCGAGAAGGGGTATACGTGGAACCGTTTTTGACCACTGGGGCCTGGGAACCCTGGTC ACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCC GAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTC CCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCC TCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCA GCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACA CTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGG AAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCA CCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAG AGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCA GCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGA GCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACG GCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGA ATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGTC CCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 279) HC amino acid sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK * (SEQ ID NO: 163) LC DNA sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCA CCCTCACTTGTCGGGCCAGTCAGAGTATTAGTAACAAGTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAACCTCCTGATCTATAAGGCGTCTAATTTAGAAAGTGGGGTC CCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCC TGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCGTGGACG TTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCA TCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAA TCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAG AGTGTTAG (SEQ ID NO: 280) LC amino acid sequence DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC * (SEQ ID NO: 164) REGN10783 HCVR DNA sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGACGTCCCTGAG ACTCTCCTGTGCAGCGTCAGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGATTGATGGAAGTAAT AAATATTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGA ACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG TGCGAGAAGGGGGGTATAGTAGTAGCTGCCCCCTTTGACTACTGGGCCAGGGAAC CCTGGTCACCGTCTCCTCA (SEQ ID NO: 281) HCVR amino acid sequence QVQLVESGGGVVQPGTSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWIDGSNKY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGGIVVAAPFDYWGQGTLVTV SS (SEQ ID NO: 81) HCDR1 DNA sequence GGATTCACCTTCAGTAGCTATGGC (SEQ ID NO: 282) HCDR1 amino acid sequence GFTFSSYG (SEQ ID NO: 82) HCDR2 DNA sequence ATATGGATTGATGGAAGTAATAAA (SEQ ID NO: 283) HCDR2 amino acid sequence IWIDGSNK (SEQ ID NO: 83) HCDR3 DNA sequence GCGAGAAGGGGGGGTATAGTAGTAGCTGCCCCCTTTGACTAC (SEQ ID NO: 284) HCDR3 amino acid sequence ARRGGIVVAAPFDY (SEQ ID NO: 84) LCVR DNA sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAA ACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTC CCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTC TGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATC ACCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 285) LCVR amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 85) LCDR1 DNA sequence CAGAGCATTAGCAGCTAT (SEQ ID NO: 286) LCDR1 amino acid sequence QSISSY (SEQ ID NO: 86) LCDR2 DNA sequence GCTGCATCC (SEQ ID NO: 287) LCDR2 amino acid sequence AAS (SEQ ID NO: 87) LCDR3 DNA sequence CAACAGAGTTACAGTACCCCTCCGATCACC (SEQ ID NO: 288) LCDR3 amino acid sequence QQSYSTPPIT (SEQ ID NO: 88) HC DNA sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGACGTCCCTGAG ACTCTCCTGTGCAGCGTCAGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGATTGATGGAAGTAAT AAATATTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGA ACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG TGCGAGAAGGGGGGGTATAGTAGTAGCTGCCCCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCC CTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTA CTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGC ACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGAC CGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCC CAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACC CTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCC AAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTG AGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCAT AATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGC GTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGC CCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACC AGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGT GGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACT CCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGG AGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACA GAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 289) HC amino acid sequence QVQLVESGGGVVQPGTSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWIDGSNKY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGGIVVAAPFDYWGQGTLVTV SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK * (SEQ ID NO: 165) LC DNA sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAA ACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTC CCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTC TGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATC ACCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCT TCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCT GCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTAC AGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGG GGAGAGTGTTAG (SEQ ID NO: 290) LC amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC * (SEQ ID NO: 166) REGN7854 HCVR DNA sequence CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAG GTCTCCTGCAAGGCTTCTGGTTACGCCTTCACCACCTATGGTATCACCTGGGTGCGACAGGCCCCTGGACAAGGACTTGAGTGGATGGGATGGATCAGCGCTTACAATGGAAATA CAAACTATGCAGAGAAGGTCCAGGGCAGATTCACCATGACCACAGACACATCCACGAA TACAGCCTACATGGAGCTGAGGAGCCTGAGATCCGACGACACGGCCGTGTATTTCTGT GCGAGAAAGGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTTTG GGGCCAAGGGACAATGGTCACCGTCTCTTCA (SEQ ID NO: 291) HCVR amino acid sequence QVQLVQSGAEVKKPGASVKVSCKASGYAFTTYGITWVRQAPGQGLEWMGWISAYNGNT NYAEKVQGRFTMTTDTSTNTAYMELRSLRSDDTAVYFCARKGHYGSGTYYNPFGFDFWG QGTMVTVSS (SEQ ID NO: 89) HCDR1 DNA sequence GGTTACGCCTTCACCACCTATGGT (SEQ ID NO: 292) HCDR1 amino acid sequence GYAFTTYG (SEQ ID NO: 90) HCDR2 DNA sequence ATCAGCGCTTACAATGGAAATACA (SEQ ID NO: 293) HCDR2 amino acid sequence ISAYNGNT (SEQ ID NO: 91) HCDR3 DNA sequence GCGAGAAAGGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTT (SEQ ID NO: 294) HCDR3 amino acid sequence ARKGHYGSGTYYNPFGFDF (SEQ ID NO: 92) LCVR DNA sequence GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAACA GAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGG CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGC AGACTGGAGCCTGAAGATTTTGCTTTGTATTTCTGTCAGCAGTATTATGGCTCACCTTG GACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 295) LCVR amino acid sequence EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPD RFSGSGSGTDFTLTISRLEPEDFALYFCQQYYGSPWTFGQGTKVEIK (SEQ ID NO: 93) LCDR1 DNA sequence CAGAGTGTTAGCAGCAGCTAC (SEQ ID NO: 296) LCDR1 amino acid sequence QSVSSSY (SEQ ID NO: 94) LCDR2 DNA sequence GGTGCATCC (SEQ ID NO: 297) LCDR2 amino acid sequence GAS (SEQ ID NO: 95) LCDR3 DNA sequence CAGCAGTATTATGGCTCACCTTGGACG (SEQ ID NO: 298) LCDR3 amino acid sequence QQYYGSPWT (SEQ ID NO: 96) HC DNA sequence CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAG GTCTCCTGCAAGGCTTCTGGTTACGCCTTCACCACCTATGGTATCACCTGGGTGCGAC AGGCCCCTGGACAAGGACTTGAGTGGATGGGATGGATCAGCGCTTACAATGGAAATA CAAACTATGCAGAGAAGGTCCAGGGCAGATTCACCATGACCACAGACACATCCACGAA TACAGCCTACATGGAGCTGAGGAGCCTGAGATCCGACGACACGGCCGTGTATTTCTGT GCGAGAAAGGGTCACTATGGTTCGGGGACTTATTATAACCCCTTTGGTTTTGATTTTTG GGGCCAAGGGACAATGGTCACCGTCTCTTCAGCCTCCACCAAGGGCCCATCGGTCTT CCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCC TGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGA CCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCA GCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACG TAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCC CCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTT CCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGT GGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGG CGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTA CCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAA GCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGA GATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGA CATCGCCGTGGAGTGGGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGC CTCCCGTGCTGGACTCCGACGGCTCCTTCTTTCCTCTACAGCAGGCTCACCGTGGACAA GAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCA CAACCACTACACACAGAAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 299) HC amino acid sequence QVQLVQSGAEVKKPGASVKVSCKASGYAFTTYGITWVRQAPGQGLEWMGWISAYNGNT NYAEKVQGRFTMTTDTSTNTAYMELRSLRSDDTAVYFCARKGHYGSGTYYNPFGFDFWG QGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPA PEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLP PSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTV DKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 167) LC DNA sequence GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAACA GAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGG CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGC AGACTGGAGCCTGAAGATTTTGCTTTGTATTTCTGTCAGCAGTATTATGGCTCACCTTG GACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGT CTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCC TGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCT CCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTA CAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTA CGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAG GGGAGAGTGTTAG (SEQ ID NO: 300) LC amino acid sequence EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPD RFSGSGSGTDFTLTISRLEPEDFALYFCQQYYGSPWTFGQGTKVEIKRTVAAPSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 168) REGN14570 HCVR DNA sequence CAGGTGCAGCTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGCGACCCTGTCC CGCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTACTGGAACTGGATCCGCC AGTCCCAGGGAAGGGGCTGGAATGGATTGGGGAAATCCTTCATAGTGGAAGAACCA ACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCA GTTCTCCTGAAGCTGACCTCTGTGACCGCCGCGGACACGGCTGTATATTACTGTGCG GGAAGGATAGCAGCTCGTCACGGCTGGTTCGACCCCTGGGGCCAGGGAACCCTGGT CACCGTCTCCTCA (SEQ ID NO: 301) HCVR amino acid sequence QVQLQQWGAGLLKPSATLSRTCAVYGGSFSGYYWNWIRQSPGKGLEWIGEILHSGRTNY NPSLKSRVTISVDTSKNQFSLKLTSVTAADTAVYYCAGRIAARHGWFDPWGQGTLVTVSS (SEQ ID NO: 97) HCDR1 DNA sequence GGTGGGTCCTTCAGTGGTTACTAC (SEQ ID NO: 302) HCDR1 amino acid sequence GGSFSGYY (SEQ ID NO: 98) HCDR2 DNA sequence ATCCTTCATAGTGGAAGAACC (SEQ ID NO: 303) HCDR2 amino acid sequence ILHSGRT (SEQ ID NO: 99) HCDR3 DNA sequence GCGGGAAGGATAGCAGCTCGTCACGGCTGGTTCGACCCC (SEQ ID NO: 304) HCDR3 amino acid sequence AGRIAARHGWFDP (SEQ ID NO: 100) LCVR DNA sequence GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTACATCTGTAGGAGACAGAGTCA CCATCTCTTGTCGGGCGAGTCAGGATATTCGCAAGTGGTTAGCCTGGTATCAACAGAA ACCAGGAAAAGCCCCTAAACTCCTGATCTATGCTACATCCAGTTTGCAAAGTGGGGTC CCTTCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCC TGCAGCCTGAGGATTTTGCAACTTACTTTTGTCAACAGGCTAACAGTTTCCCGTTCACT TTTGGCCAGGGGACCAAGCTGGAGATCAAA (SEQ ID NO: 305) LCVR amino acid sequence DIQMTQSPSSVSTSVGDRVTISCRASQDIRKWLAWYQQKPGKAPKLLIYATSSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYFCQQANSFPFTFGQGTKLEIK (SEQ ID NO: 101) LCDR1 DNA sequence CAGGATATTCGCAAGTGG (SEQ ID NO: 306) LCDR1 amino acid sequence QDIRKW (SEQ ID NO: 102) LCDR2 DNA sequence GCTACATCC (SEQ ID NO: 307) LCDR2 amino acid sequence ATS (SEQ ID NO: 103) LCDR3 DNA sequence CAACAGGCTAACAGTTTCCCGTTCACT (SEQ ID NO: 308) LCDR3 amino acid sequence QQANSFPFT (SEQ ID NO: 104) HC DNA sequence CAGGTGCAGCTACAGCAGTGGGCGCAGGACTGTTGAAGCCTTCGGCGACCCTGTCC CGCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGGTTACTACTGGAACTGGATCCGCC AGTCCCCAGGGAAGGGGCTGGAATGGATTGGGGGAAATCCTTCATAGTGGAAGAACCA ACTACAACCCGTCCTCAAGAGCGAGTCACCATATCAGTAGACACGTCCAAGAACCA GTTCCCCTGAAGCTGACCCTTGTGACCCGCGCGGACACGGCTGTATATTACTGTTGCG GGAAGGATAGCAGCTCGTCACGGCCTGTTCGACCCCTGGGCCAGGGAACCCTGT CACCGTCTCCTCCAGCCCCATCGGTTCCCCCCTGGCACCCTCCTC CAAGAGCACCTCTGGGGCCACAGCGGCCCTGGGCTCGTCAAGGACTACTTCCC CGAACCGGTGACGGTTCGTGGGAACTCAGGCGCGTCCGGAACTCACCAGCGGTGCGCTGCACACCTT CCCGGGCTTCCTACAGTCTCCAGGACTCTACTCCCCCAGCAGCGGTGTGACCGTGCC CTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAAC ACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAAACTCACACATGCCCAC CGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTCCCCAAAAC CCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGTGGACG TGAGCCACGAAGACCCTGCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGC ATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACCAAAGCACGTACCGTGTGGTCA GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCA GCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGA GTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA CTCCGACGGCTCCTTCTTCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCA GCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACG CAGAAGTCCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 309) HC amino acid sequence (N297Q is shown in bold)

[0237] [ka] (SEQ ID NO: 169) LC DNA sequence GACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTACATCTGTAGGAGACAGAGTCA CCATCTCTTGTCGGGCGAGTCAGGATATTCGCAAGTGGTTAGCCTGGTATCAACAGAA ACCAGGAAAAGCCCCTAAACTCCTGATCTATGCTACATCCAGTTTGCAAAGTGGGGTC CCTTCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCC TGCAGCCTGAGGATTTTGCAACTTACTTTTGTCAACAGGCTAACAGTTTCCCGTTCACT TTTGGCCAGGGGACCAAGCTGGAGATCAAACGAACTGTGGCTGCACCATCTGTCTTCA TCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAA TCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAG AGTGTTAG (SEQ ID NO: 310) LC amino acid sequence DIQMTQSPSSVSTSVGDRVTISCRASQDIRKWLAWYQQKPGKAPKLLIYATSSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYFCQQANSFPFTFGQGTKLEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 170) REGN14571 HCVR DNA sequence CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTC CCTCACCTGCACTGTCTCTGGTGACTCCATCAAATAATTACTACTGGACCTGGCTCCG AGTTCTCCCTGAAGCTAAATTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGC GAGAGGGGCGGTCAAGTACTTCCGGCATTGGGCCAGGGCACCCTGGTCACCGTCT CCTCA (SEQ ID NO: 311) HCVR amino acid sequence QVQLQESGPGLVKPSETLSLTTCTVSGDSINNYYWTWLRQPPGKGLEWIGYIYYSGSANYN PSLKSRVTISVDTSKNQFSLKLNSVTAADTAVYYCARGAVKYFRHWGQGTLVTVSS (SEQ ID NO: 105) HCDR1 DNA sequence GGTGACTCCATCAATAATTACTAC (SEQ ID NO: 312) HCDR1 amino acid sequence GDSINNYY (SEQ ID NO: 106) HCDR2 DNA sequence ATCTATTACAGTGGGAGCGCC (SEQ ID NO: 313) HCDR2 amino acid sequence IYYSGSA (SEQ ID NO: 107) HCDR3 DNA sequence GCGAGAGGGGCGGTCAAGTACTTCCGGCAT (SEQ ID NO: 314) HCDR3 amino acid sequence ARGAVKYFRH (SEQ ID NO: 108) LCVR DNA sequence GAAATTGTGTTGACGCAGTCTCCGGGCACCCTCTCTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGGGCCAGTCAGACTATTAACCACAACAACTTAGCCTGGTACCAGCA GAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAACAGGGCCACTGC CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGAAGTGTATTCTTGTCAGCAGTATGGTAGCTTGCCGC TCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 315) LCVR amino acid sequence EIVLTQSPGTLSLSPGERATLSCRASQTINHNNLAWYQQRPGQAPRLLIYGASNRATAIPD RFSGSGSGTDFTLTISRLEPEDFEVYSCQQYGSLPLTFGGGTKVEIK (SEQ ID NO: 109) LCDR1 DNA sequence CAGACTATTAACCACAACAAC (SEQ ID NO: 316) LCDR1 amino acid sequence QTINHNN (SEQ ID NO: 110) LCDR2 DNA sequence GGTGCATCC (SEQ ID NO: 317) LCDR2 amino acid sequence GAS (SEQ ID NO: 111) LCDR3 DNA sequence CAGCAGTATGGTAGCTTGCCGCTCACT (SEQ ID NO: 318) LCDR3 amino acid sequence QQYGSLPLT (SEQ ID NO: 112) HC DNA sequence CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTC CCTCACCTGCACTGTCTCTGGTGACTCCATCAATAATTACTACTGGACCTGGCTCCGG CAGCCCCCAGGGAAGGGACTGGAGTGGATTGGTTATATCTATTACAGTGGGAGCGCC AACTACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACC AGTTCTCCCTGAAGCTAAATTCTGTGACCGCTGCGGACACGGCCGTGTATTACTGTGC GAGAGGGGCGGTCAAGTACTTCCGGCATTGGGGCCAGGGCACCCTGGTCACCGTCT CCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCA CCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCG GTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCT GTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGC AGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAG GTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCC CAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGG ACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCC ACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATG CCAAGACAAAGCCGCGGGAGGAGCAGTACCAAAGCACGTACCGTGTGGTCAGCGTCC TCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCC GAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGG TCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCG ACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGG GGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAA GTCCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 319) HC amino acid sequence (N297Q is shown in bold)

[0238] [ka] (SEQ ID NO: 171) LC DNA sequence GAAATTGTGTTGACGCAGTCTCCGGGCACCCTCTCTTTGTCTCCAGGGGAAAGAGCCA CCCTCTCCTGCAGGGCCAGTCAGACTATTAACCACAACAACTTAGCCTGGTACCAGCA GAGACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAACAGGGCCACTGC CATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGC AGACTGGAGCCTGAAGATTTTGAAGTGTATTCTTGTCAGCAGTATGGTAGCTTGCCGC TCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACTGTGGCTGCACCATCTG TCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGC CTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCC TCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCT ACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAG GGGAGAGTGTTAG (SEQ ID NO: 320) LC amino acid sequence EIVLTQSPGTLSLSPGERATLSCRASQTINHNNLAWYQQRPGQAPRLLIYGASNRATAIPD RFSGSGSGTDFTLTISRLEPEDFEVYSCQQYGSLPLTFGGGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 172) REGN14572 HCVR DNA sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTACATATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATTTGGCATGATGGAAGTGAT AAATATTATGTAGACTCCGTGAAGGGCCGATTCTCCATCGCCAGAGACAATTCCAAGA ACACGCTTTATCTGCAAATGAATAGTCTGAGAGTCGAGGACACGGGTATATATTACTGT GCGAGAAGGGGTATACGTGGAACCGTTTTGACCACTGGGGCCTGGGAACCCTGGTC ACCGTCTCCTCA (SEQ ID NO: 321) HCVR amino acid sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWHDGSDK YYVDSVKGRFSIARDNSKNTLYLQMNSLRVEDTGIYYCARRGIRGTVFDHWGLGTLVTVSS (SEQ ID NO: 113) HCDR1 DNA sequence GGATTCACCTTCAGTACATATGGC (SEQ ID NO: 322) HCDR1 amino acid sequence GFTFSTYG (SEQ ID NO: 114) HCDR2 DNA sequence ATTTGGCATGATGGAAGTGATAAA (SEQ ID NO: 323) HCDR2 amino acid sequence IWHDGSDK (SEQ ID NO: 115) HCDR3 DNA sequence GCGAGAAGGGGTATACGTGGAACCGTTTTTGACCAC (SEQ ID NO: 324) HCDR3 amino acid sequence ARRGIRGTVFDH (SEQ ID NO: 116) LCVR DNA sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCA CCCTCACTTGTCGGGCCAGTCAGAGTATTAGTAACAAGTTGGCCTGGTATCAGCAGAA ACCAGGGAAAGCCCCTAACCTCCTGATCTATAAGGCGTCTAATTTAGAAAGTGGGGTC CCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCC TGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCGTGGACG TTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 325) LCVR amino acid sequence DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIK (SEQ ID NO: 117) LCDR1 DNA sequence CAGAGTATTAGTAACAAG (SEQ ID NO: 326) LCDR1 amino acid sequence QSISNK (SEQ ID NO: 118) LCDR2 DNA sequence AAGGCGTCT (SEQ ID NO: 327) LCDR2 amino acid sequence KAS (SEQ ID NO: 119) LCDR3 DNA sequence CAACAGTATAATAGTTATTCGTGGACG (SEQ ID NO: 328) LCDR3 amino acid sequence QQYNSYSWT (SEQ ID NO: 120) HC DNA sequence CAGGTGCAGCTGGTGGAGTCTGGGGGGAGGCGTGGTCCAGCCTGGAGGTCCCTGAG ACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTACATATGGCATGCACTGGGTCCGC CAGGCTCCAGGAAGGGGCTGGAGTGGGTGGCAGTTTATTGGCATGATGGAAGTGAT AAATATTATGTAGACTCCGTGAAGGGCCGATTCTCCATCGCCAGAGCAATTCCAAGA ACACGCTTTATCTGCAAATGAATAGTCTGAGAGTCGAGGACACGGGTATATTACTGT GCGAGAAGGGGTATACGTGGAACCGTTTTTTGACCACTGGGGCCTGGGAACCCTGGTC ACCGTCTCCTCAGCCTCCACCAAGGGCCATCGGTTCCCCCTGGCACCCTCCTCC AAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCC GAACCGGTGACGGTGTCGTGGAACTCAGGGCCCCTGACCAGCGGCTGCACACCTTC CCGGCTGTCCTCTACAGTCCTCCAGGACTCTACTCCCTCAGCGTGGTGACCTGCCC TCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAAATCACAAGCCCAGCAACA CCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGGACAAAACTCACACATGCCCACC GTGCCCAGCACCCTGAACTCCTGGGGGGGACGTCAGCTCTTCCTCTCCCCCCAAAACC CAAGGACCCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGT GAGCCACGAAGACCCTGAGGTCAAGTTCCAACTGTTGGACGGCGTGGAGGTGCATAATGCCAAGAAACCCGGGAGGAGCAGTACCAAAGCACGTACCGTGTGGTCAG CGTCCTCACCGTCCTGGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCA GCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGA GTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA CTCCGACGGCTCCTTCTTCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCA GCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACG CAGAAGTCCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 329) HC amino acid sequence (N297Q is shown in bold)

[0239] [ka] (SEQ ID NO: 173) LC DNA sequence GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCA CCCTCACTTGTCGGGCCAGTCAGAGTATTAGTAACAAGTTGGCCTGGTATCAGCAGAA ACCAGGGAAAGCCCCTAACCTCCTGATCTATAAGGCGTCTAATTTAGAAAGTGGGGTC CCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCC TGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCGTGGACG TTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCT GAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAA TCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGC CTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCT GCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAG AGTGTTAG (SEQ ID NO: 330) LC amino acid sequence DIQMTQSPSTLSASVGDRVTLTCRASQSISNKLAWYQQKPGKAPNLLIYKASNLESGVPSR FSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSWTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 174) REGN14573 HCVR DNA sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAAACTTGGTACAGCCTGGGGGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACCTTTACCAGCCATGCCATGAACTGGGTCCGC CAGGCTCCAGGGAAGGCTGGAGTGGGTCTCAGTTATTACTGGTAGAGGTTTTGAC ACACACTACGCTGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACATTTCCAAAA ACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTTTATTACTG TGCGAAAGGTCTCTATGATTCGGGGAATTATTATATCGATTACTGGGGCCAGGGAACC CTGGTCACCGTCTCCTCA (SEQ ID NO: 331) HCVR amino acid sequence EVQLVESGGNLVQPGGSLRLSCAASGFTFTSHAMNWVRQAPGKGLEWVSVITGRGFDTH YADSVKGRFTISRDISKNTLYLQMNSLRAEDTAVYYCAKGLYDSGNYYIDYWGQGTLVTVSS (SEQ ID NO: 121) HCDR1 DNA sequence GGATTCACCTTTACCAGCCATGCC (SEQ ID NO: 332) HCDR1 amino acid sequence GFTFTSHA (SEQ ID NO: 122) HCDR2 DNA sequence ATTACTGGTAGAGGTTTTGACACA (SEQ ID NO: 333) HCDR2 amino acid sequence ITGRGFDT (SEQ ID NO: 123) HCDR3 DNA sequence GCGAAAGGTCTCTATGATTCGGGGAATTATTATATCGATTAC (SEQ ID NO: 334) HCDR3 amino acid sequence AKGLYDSGNYYIDY (SEQ ID NO: 124) LCVR DNA sequence CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCAGGACAGAAGGTCACC ATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTTTCCTGGTACCAGCA GCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGG ATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCG GACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATCTCAGCCTGA GTTTCAATTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA (SEQ ID NO: 335) LCVR amino acid sequence QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPD RFSGSKSGTSATLGITGLQTGDEADYYCGTWDLSLSFNWVFGGGTKLTVL (SEQ ID NO: 125) LCDR1 DNA sequence AGCTCCAACATTGGGAATAATTAT (SEQ ID NO: 336) LCDR1 amino acid sequence SSNIGNNY (SEQ ID NO: 126) CDR2 DNA sequence GACAATAAT (SEQ ID NO: 337) LCDR2 amino acid sequence DNN (SEQ ID NO: 127) LCDR3 DNA sequence GGAACATGGGATCTCAGCCTGAGTTTCAATTGGGTG (SEQ ID NO: 338) LCDR3 amino acid sequence GTWDLSLSFNWV (SEQ ID NO: 128) HC DNA sequence GAGGTGCAGCTGGTGGAGTCTGGGGGAAACTTGGTACAGCCTGGGGGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACCTTTACCAGCCATGCCATGAACTGGGTCCGC CAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGTTATTACTGGTAGAGGTTTTGAC ACACACTACGCTGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACATTTCCAAAA ACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTTTATTACTG TGCGAAAGGTCTCTATGATTCGGGGAATTATTATATCGATTACTGGGGCCAGGGAACC CTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCC TCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTAC TTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCA CACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCC AGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACAT GCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCC CAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGG TGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGG AGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACCAAAGCACGTACCGTG TGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAA AGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGAC CAAGAACCAGGTCAGCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGC CGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGT GCTGGACTCCGACGGCTCCTTCTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAG GTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCA CTACACGCAGAAGTCCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 339) HC amino acid sequence (N297Q is shown in bold)

[0240] [ka] (SEQ ID NO: 175) LC DNA sequence CAGTCTGTGTTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACC ATCTCCTGCTCTGGAAGCAGCTCCAACATTGGGAATAATTATGTTTCCTGGTACCAGCA GCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATAATAAGCGACCCTCAGGG ATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGGCATCACCG GACTCCAGACTGGGGACGAGGCCGATTATTACTGCGGAACATGGGATCTCAGCCTGA GTTTCAATTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGCCAGCCCAAGG CCGCCCCCTCCGTGACCCTGTTCCCCCCCTCCTCCGAGGAGCTGCAGGCCAACAAGG CCACCCTGGTGTGCCTGATCTCCGACTTCTACCCCGGCGCCGTGACCGTGGCCTGGA AGGCCGACTCCTCCCCCGTGAAGGCCGGCGTGGAGACCACCACCCCCTCCAAGCAG TCCAACAACAAGTACGCCGCCTCCTCCTACCTGTCCCTGACCCCCGAGCAGTGGAAGT CCCACCGGTCCTACTCCTGCCAGGTGACCCACGAGGGCTCCACCGTGGAGAAGACCG TGGCCCCCACCGAGTGCTCCTGA (SEQ ID NO: 340) LC amino acid sequence QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYDNNKRPSGIPD RFSGSKSGTSATLGITGLQTGDEADYYCGTWDLSLSFNWVFGGGTKLTVLGQPKAAPSVT LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSY LSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 176) REGN14574 HCVR DNA sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGACGTCCCTGAG ACTCTCCTGTGCAGCGTCAGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGATTGATGGAAGTAAT AAATATTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGA ACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAAGGGGGGTATAGTAGTAGCTGCCCCCTTTGACTACTGGGCCAGGGAAC CCTGGTCACCGTCTCCTCA (SEQ ID NO: 341) HCVR amino acid sequence QVQLVESGGGVVQPGTSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWIDGSNKY YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRGGIVVAAPFDYWGQGTLVTV SS (SEQ ID NO: 129) HCDR1 DNA sequence GGATTCACCTTCAGTAGCTATGGC (SEQ ID NO: 342) HCDR1 amino acid sequence GFTFSSYG (SEQ ID NO: 130) HCDR2 DNA sequence ATATGGATTGATGGAAGTAATAAA (SEQ ID NO: 343) HCDR2 amino acid sequence IWIDGSNK (SEQ ID NO: 131) HCDR3 DNA sequence GCGAGAAGGGGGGGTATAGTAGTAGCTGCCCCCTTTGACTAC (SEQ ID NO: 344) HCDR3 amino acid sequence ARRGGIVVAAPFDY (SEQ ID NO: 132) LCVR DNA sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAA ACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTC CCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTC TGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATC ACCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 345) LCVR amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 133) LCDR1 DNA sequence CAGAGCATTAGCAGCTAT (SEQ ID NO: 346) LCDR1 amino acid sequence QSISSY (SEQ ID NO: 134) LCDR2 DNA sequence GCTGCATCC (SEQ ID NO: 347) LCDR2 amino acid sequence AAS (SEQ ID NO: 135) LCDR3 DNA sequence CAACAGAGTTACAGTACCCCTCCGATCACC (SEQ ID NO: 348) LCDR3 amino acid sequence QQSYSTPPIT (SEQ ID NO: 136) HC DNA sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGACGTCCCTGAG ACTCTCCTGTGCAGCGTCAGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATGGATTGATGGAAGTAAT AAATATTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTG TGCGAGAAGGGGGGGTATAGTAGTAGCTGCCCCCTTTGACTACTGGGGCCAGGGAAC CCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACC CTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTA CTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGC ACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGAC CGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCC CAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACA TGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCC CCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTG GTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG GAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACCAAAGCACGTACCGT GTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCA AAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGA CCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCG CCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCC GTGCTGGACTCCGACGGCTCCTTCTCCTCTACAGCAAGCTCACCGTGGACAAGAGCA GGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACC ACTACACGCAGAAGTCCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 349) HC amino acid sequence (N297Q is shown in bold)

[0241] [ka] (SEQ ID NO: 177) LC DNA sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAA ACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTC CCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTC TGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATC ACCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCT TCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCT GCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTAC AGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGG GGAGAGTGTTAG (SEQ ID NO: 350) LC amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 178) REGN14647 HCVR DNA sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTACAGCGTCTGGAATCACCTTCAGAAATTATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATGTGGTATGATGGAAGTAAT AAGTACTATGCAGACTCCGTGAAGGGCCGTTTCACCATCTCCGGAGACAATTCCAAGG TGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTATATTACTGTGCGAG AAGGGGCACTATAAGAACAGCTGCCCCTTTTGACTACTGGGGTCAGGGAACCCTGGT CACCGTCTCCTCA (SEQ ID NO: 351) HCVR amino acid sequence QVQLVESGGGVVQPGRSLRLSCTASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSN KYYADSVKGRFTISGDNSKVYLQMNSLRAEDTAVYYCARRGTIRTAAPFDYWGQGTLVTV SS (SEQ ID NO: 137) HCDR1 DNA sequence GGAATCACCTTCAGAAATTATGGC (SEQ ID NO: 352) HCDR1 amino acid sequence GITFRNYG (SEQ ID NO: 138) HCDR2 DNA sequence ATGTGGTATGATGGAAGTAATAAG (SEQ ID NO: 353) HCDR2 amino acid sequence MWYDGSNK (SEQ ID NO: 139) HCDR3 DNA sequence GCGAGAAGGGGCACTATAAGAACAGCTGCCCCTTTTGACTAC (SEQ ID NO: 354) HCDR3 amino acid sequence ARRGTIRTAAPFDY (SEQ ID NO: 140) LCVR DNA sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAA ACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTC CCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTC TGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATC ACCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 355) LCVR amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIK (SEQ ID NO: 141) LCDR1 DNA sequence CAGAGCATTAGCAGCTAT (SEQ ID NO: 356) LCDR1 amino acid sequence QSISSY (SEQ ID NO: 142) LCDR2 DNA sequence GCTGCATCC (SEQ ID NO: 357) LCDR2 amino acid sequence AAS (SEQ ID NO: 143) LCDR3 DNA sequence CAACAGAGTTACAGTACCCCTCCGATCACC (SEQ ID NO: 358) LCDR3 amino acid sequence QQSYSTPPIT (SEQ ID NO: 144) HC DNA sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGGTCCAGCCTGGGGAGTCCCTGAG ACTCTCCTGTACAGCGTCTGGGAATCACCTTCAGAAATTATGGCATGCACTGGGTCCGC CAGGCTCCAGGCAAGGGGCTGGGAGTGGTGGCAGTTATGTGGTATGTAGAGTAAT AAGTACTATGCAGACTCCGTGAAGGGCCGTTTCACCCATCTCCCGGAGACAATTCCAAGG TGTATCTGCAAATGAACACCCTGAGAGCCGAGACACGGCTGTATATTACTGTGCGAG AAGGGGCACTATAAGAACAGCTGCCCCTTTTGACTACTGGGTCAGGGAACCCTGGT CACCGTCTCCTCCAGCCCTCCGGTTCCCCTGGCACCCTCCTC CAAGAGCACCTCTGGGGCCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC CGAACCGGTGACGGTTCGTGGAACTCAGGCGCGTCCGGAACTCACCCCTGGCCACCTT CCCGGCTGTCCTACAGTCTCCAGGACTCTACTCCCCCAGCCGTGGTGAACCCGTGC CTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAAC ACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAAACTCACACATGCCCAC CGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTTCTCCTTCCCCCCAAAAC CCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGTGGACG TGAGCCACGAAGACCTGAGGTCCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGC ATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACCAAAGCACGTACCGTGTGGTCA GCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCA GCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAA CCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGA GTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGA CTCCGACGGCTCCTTCTTCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCA GCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACG CAGAAGTCCCTCTCCCTGTCTCCGGGTAAATGA (SEQ ID NO: 359) HC amino acid sequence QVQLVESGGGVVQPGRSLRLSCTASGITFRNYGMHWVRQAPGKGLEWVAVMWYDGSN KYYADSVKGRFTISGDNSKVYLQMNSLRAEDTAVYYCARRGTIRTAAPFDYWGQGTLVTV SSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY QSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 179) LC DNA sequence GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAA ACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTC CCGTCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTC TGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACAGTACCCCTCCGATC ACCTTCGGCCAAGGGACACGACTGGAGATTAAACGAACTGTGGCTGCACCATCTGTCT TCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCT GCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTAC AGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGG GGAGAGTGTTAG (SEQ ID NO: 360) LC amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 180) REGN10712 HCVR DNA sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACATTCAGTACCTATGGCATGTACTGGGTCCGC CAGACTCCAGGCAAGGGGCTGGAGTGGGTGACAGTTATATCATTTGATGGAAATAAAA AATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAAAA CACGCTGTTTCTGCAAATGAACAGCCTGAAAACTGAGGACACGGCTGTATATTACTGT GCGAAATCTTCTAACTGGAACTACGGTTCTTTTGATATATGGGGCCAAGGGACAATGG TCACCGTCTCTTCA (SEQ ID NO: 428) HCVR amino acid sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMYWVRQTPGKGLEWVTVISFDGNKKY YADSVKGRFTISRDNSKNTLFLQMNSLKTEDTAVYYCAKSSNWNYGSFDIWGQGTMVTVSS (SEQ ID NO: 429) HCDR1 DNA sequence GGATTCACATTCAGTACCTATGGC (SEQ ID NO: 430) HCDR1 amino acid sequence GFTFSTYG (SEQ ID NO: 431) HCDR2 DNA sequence ATATCATTTGATGGAAATAAAAAA (SEQ ID NO: 432) HCDR2 amino acid sequence ISFDGNKK (SEQ ID NO: 433) HCDR3 DNA sequence GCGAAATCTTCTAACTGGAACTACGGTTCTTTTGATATA (SEQ ID NO: 434) HCDR3 amino acid sequence AKSSNWNYGSFDI (SEQ ID NO: 435) LCVR DNA sequence CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCAC CATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACACTGGTAC CAGCAGCTTCCAGGCACAGCCCCCAGACTCCTCATCTCTTATAACAGCAATCGGCCCT CAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA TCACTGGGCTCCAGGCTGAGGATGAGGCTGACTATTACTGCCAGTCCTATGACAGAAG CCTGAGTGGTTCTGTGTTCGGAGGAGGCACCCAGCTGACCGTCCTC (SEQ ID NO: 436) LCVR amino acid sequence QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPRLLISYNSNRPSGV PDRFGSKSGTSASLAITGLQAEDEADYYCQSYDRSLSGSVFGGGTQLTVL (SEQ ID NO: 437) LCDR1 DNA sequence AGCTCCAACATCGGGGCAGGTTATGAT (SEQ ID NO: 438) LCDR1 amino acid sequence SSNIGAGYD (SEQ ID NO: 439) LCDR2 DNA sequence TATAACAGC LCDR2 amino acid sequence YNS LCDR3 DNA sequence CAGTCCTATGACAGAAGCCTGAGTGGTTCTGTG (SEQ ID NO: 440) LCDR3 amino acid sequence QSYDRSLSGSV (SEQ ID NO: 441) HC DNA sequence CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACATTCAGTACCTATGGCATGTACTGGGTCCGC CAGACTCCAGGCAAGGGGCTGGAGTGGGTGACAGTTATATCATTTGATGGAAATAAAA AATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAAAA CACGCTGTTTCTGCAAATGAACAGCCTGAAAACTGAGGACACGGCTGTATATTACTGT GCGAAATCTTCTAACTGGAACTACGGTTCTTTTGATATATGGGGCCAAGGGACAATGG TCACCGTCTCTTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCT CCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCC CCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACC TTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGC CCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCA ACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCC CAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGA CACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCA GGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGC CAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCT CACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCG AGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGT CAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGA GAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGA CGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGG GAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAG TCCCCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 442) HC amino acid sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMYWVRQTPGKGLEWVTVISFDGNKKY YADSVKGRFTISRDNSKNTLFLQMNSLKTEDTAVYYCAKSSNWNYGSFDIWGQGTMVTVS SASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNST YRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE GNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 443) HC constant, hlgG4(S108P) DNA sequence GCCTCCACCAAGGGCCCATCGGTCTTCCCCCCTGGGCCCCTGCTCCAGGAGCACCTCCC GAGAGCACACACGCCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCCGAACCGGTGACG GTGTCGTGGAACTCAGGCGCTGACCAGCGGTGGTGACCGGTGCCTCCCAGCCTTG GGCACGAAGACCTACACCTACACCTGCAACGTAGATCACAAGCCAGCAACACCAAGGTGGAC AAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTCGCCAGCCACCTGAGTTCC TGGGGGGACCATCAGTCTTCCTGTTCCCCAAAACCCAAGGACACTCTCATGATCTC CCGGACCCCTGAGGTCAGGTCGTGGTGGTGGACGTGAGCCAGGAAGACCCCAGG TCCAGTTCAACTGGTACGTGGATGCGTGGAGGTGCATAATGCCAAAAGCCGC GGGAGGAGCAGTTCAACAGCACGTACGTGTGGTCAGCGTCTCACGTCCTCACGTCCTCGCTCTCCCTCCAAAACCCAAGGACCACTCTCATGATCTCTCCCCCCAAAACCCAAGGACCACTCTCATGATCTC CCGGACCCCTGAGGTCCGTGGTGGTGGACGTGTGGACGCAGAAGACCCCAGG TCCAGTTCAACTGGTACGTGGATGGCTGAGGGTGCATAATGCCAAAAGCCGC GGGAGGAGCAGTTCAACAGCACGTACGTACGTCGTGTGTCGCTCTCGCTCTCGCTCTCGCTCTCGCTCTCGCTCTCGCTCTCGCTCTCGCTCTCGCTCTCGCTCTCGCTCTCGCTCTCGCTCTCGCTCTCGCTCTCGCTCTCGCTCTCGCTCTCGCTCTCGCTCTCGCTCTC AGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGT CCTCCATCGGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGGTGT ACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCC TGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGC CGGAGAACAAACTACAAGACCACGCTCCCGTGCTGACTCCGACGCTTCTTCCCT CTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATG CTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAGTCCCTCTCCCTGTCTCTGGGTAAATGA (SEQ ID NO: 444) HC constant, hlgG4(S108P) amino acid sequence ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPSQEEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 445) LC DNA sequence CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCAC CATCTCCTGCACTGGGAGCAGCTCCAACATCGGGGCAGGTTATGATGTACACTGGTAC CAGCAGCTTCCAGGCACAGCCCCCAGACTCCTCATCTCTTATAACAGCAATCGGCCCT CAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCA TCACTGGGCTCCAGGCTGAGGATGAGGCTGACTATTACTGCCAGTCCTATGACAGAAG CCTGAGTGGTTCTGTGTTCGGAGGAGGCACCCAGCTGACCGTCCTCGGCCAGCCCAA GGCCGCCCCCTCCGTGACCCTGTTCCCCCCCTCCTCCGAGGAGCTGCAGGCCAACAA GGCCACCCTGGTGTGCCTGATCTCCGACTTCTACCCCGGCGCCGTGACCGTGGCCTG GAAGGCCGACTCCTCCCCCGTGAAGGCCGGCGTGGAGACCACCACCCCCTCCAAGC AGTCCAACAACAAGTACGCCGCCTCCTCCTACCTGTCCCTGACCCCCGAGCAGTGGA AGTCCCACCGGTCCTACTCCTGCCAGGTGACCCACGAGGGCTCCACCGTGGAGAAGA CCGTGGCCCCCACCGAGTGCTCCTGA (SEQ ID NO: 446) LC amino acid sequence QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPRLLISYNSNRPSGV PDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDRSLSGSVFGGGTQLTVLGQPKAAPSV TLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASS YLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 447) LC constant, hLamda DNA sequence GGCCAGCCCAAGGCCGCCCCCTCCGTGACCCTGTTCCCCCCCTCCTCCGAGGAGCT GCAGGCCAACAAGGCCACCCTGGTGTGCCTGATCTCCGACTTCTACCCCGGCGCCGT GACCGTGGCCTGGAAGGCCGACTCCTCCCCCGTGAAGGCCGGCGTGGAGACCACCA CCCCCTCCAAGCAGTCCAACAACAAGTACGCCGCCTCCTCCTACCTGTCCCTGACCCC CGAGCAGTGGAAGTCCCACCGGTCCTACTCCTGCCAGGTGACCCACGAGGGCTCCAC CGTGGAGAAGACCGTGGCCCCCACCGAGTGCTCCTGA (SEQ ID NO: 448) LC constant, hLamda amino acid sequence GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQ SNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 449) REGN9908 HCVR DNA sequence GAGGTGCAGTTGTTGGAGTCTGGGGGAGGCTTGGCACAGCCTGGGGGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGTTATGCCATGAGCTGGGTCCGC CAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCTGTTAGTGGTAGTGGTGGTACC ACATATTATGCAGCCTCCGTGAAGGGCCGGTTCACCGTCTCCAGAGACAATTCCAAGA AGACGCTCTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGGGAAAGGAGGATATTGTAGTAGTAGTGGTTGCCGTCACTACGGTATGGACGTCTGG GGCCAAGGGACCACGGTCACCGTCTCCGCA (SEQ ID NO: 450) HCVR amino acid sequence EVQLLESGGGLAQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSVSGSGGTT YYAASVKGRFTVSRDNSKKTLYLQMNSLRAEDTAVYYCGKGGYCSSSGCRHYGMDVWG QGTTVTVSA (SEQ ID NO: 451) HCDR1 DNA sequence GGATTCACCTTTAGCAGTTATGCC (SEQ ID NO: 452) HCDR1 amino acid sequence GFTFSSYA (SEQ ID NO: 453) HCDR2 DNA sequence GTTAGTGGTAGTGGTGGTACCACA (SEQ ID NO: 454) HCDR2 amino acid sequence VSGSGGTT (SEQ ID NO: 455) HCDR3 DNA sequence GGGAAAGGAGGATATTGTAGTAGTAGTGGTTGCCGTCACTACGGTATGGACGTC (SEQ ID NO: 456) HCDR3 amino acid sequence GKGGYCSSSGCRHYGMDV (SEQ ID NO: 457) LCVR DNA sequence CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGACCCCGGGCAGAGGGTCGC CATTTCTTGTTCTGGAAGCAACTCCAACATCGGAAATAATTACTTATACTGGTACCAGC AGATCCAGGAACGACCCCCAAACTCCTCATCTATAGAAATAATCAGCGGCCCTCAGG GGTCCCTGACCGATTCTCTGCCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGT GGGCTCCGGTCCGGGGATGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTG AGTGGGTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA (SEQ ID NO: 458) LCVR amino acid sequence QSVLTQPPSASGTPGQRVAISCSGSNSNIGNNYLYWYQQIPGTTPKLLIYRNNQRPSGVPD RFSASKSGTSASLAISGLRSGDEADYYCAAWDDSLSGYVFGTGTKVTVL (SEQ ID NO: 459) LCDR1 DNA sequence AACTCCAACATCGGAAATAATTA (SEQ ID NO: 460) LCDR1 amino acid sequence NSNIGNN (SEQ ID NO: 461) LCDR2 DNA sequence AGAAATAAT LCDR2 amino acid sequence RNN LCDR3 DNA sequence GCAGCATGGGATGACAGCCTGAGTGGGTATGTC (SEQ ID NO: 462) LCDR3 amino acid sequence AAWDDSLSGYV (SEQ ID NO: 463) HC DNA sequence GAGGTGCAGTTGTTGGAGTCTGGGGGAGGCTTGGCACAGCCTGGGGGGTCCCTGAG ACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGTTATGCCATGAGCTGGGTCCGC CAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCATCTGTTAGTGGTAGTGGTGGTACC ACATATTATGCAGCCTCCGTGAAGGGCCGGTTCACCGTCTCCAGAGACAATTCCAAGA AGACGCTCTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTG TGGGAAAGGAGGATATTGTAGTAGTAGTGGTTGCCGTCACTACGGTATGGACGTCTGG GGCCAAGGGACCACGGTCACCGTCTCCGCAGCCAAGACAACACCTCCTTCTGTGTAT CCTCTGGCTCCTGGATGTGGAGATACAACAGGATCTTCTGTGACACTGGGATGTCTGGTGAAGGGATATTTTCCTGAATCTGTGACAGTGACATGGAACTCTGGATCTCTGTCTTCT TCTGTGCATACATTTCCTGCTCTGCTGCAGTCTGGACTGTATACAATGTCTTCTTCTGT GACAGTGCCTTCTTCTACATGGCCTTCTCAGACAGTGACATGTTCTGTGGCTCATCCTG CTTCTTCTACAACAGTGGATAAGAAGCTGGAACCTTCTGGACCTATCTCTACAATCAAT CCTTGTCCTCCTTGTAAGGAATGTCATAAGTGTCCTGCTCCTAATCTGGAAGGAGGAC CTTCTGTGTTTATCTTTCCTCCTAATATCAAGGATGTGCTGATGATCTCTCTGACACCTA AGGTGACATGTGTGGTGGTGGATGTGTCTGAAGATGATCCTGATGTGCAGATCTCTTG GTTTGTGAATAATGTGGAAGTGCATACAGCTCAGACACAGACACATAGAGAAGATTATAATTCTACAATCAGAGTGGTGTCTACACTGCCTATCCAGCATCAGGATTGGATGTCTGGA AAGGAATTTAAGTGTAAGGTGAATAATAAGGATCTGCCTTCTCCTATCGAAAGAACAAT CTCTAAGATCAAGGGACTGGTGAGAGCTCCTCAGGTGTATATCCTGCCTCCTCCTGCT GAACAGCTGTCCAGAAAGGATGTGTCTCTGACATGTCTGGTGGTGGGATTTAATCCTG GAGATATCTCTGTGGAATGGACATCTAATGGACATACAGAAGAAAATTATAAGGATACA GCTCCTGTGCTGGATTCTGATGGATCTTATTTTATCTATTCTAAGCTGAATATGAAGACA TCTAAGTGGGAAAAGACAGATTCTTTTTCTTGTAATGTGAGACATGAAGGACTGAAGAA TTATTATCTGAAGAAGACAATCTCCAGATCTCCTGGAAAGTGA (SEQ ID NO: 464) HC amino acid sequence EVQLLESGGGLAQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSVSGSGGTT YYAASVKGRFTVSRDNSKKTLYLQMNSLRAEDTAVYYCGKGGYCSSSGCRHYGMDVWG QGTTVTVSAAKTTPPSVYPLAPGCGDTTGSSVTLGCLVKGYFPESVTVTWNSGSLSSSVH TFPALLQSGLYTMSSSVTVPSSTWPSQTVTCSVAHPASSTTVDKKLEPSGPISTINPCPPC KECHKCPAPNLEGGPSVFIFPPNIKDVLMISLTPKVTCVVVDVSEDDPDVQISWFVNNVEV HTAQTQTHREDYNSTIRVVSTLPIQHQDWMSGKEFKCKVNNKDLPSPIERTISKIKGLVRAP QVYILPPPAEQLSRKDVSLTCLVVGFNPGDISVEWTSNGHTEENYKDTAPVLDSDGSYFIY SKLNMKTSKWEKTDSFSCNVRHEGLKNYYLKKTISRSPGK (SEQ ID NO: 465) HC constant, mIgG2b DNA sequence GCCAAGACAACACCTCCTTCTGTGTATCCTCTGGCTCCTGGATGTGGAGATACAACAG GATCTTCTGTGACACTGGGATGTCTGGTGAAGGGATATTTTCCTGAATCTGTGACAGT GACATGGAACTCTGGATCTCTGTCTTCTTCTGTGCATACATTTCCTGCTCTGCTGCAGT CTGGACTGTATACAATGTCTTCTTCTGTGACAGTGCCTTCTTCTACATGGCCTTCTCAG ACAGTGACATGTTCTGTGGCTCATCCTGCTTCTTCTACAACAGTGGATAAGAAGCTGGA ACCTTCTGGACCTATCTCTACAATCAATCCTTGTCCTCCTTGTAAGGAATGTCATAAGT GTCCTGCTCCTAATCTGGAAGGAGGACCTTCTGTGTTTATCTTTCCTCCTAATATCAAG GATGTGCTGATGATCTCTCTGACACCTAAGGTGACATGTGTGGTGGTGGATGTGTCTG AAGATGATCCTGATGTGCAGATCTCTTGGTTTGTGAATAATGTGGAAGTGCATACAGCT CAGACACAGACACATAGAGAAGATTATAATTCTACAATCAGAGTGGTGTCTACACTGCC TATCCAGCATCAGGATTGGATGTCTGGAAAGGAATTTAAGTGTAAGGTGAATAATAAGG ATCTGCCTTCTCCTATCGAAAGAACAATCTCTAAGATCAAGGGACTGGTGAGAGCTCCT CAGGTGTATATCCTGCCTCCTCCTGCTGAACAGCTGTCCAGAAAGGATGTGTCTCTGA CATGTCTGGTGGTGGGATTTAATCCTGGAGATATCTCTGTGGAATGGACATCTAATGG ACATACAGAAGAAAATTATAAGGATACAGCTCCTGTGCTGGATTCTGATGGATCTTATT TTATCTATTCTAAGCTGAATATGAAGACATCTAAGTGGGAAAAGACAGATTCTTTTTCTTGTAATGTGAGACATGAAGGACTGAAGAATTATTATCTGAAGAAGACAATCTCCAGATCT CCTGGAAAGTGA (SEQ ID NO: 466) HC constant, mIgG2b amino acid sequence AKTTPPSVYPLAPGCGDTTGSSVTLGCLVKGYFPESVTVTWNSGSLSSSVHTFPALLQSG LYTMSSSVTVPSSTWPSQTVTCSVAHPASSTTVDKKLEPSGPISTINPCPPCKECHKCPAP NLEGGPSVFIFPPNIKDVLMISLTPKVTCVVVDVSEEDDPDVQISWFVNNVEVHTAQTQTHR EDYNSTIRVVSTLPIQHQDWMSGKEFKCKVNNKDLPSPIERTISKIKGLVRAPQVYILPPPAE QLSRKDVSLTCLVVGFNPGDISVEWTSNGHTEENYKDTAPVLDSDGSYFIYSKLNMKTSK WEKTDSFSCNVRHEGLKNYYLKKTISRSPGK (SEQ ID NO: 467) LC DNA sequence CAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCGC CATTTCTTGTTCTGGAAGCAACTCCAACATCGGAAATAATTACTTATACTGGTACCAGC AGATCCCAGGAACGACCCCCAAACTCCTCATCTATAGAAATAATCAGCGGCCCTCAGG GGTCCCTGACCGATTCTCTGCCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGT GGGCTCCGGTCCGGGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTG AGTGGGTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTAGGCCAACCTAAATCAT CTCCATCCGTTACTCTCTTCCCCCCATCTTCAGAAGAACTCGAAACCAATAAAGCCACA CTCGTTTGCACCATTACAGATTTCTATCCAGGAGTAGTTACAGTCGATTGGAAAGTAGA CGGAACACCAGTTACACAGGGTATGGAAACCACACAACCATCTAAGCAGTCTAATAAC AAATACATGGCCTCATCATACCTCACTCTTACCGCCCGCGCATGGGAAAGACATTCAT CATATTCTTGCCAGGTAACCCACGAAGGACACACAGTTGAAAAATCTTTGAGTAGAGCA GATTGTAGTTGA (SEQ ID NO: 468) LC amino acid sequence QSVLTQPPSASGTPGQRVAISCSGSNSNIGNNYLYWYQQIPGTTPKLLIYRNNQRPSGVPD RFSASKSGTSASLAISGLRSGDEADYYCAAWDDSLSGYVFGTGTKVTVLGQPKSSPSVTL FPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSY LTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS (SEQ ID NO: 469) LC constant, mLambda DNA sequence GGCCAACCTAAATCATCTCCATCCGTTACTCTCTTCCCCCCATCTTCAGAAGAACTCGA AACCAATAAAGCCACACTCGTTTGCACCATTACAGATTTCTATCCAGGAGTAGTTACAG TCGATTGGAAAGTAGACGGAACACCAGTTACACAGGGTATGGAAACCACACAACCATC TAAGCAGTCTAATAACAAATACATGGCCTCATCATACCTCACTCTTACCGCCCGCGCATGGGAAAGACATTCATCATATTCTTGCCAGGTAACCCACGAAGGACACACAGTTGAAAA ATCTTTGAGTAGAGCAGATTGTAGTTGA (SEQ ID NO: 470) LC constant, mLambda amino acid sequence GQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSK QSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS (SEQ ID NO: 471)

[0242] In one aspect, the disclosure provides an antigen binding protein that specifically binds to calcium voltage-gated channel accessory subunit gamma 1 (CACNG1), comprising: (i) a HCVR that comprises HCDR1, HCDR2, and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 1, 9, 17, 25, 33, 41, 49, 57, 65, 73, 81, 89, 97, 105, 113, 121, 129, 137, 429, or 451 (or a variant thereof); and / or (ii) a LCVR that comprises LCDR1, LCDR2, and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 5, 13, 21, 29, 37, 45, 53, 61, 69, 77, 85, 93, 101, 109, 117, 125, 133, 141, 437, or 459 (or a variant thereof).

[0243] In some embodiments, the antigen binding proteins described herein comprise: (1) an HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 1 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 5 (or a variant thereof); (2) an HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 9, and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 13 (or a variant thereof). (3) an LCVR comprising an HCVR comprising an HCDR1, an HCDR2, and an HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 17, and an LCVR comprising an LCDR1, an LCDR2, and an LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 21 (or a variant thereof); (4) an HCVR comprising an HCDR1, an HCDR2, and an HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 25 (or a variant thereof), and an LCVR comprising an amino acid sequence set forth in SEQ ID NO: 29 (or a variant thereof). (5) an LCVR comprising an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence shown in SEQ ID NO: 33 (or a variant thereof), and an LCVR comprising an LCDR1, LCDR2, and LCDR3 of an HCVR comprising the amino acid sequence shown in SEQ ID NO: 37 (or a variant thereof); (6) an HCVR comprising an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence shown in SEQ ID NO: 41 (or a variant thereof), and an LCVR comprising an HCDR1, HCDR2, and LCDR3 of an HCVR comprising the amino acid sequence shown in SEQ ID NO: 45 (7) an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence (or a variant thereof) set forth in SEQ ID NO: 49, and an HCVR comprising LCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence (or a variant thereof) set forth in SEQ ID NO: 53; (8) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence (or a variant thereof) set forth in SEQ ID NO: 57;and an LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 61 (or a variant thereof); (9) an HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 65 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 69 (or a variant thereof); (10) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 73 (or a variant thereof); and HCDR3, and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 77 (or a variant thereof); (11) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 81 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 85 (or a variant thereof); (12) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 89 (or a variant thereof). (12) an HCVR comprising HCDR1, HCDR2, and HCDR3 of CVR and LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 93 (or a variant thereof); (13) an HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 97 (or a variant thereof), and LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 101 (or a variant thereof); (14) an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 105 (14) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence (or a variant thereof) set forth in SEQ ID NO: 109, and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence (or a variant thereof) set forth in SEQ ID NO: 109; (15) an HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence (or a variant thereof) set forth in SEQ ID NO: 113, and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence (or a variant thereof) set forth in SEQ ID NO: 117;(16) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 121 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence shown in SEQ ID NO: 125 (or a variant thereof); (17) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 129 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence shown in SEQ ID NO: 133 (or a variant thereof); (18) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 137 (or a variant thereof); and (19) an LCVR comprising an HCVR comprising an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 429 (or a variant thereof), and an LCVR comprising an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 437 (or a variant thereof); or (20) an HCVR comprising an HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 451 (or a variant thereof), and an LCVR comprising an LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 459 (or a variant thereof).

[0244] In some embodiments, the antigen binding proteins described herein include (a) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 2 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 3 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 4 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 6 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 7 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 8 (or a variant thereof); (b) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 10 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 11 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 12 (or a variant thereof), and an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15 (or a variant thereof), and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 16 (or a variant thereof). (c) an LCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 18 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 19 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 20 (or a variant thereof), as well as an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 22 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 24 (or a variant thereof); (d) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28 (or a variant thereof), as well as an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 30 (or a variant thereof), and an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 31 (or a variant thereof);and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 32 (or a variant thereof); (e) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36 (or a variant thereof), as well as an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 38 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 39 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40 (or a variant thereof); (f) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 42 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 43 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 44 (or a variant thereof), as well as an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46 (or a variant thereof), and an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47 (or a variant thereof); and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48 (or a variant thereof); (g) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 50 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 51 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 52 (or a variant thereof), as well as an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 54 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 55 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56 (or a variant thereof); (h) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 58 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 59 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 60 (or a variant thereof), as well as an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 62 (or a variant thereof), and an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 63 (or a variant thereof);and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64 (or a variant thereof), (i) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 66 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68 (or a variant thereof), as well as an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 70 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 71 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72 (or a variant thereof), (j) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 74 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 75 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76 (or a variant thereof), as well as an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 78 (or a variant thereof), and an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 79 (or a variant thereof), and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 80 (or a variant thereof); (k) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 82 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 83 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 84 (or a variant thereof), as well as an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 86 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 87 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 88 (or a variant thereof); (l) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 90 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 91 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 92 (or a variant thereof), as well as an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94 (or a variant thereof), and an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95 (or a variant thereof);and an LCVR comprising an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96 (or a variant thereof), (m) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 98 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 99 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 100 (or a variant thereof), as well as an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 103 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 104 (or a variant thereof), (n) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 107 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 108 (or a variant thereof), as well as an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 110 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 111 (or a variant thereof), or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112 (or a variant thereof); (o) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 114 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 115 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116 (or a variant thereof), as well as an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 118 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 119 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof); (p) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 123 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 124 (or a variant thereof), and an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 126 (or a variant thereof);(q) an LCVR comprising an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 127 (or a variant thereof) and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128 (or a variant thereof); (q) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 131 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof); and an LCDR comprising the amino acid sequence set forth in SEQ ID NO: 134 (or a variant thereof). 1. LCVR comprising an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 (or a variant thereof) and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136 (or a variant thereof); (r) HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140 (or a variant thereof); and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 142 (or a variant thereof). an LCVR comprising an LCDR1, an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 143 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 144 (or a variant thereof); (s) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 431 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 433 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 435 (or a variant thereof); and an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 439 (or a variant thereof). an LCVR comprising an LCDR1, an LCDR2 comprising the amino acid sequence YNS (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 441 (or a variant thereof); or (t) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 453 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 455 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 457 (or a variant thereof), and an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 461 (or a variant thereof);It comprises an LCVR comprising an LCDR2 comprising the amino acid sequence RNN (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 463 (or a variant thereof).

[0245] In some embodiments, the antigen binding proteins described herein are selected from the group consisting of: (1) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 1 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 5 (or a variant thereof); (2) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 9, and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 13 (or a variant thereof); (3) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 17, and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 21 (or a variant thereof); (4) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 25 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 29 (or a variant thereof); (5) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 33 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 37 (or a variant thereof); (6) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 41 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 45 (or a variant thereof); (8) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 57 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 61 (or a variant thereof); (9) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 65 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 69 (or a variant thereof); (10) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 73 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 77 (or a variant thereof); (11) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 81 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 85 (or a variant thereof); or (12) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 89 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 93 (or a variant thereof); (13) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 97 (or a variant thereof);and LCVR having the amino acid sequence shown in SEQ ID NO: 101 (or a variant thereof), (14) HCVR having the amino acid sequence shown in SEQ ID NO: 105 (or a variant thereof), and LCVR having the amino acid sequence shown in SEQ ID NO: 109 (or a variant thereof), (15) HCVR having the amino acid sequence shown in SEQ ID NO: 113 (or a variant thereof), and LCVR having the amino acid sequence shown in SEQ ID NO: 117 (or a variant thereof), (16) HCVR having the amino acid sequence shown in SEQ ID NO: 121 (or a variant thereof), and LCVR having the amino acid sequence shown in SEQ ID NO: 125 (or a variant thereof), (17) the amino acid sequence shown in SEQ ID NO: 129 ( (17) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 138 (or a variant thereof), (18) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 141 (or a variant thereof), (19) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 429 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 437 (or a variant thereof), or (20) an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 451 (or a variant thereof) and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 459 (or a variant thereof).

[0246] In some embodiments, the antigen binding proteins described herein comprise: (a) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 145 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 146 (or a variant thereof); (b) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 147 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 148 (or a variant thereof); (c) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 149 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 150 (or a variant thereof); (d) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 151 (or a variant thereof) and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 152 (or a variant thereof); (e) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 153 (or a variant thereof) and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 154 (or a variant thereof); (f) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 155 (or a variant thereof) and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 156 (or a variant thereof); (g) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 156 (or a variant thereof); (h) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 159 (or a variant thereof) and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 160 (or a variant thereof); (i) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 161 (or a variant thereof) and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 162 (or a variant thereof); (j) an amino acid sequence set forth in SEQ ID NO: 163 (k) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 165 (or a variant thereof) and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 166 (or a variant thereof); (l) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 167 (or a variant thereof) and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 168 (or a variant thereof); (m) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 169 (or a variant thereof);and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 170 (or a variant thereof), (n) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 171 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 172 (or a variant thereof), (o) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 173 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 174 (or a variant thereof), (p) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 175 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 176 (or a variant thereof), (q) an amino acid sequence set forth in SEQ ID NO: 177 (r) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 179 (or a variant thereof) and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 180 (or a variant thereof); (s) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 443 (or a variant thereof) and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 447 (or a variant thereof); (t) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 465 (or a variant thereof) and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 469 (or a variant thereof).

[0247] The present disclosure further provides an anti-CACNG1 protein-drug conjugate comprising an antibody or antigen-binding fragment thereof that specifically binds to CACNG1 or an antigen-binding fragment thereof, comprising a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 1, 9, 17, 25, 33, 41, 49, 57, 65, 73, 81, 89, 97, 105, 113, 121, 129, 137, 429, or 451, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 5, 13, 21, 29, 37, 45, 53, 61, 69, 77, 85, 93, 101, 109, 117, 125, 133, 141, 437, or 459.

[0248] The present disclosure provides an anti-CACNG1 protein-drug conjugate comprising an isolated antibody or antigen-binding fragment thereof that specifically binds to CACNG1 or an antigenic fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises: (a) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 1, and a light chain variable region (LCVR) comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 5; (b) a heavy chain variable region (HCVR) comprising HCDR1, HCDR2, and LCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 9; (c) an LCVR comprising an HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 17, and an LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence set forth in SEQ ID NO: 21; (d) an HCDR1 and HCDR2 of a heavy chain variable region (HCVR) comprising the amino acid seque...

Claims

1. 1. An antigen binding protein that specifically binds to calcium voltage-gated channel accessory subunit gamma 1 (CACNG1), (i) an HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 1, 9, 17, 25, 33, 41, 49, 57, 65, 73, 81, 89, 97, 105, 113, 121, 129, 137, 429, or 451 (or a variant thereof); and / or (ii) An antigen binding protein comprising an LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 5, 13, 21, 29, 37, 45, 53, 61, 69, 77, 85, 93, 101, 109, 117, 125, 133, 141, 437, or 459 (or a variant thereof).

2. (1) An HCVR comprising HCDR1, HCDR2, and HCDR3 of an HCVR comprising the amino acid sequence shown in SEQ ID NO: 1 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of an LCVR comprising the amino acid sequence shown in SEQ ID NO: 5 (or a variant thereof); (2) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 9, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 13 (or a variant thereof); (3) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 17, and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 21 (or a variant thereof); (4) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 25 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence shown in SEQ ID NO: 29 (or a variant thereof); (5) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 33 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence shown in SEQ ID NO: 37 (or a variant thereof); (6) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 41 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 45 (or a variant thereof); (7) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 49 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence shown in SEQ ID NO: 53 (or a variant thereof); (8) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 57 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 61 (or a variant thereof); (9) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 65 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 69 (or a variant thereof); (10) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 73 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 77 (or a variant thereof); (11) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence shown in SEQ ID NO: 81 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence shown in SEQ ID NO: 85 (or a variant thereof); (12) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 89 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 93 (or a variant thereof); (13) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 97 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 101 (or a variant thereof); (14) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 105 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 109 (or a variant thereof); (15) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 113 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 117 (or a variant thereof); (16) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 121 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 125 (or a variant thereof); (17) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 129 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 133 (or a variant thereof); (18) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 137 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 141 (or a variant thereof); (19) HCVR comprising HCDR1, HCDR2, and HCDR3 of HCVR comprising the amino acid sequence set forth in SEQ ID NO: 429 (or a variant thereof), and LCVR comprising LCDR1, LCDR2, and LCDR3 of LCVR comprising the amino acid sequence set forth in SEQ ID NO: 437 (or a variant thereof); or (20) The antigen-binding protein of claim 1, comprising an HCVR comprising HCDR1, HCDR2, and HCDR3 of the HCVR comprising the amino acid sequence set forth in SEQ ID NO: 451 (or a variant thereof), and an LCVR comprising LCDR1, LCDR2, and LCDR3 of the LCVR comprising the amino acid sequence set forth in SEQ ID NO: 459 (or a variant thereof).

3. (a) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 2 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 3 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 4 (or a variant thereof); an LCVR comprising an LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 6 (or a variant thereof), an LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 7 (or a variant thereof), and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 8 (or a variant thereof); (b) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 10 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 11 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 12 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 14 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 15 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 16 (or a variant thereof); (c) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 18 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 19 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 20 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 22 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 23 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 24 (or a variant thereof); (d) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 26 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 27 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 28 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 30 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 31 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 32 (or a variant thereof); (e) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 38 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 39 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40 (or a variant thereof); (f) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 42 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 43 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 44 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 46 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 47 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 48 (or a variant thereof); (g) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 50 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 51 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 52 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 54 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 55 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 56 (or a variant thereof); (h) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 58 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 59 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 60 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 62 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 63 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64 (or a variant thereof); (i) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 66 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 67 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68 (or a variant thereof); an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 70 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 71 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72 (or a variant thereof); (j) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 74 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 75 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 78 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 79 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 80 (or a variant thereof); (k) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 82 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 83 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 84 (or a variant thereof); an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 86 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 87 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 88 (or a variant thereof); (l) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 90 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 91 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 92 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 94 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 95 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 96 (or a variant thereof); (m) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 98 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 99 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 100 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 103 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 104 (or a variant thereof); (n) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 106 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 107 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 108 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 110 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 111 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 112 (or a variant thereof); (o) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 114 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 115 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 116 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 118 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 119 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 102 (or a variant thereof); (p) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 122 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 123 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 124 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 126 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 127 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 128 (or a variant thereof); (q) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 130 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 131 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 132 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 134 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 135 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 136 (or a variant thereof); (r) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 138 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 139 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 140 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 142 (or a variant thereof), an LCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 143 (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 144 (or a variant thereof); (s) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 431 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 433 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 435 (or a variant thereof); and an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 439 (or a variant thereof), an LCDR2 comprising the amino acid sequence YNS (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 441 (or a variant thereof); or (t) an HCVR comprising an HCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 453 (or a variant thereof), an HCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 455 (or a variant thereof), and an HCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 457 (or a variant thereof); and 3. The antigen-binding protein of claim 1 or 2, comprising an LCVR comprising an LCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 461 (or a variant thereof), an LCDR2 comprising the amino acid sequence RNN (or a variant thereof), and an LCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 463 (or a variant thereof).

4. (1) An HCVR comprising the amino acid sequence shown in SEQ ID NO: 1 (or a variant thereof), and an LCVR comprising the amino acid sequence shown in SEQ ID NO: 5 (or a variant thereof); (2) HCVR comprising the amino acid sequence shown in SEQ ID NO: 9, and LCVR comprising the amino acid sequence shown in SEQ ID NO: 13 (or a variant thereof); (3) HCVR comprising the amino acid sequence shown in SEQ ID NO: 17, and LCVR comprising the amino acid sequence shown in SEQ ID NO: 21 (or a variant thereof); (4) HCVR comprising the amino acid sequence shown in SEQ ID NO: 25 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 29 (or a variant thereof); (5) HCVR comprising the amino acid sequence shown in SEQ ID NO: 33 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 37 (or a variant thereof); (6) HCVR comprising the amino acid sequence shown in SEQ ID NO: 41 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 45 (or a variant thereof); (7) HCVR comprising the amino acid sequence shown in SEQ ID NO: 49 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 53 (or a variant thereof); (8) HCVR comprising the amino acid sequence shown in SEQ ID NO: 57 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 61 (or a variant thereof); (9) HCVR comprising the amino acid sequence shown in SEQ ID NO: 65 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 69 (or a variant thereof); (10) HCVR comprising the amino acid sequence shown in SEQ ID NO: 73 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 77 (or a variant thereof); (11) HCVR comprising the amino acid sequence shown in SEQ ID NO: 81 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 85 (or a variant thereof); or (12) HCVR comprising the amino acid sequence shown in SEQ ID NO: 89 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 93 (or a variant thereof); (13) HCVR comprising the amino acid sequence shown in SEQ ID NO: 97 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 101 (or a variant thereof); (14) HCVR comprising the amino acid sequence shown in SEQ ID NO: 105 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 109 (or a variant thereof); (15) HCVR comprising the amino acid sequence shown in SEQ ID NO: 113 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 117 (or a variant thereof); (16) HCVR comprising the amino acid sequence shown in SEQ ID NO: 121 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 125 (or a variant thereof); (17) HCVR comprising the amino acid sequence shown in SEQ ID NO: 129 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 133 (or a variant thereof); (18) HCVR comprising the amino acid sequence shown in SEQ ID NO: 137 (or a variant thereof), and LCVR comprising the amino acid sequence shown in SEQ ID NO: 141 (or a variant thereof); (19) HCVR comprising the amino acid sequence set forth in SEQ ID NO: 429 (or a variant thereof), and LCVR comprising the amino acid sequence set forth in SEQ ID NO: 437 (or a variant thereof); or (20) The antigen-binding protein of any one of claims 1 to 3, comprising an HCVR comprising the amino acid sequence set forth in SEQ ID NO: 451 (or a variant thereof), and an LCVR comprising the amino acid sequence set forth in SEQ ID NO: 459 (or a variant thereof).

5. (a) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 145 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 146 (or a variant thereof); (b) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 147 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 148 (or a variant thereof); (c) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 149 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 150 (or a variant thereof); (d) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 151 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 152 (or a variant thereof); (e) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 153 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 154 (or a variant thereof); (f) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 155 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 156 (or a variant thereof); (g) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 157 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 158 (or a variant thereof); (h) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 159 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 160 (or a variant thereof); (i) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 161 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 162 (or a variant thereof); (j) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 163 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 164 (or a variant thereof); (k) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 165 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 166 (or a variant thereof); (l) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 167 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 168 (or a variant thereof); (m) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 169 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 170 (or a variant thereof); (n) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 171 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 172 (or a variant thereof); (o) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 173 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 174 (or a variant thereof); (p) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 175 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 176 (or a variant thereof); (q) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 177 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 178 (or a variant thereof); (r) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 179 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 180 (or a variant thereof); (s) a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 443 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 447 (or a variant thereof); or (t) the antigen-binding protein of any one of claims 1 to 4, comprising a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 465 (or a variant thereof), and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 469 (or a variant thereof).

6. An antigen-binding protein that binds to the same epitope on CACNG1 as an antibody comprising the HCVR / LCVR amino acid sequence pair shown in Table 1-1.

7. An antigen-binding protein that competes for binding to CACNG1 with an antibody comprising an HCVR / LCVR amino acid sequence pair shown in Table 1-1.

8. 8. The antigen-binding protein of claim 1, wherein the antigen-binding protein comprises an antibody or an antigen-binding fragment thereof.

9. 8. The antigen-binding protein of any one of claims 1 to 7, wherein the antigen-binding protein is a humanized antibody or antigen-binding fragment thereof, a human antibody or antigen-binding fragment thereof, a murine antibody or antigen-binding fragment thereof, a chimeric antibody or antigen-binding fragment thereof, a monovalent Fab', a bivalent Fab2, an F(ab)'3 fragment, a single-chain fragment variable (scFv), a bis-scFv, an (scFv)2, a diabody, a minibody, a nanobody, a triabody, a tetrabody, a disulfide-stabilized Fv protein (dsFv), a single domain antibody (sdAb), an Ig NAR, a single heavy chain antibody, a bispecific antibody or binding fragment thereof, a bispecific T-cell engager (BiTE), a trispecific antibody, or a chemically modified derivative thereof.

10. 10. The antigen binding protein of claim 9, wherein the antigen binding protein comprises a fragment antigen binding region (Fab).

11. 10. The antigen binding protein of claim 9, wherein the antigen binding protein comprises a single chain fragment variable (scFv).

12. 12. The antigen binding protein of claim 11, wherein the scFv comprises variable regions arranged from N-terminus to C-terminus in the following orientation: HCVR-LCVR.

13. 12. The antigen binding protein of claim 11, wherein the scFv comprises variable regions arranged from N-terminus to C-terminus in the following orientation: LCVR-HCVR.

14. The antigen-binding protein according to any one of claims 11 to 13, wherein the variable regions in the scFv are connected by a linker.

15. 15. The antigen-binding protein of claim 14, wherein the linker is a peptide linker.

16. The peptide linker is -(GGGGS) ｎ - (SEQ ID NO: 411), wherein n is any integer selected from 1 to 10.

17. 17. The antigen-binding protein of any one of claims 1 to 16, wherein the antigen-binding protein specifically binds to human CACNG1.

18. The antigen-binding protein is about 1 x 10 －７ K of M Ｄ 18. The antigen-binding protein of claim 17, which binds to human hCACNG1 with greater affinity than or equal to 18 .

19. The anti-hCACNG1 antibody or antigen-binding fragment thereof is about 1 x 10 －７ ~Approx. 1×10 －１０ K Ｄ 19. The antigen-binding protein of claim 18, which binds to hCACNG1 at

20. The anti-hCACNG1 antibody or antigen-binding fragment thereof is about 5 x 10 －９ ~Approx. 1×10 －１０ K Ｄ 19. The antigen-binding protein of claim 18, which binds to hCACNG1 at

21. An isolated polynucleotide encoding the antigen-binding protein of any one of claims 1 to 20.

22. A vector comprising the isolated polynucleotide of claim 21.

23. 23. A host cell comprising the antigen-binding protein of any one of claims 1 to 20, the isolated polynucleotide of claim 21, or the vector of claim 22.

24. 24. The host cell of claim 23, which is a Chinese hamster ovary (CHO) cell.

25. A protein-drug conjugate comprising an antigen-binding protein that specifically binds to calcium voltage-gated channel accessory subunit gamma 1 (CACNG1) and is conjugated to a molecular cargo.

26. 26. The protein-drug conjugate of claim 25, wherein the antigen-binding protein comprises an antigen-binding protein according to any one of claims 1 to 20.

27. The protein-drug conjugate of claim 25 or 26, wherein the antigen-binding protein and the molecular cargo are conjugated via a linker.

28. The protein-drug conjugate of any one of claims 25 to 27, wherein the molecular cargo comprises a polynucleotide molecule, a polypeptide molecule, a carrier, or a small molecule.

29. 29. The protein-drug conjugate of claim 28, wherein the molecular cargo comprises a polynucleotide molecule.

30. 30. The protein-drug conjugate of claim 29, wherein the polynucleotide molecule is an interfering nucleic acid molecule, a guide RNA, a ribozyme, an aptamer, a mixer, a multimer, or an mRNA.

31. The protein-drug conjugate of claim 30, wherein the interfering nucleic acid molecule is an siRNA, shRNA, miRNA, an antisense oligonucleotide, or a gapmer.

32. The protein-drug conjugate of claim 31 , wherein the interfering nucleic acid molecule is an siRNA.

33. The protein-drug conjugate of claim 32, wherein the siRNA comprises a sense strand that is 21 nucleotides in length.

34. The protein-drug conjugate of claim 32 or 33, wherein the siRNA comprises an antisense strand 23 nucleotides in length.

35. The protein-drug conjugate of any one of claims 32 to 34, wherein the siRNA comprises two phosphorothioate linkages in the first and second internucleoside linkages at the 5' end of the sense strand.

36. The protein-drug conjugate of any one of claims 32 to 35, wherein the siRNA comprises two phosphorothioate linkages in the first and second internucleoside linkages at the 3' and / or 5' end of the antisense strand.

37. 32. The protein-drug conjugate of claim 31, wherein the interfering nucleic acid is an antisense oligonucleotide.

38. The protein-drug conjugate of claim 30, wherein the polynucleotide molecule is a guide RNA.

39. 39. The protein-drug conjugate of any one of claims 29 to 38, wherein the polynucleotide molecule targets a gene or gene product associated with a skeletal muscle disease or disorder.

40. The gene or gene product associated with a skeletal muscle disease or disorder is double homeobox 4 (DUX4), myotonic dystrophy protein kinase (DMPK), dystrophin (DMD), F-box only protein 32 (FBX032), tripartite motif-containing 63 (TRIM63), inhibin subunit beta A (INHBA), myostatin (MSTN), myocyte enhancer factor 2D (MEF2D), KLF transcription factor 15 (KLF15), or a combination thereof. ), mediator complex subunit 1 (MED1), mediator complex subunit 13 (MED13), protein phosphatase 1 regulatory subunit 3A (PPP1R3A), myosin light chain kinase (MLCK1), activin A receptor type 1B (ACVR1B), type II SH2 domain-containing inositol 5-phosphatase (SHIP2), or a gene disclosed in Tables 1-3.

41. The protein-drug conjugate of any one of claims 29 to 40, wherein the polynucleotide molecule comprises one or more modified nucleotides.

42. 29. The protein-drug conjugate of claim 28, wherein the molecular cargo comprises a polypeptide molecule.

43. 43. The protein-drug conjugate of claim 42, wherein the polypeptide molecule is an enzyme or antigen-binding protein that binds to a target other than CACNG1.

44. 44. The protein-drug conjugate of claim 42 or 43, wherein the polypeptide molecule is associated with a skeletal muscle disease or disorder.

45. 29. The protein-drug conjugate of claim 28, wherein the molecular cargo comprises a small molecule.

46. 46. ​​The protein drug conjugate of claim 45, wherein the small molecule is an androgen, a glucocorticoid, a β2-adrenergic receptor agonist, rapamycin or an analog thereof, a MAPK inhibitor, or a histone deacetylase inhibitor.

47. 47. The protein-drug conjugate of claim 45 or 46, wherein the small molecule is an androgen.

48. 48. The protein-drug conjugate of claim 47, wherein the androgen is dihydrotestosterone (DHT).

49. The protein-drug conjugate of claim 45 or 46, wherein the small molecule is a glucocorticoid.

50. 50. The protein-drug conjugate of claim 49, wherein the glucocorticoid is budesonide.

51. 51. The protein-drug conjugate of any one of claims 28 and 45-50, wherein the antigen binding protein and the small molecule are conjugated via a valine-citrulline para-aminobenzylcarbamate (VC-PAB) and / or glutamic acid-valine-citrulline para-aminobenzylcarbamate (EVC-PAB) linker.

52. 52. A protein-drug conjugate according to any one of claims 25 to 51 for use in treating, preventing or reducing the likelihood of a skeletal muscle disease or disorder.

53. 53. The protein-drug conjugate of any one of claims 39, 40, 44, and 52, wherein the skeletal muscle disease or disorder is muscular dystrophy, muscular atrophy, inflammatory myopathy, a disease of peripheral nerves, a disease of the neuromuscular junction, a metabolic disease of muscle, central core disease, hyperthyroid myopathy, congenital myotonia, myotubular myopathy, nemaline myopathy, congenital paramyotonia, periodic paralysis-hypokalemia-hyperkalemia, centronuclear myopathy, distal Laing myopathy, myofibrillar myopathy, or a disease or disorder disclosed in Tables 1-3.

54. 54. The protein-drug conjugate of claim 53, wherein the muscular dystrophy is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), congenital muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, myotonic muscular dystrophy, or oculopharyngeal muscular dystrophy.

55. 54. The protein-drug conjugate of claim 53, wherein the muscle atrophy is spinal muscular atrophy, or muscle atrophy induced by cancer cachexia, disuse, heart failure, chronic obstructive pulmonary disease, or chronic infection.

56. 56. The protein-drug conjugate of claim 55, wherein the spinal muscular atrophy is amyotrophic lateral sclerosis (ALS), infantile progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, or adult spinal muscular atrophy.

57. 54. The protein-drug conjugate of claim 53, wherein the inflammatory myopathy is dermatomyositis, polymyositis, or inclusion body myositis.

58. 54. The protein-drug conjugate of claim 53, wherein the peripheral nerve disease is Charcot-Marie-Tooth disease, Dejerine-Sottas disease, or Friedreich's ataxia.

59. 54. The protein-drug conjugate of claim 53, wherein the neuromuscular junction disease is myasthenia gravis, Lambert-Eaton syndrome, or botulism.

60. 54. The protein-drug conjugate of claim 53, wherein the muscle metabolic disorder is acid maltase deficiency, carnitine deficiency, carnitine palmityltransferase deficiency, debranching enzyme deficiency, lactate dehydrogenase deficiency, mitochondrial myopathy, myoadenylate deaminase deficiency, phosphorylase deficiency, phosphofructokinase deficiency, or phosphoglycerate kinase deficiency.

61. 45. The protein-drug conjugate of any one of claims 42 to 44, wherein the polypeptide molecule is double homeobox 4 (DUX4), myotonic dystrophy protein kinase (DMPK), dystrophin (DMD), F-box only protein 32 (FBX032), tripartite motif-containing 63 (TRIM63), inhibin subunit beta A (INHBA), myostatin (MSTN), myocyte enhancer factor 2D (MEF2D), KLF transcription factor 15 (KLF15), mediator complex subunit 1 (MED1), mediator complex subunit 13 (MED13), protein phosphatase 1 regulatory subunit 3A (PPP1R3A), myosin light chain kinase (MLCK1), activin A receptor type 1B (ACVR1B), type II SH2 domain-containing inositol 5-phosphatase (SHIP2), or a protein disclosed in Tables 1-3.

62. 29. The protein-drug conjugate of claim 28, wherein the molecular cargo comprises a carrier.

63. 63. The protein-drug conjugate of claim 62, wherein the carrier is a lipid-based carrier.

64. 64. The protein-drug conjugate of claim 63, wherein the lipid-based carrier is a lipid nanoparticle (LNP), a liposome, a lipidoid, or a lipoplex.

65. 65. The protein-drug conjugate of claim 64, wherein the lipid-based carrier is a lipid nanoparticle (LNP).

66. The protein-drug conjugate of claim 65, wherein the LNP further comprises a polynucleotide molecule and / or a polypeptide molecule.

67. 67. The protein-drug conjugate of claim 65 or 66, wherein the LNP comprises one or more components of a gene editing system.

68. The LNP is (a) a Cas nuclease or a nucleic acid encoding said Cas nuclease, and / or (b) a guide RNA or one or more DNAs encoding said guide RNA.

69. 69. The protein-drug conjugate of claim 68, wherein the Cas nuclease is a Cas9 protein.

70. 70. The protein-drug conjugate of claim 69, wherein the Cas9 protein is derived from a Streptococcus pyogenes Cas9 protein, a Staphylococcus aureus Cas9 protein, a Campylobacter jejuni Cas9 protein, a Streptococcus thermophilus Cas9 protein, or a Neisseria meningitidis Cas9 protein.

71. 71. The protein-drug conjugate of any one of claims 68 to 70, wherein the nucleic acid encoding the Cas nuclease is codon-optimized for expression in a mammalian cell.

72. 72. The protein-drug conjugate of claim 71, wherein the nucleic acid encoding the Cas nuclease is codon-optimized for expression in a human cell.

73. 73. The protein-drug conjugate of any one of claims 68 to 72, wherein the nucleic acid encoding the Cas nuclease is mRNA.

74. 74. The protein-drug conjugate of any one of claims 30, 38-41, and 68-73, wherein the guide RNA is a single guide RNA (sgRNA).

75. 68. The protein-drug conjugate of claim 67, wherein the LNP comprises a zinc finger nuclease (ZFN) or a transcription activator-like effector nuclease (TALEN).

76. The protein-drug conjugate of any one of claims 65 to 75, wherein the LNP comprises a cationic lipid, a neutral lipid, a helper lipid, a stealth lipid, or any combination thereof.

77. 77. The protein-drug conjugate of claim 76, wherein the neutral lipid is distearoylphosphatidylcholine (DSPC).

78. 77. The protein-drug conjugate of claim 76, wherein the helper lipid is cholesterol.

79. 77. The protein-drug conjugate of claim 76, wherein the stealth lipid is PEG2k-DMG.

80. 80. A pharmaceutical composition comprising the antigen-binding protein of any one of claims 1 to 20, the isolated polynucleotide of claim 21, the vector of claim 22, or the protein-drug conjugate of any one of claims 25 to 79, and a pharmaceutically acceptable carrier.

81. 81. A composition or kit comprising the antigen-binding protein of any one of claims 1 to 20, the isolated polynucleotide of claim 21, the vector of claim 22, the protein-drug conjugate of any one of claims 25 to 79, or the pharmaceutical composition of claim 80, and a further therapeutic agent.

82. 80. A complex comprising the antigen binding protein of any one of claims 1 to 20 or the protein-drug conjugate of any one of claims 25 to 79 bound to calcium voltage-gated channel accessory subunit gamma 1 (CACNG1).

83. 21. A method for producing an antigen binding protein according to any one of claims 1 to 20, comprising culturing a host cell comprising a polynucleotide encoding said antigen binding protein in a culture medium under conditions favouring expression of said antigen binding protein.

84. (a) introducing the polynucleotide into a host cell; (b) culturing said host cells under conditions favorable for expression of said antigen binding protein; (c) optionally isolating the antigen binding protein from the culture medium and / or host cell; (d) optionally conjugating said antigen binding protein to a molecular cargo.

85. 85. An antigen binding protein produced or obtainable by the method of claim 83 or claim 84.

86. (a) contacting said antigen binding protein with said molecular cargo under conditions favoring conjugation of said antigen binding protein to said molecular cargo; (b) optionally isolating the protein-drug conjugate produced in step (a).

87. the molecular cargo comprises a polypeptide molecule; (a) culturing a host cell comprising a polynucleotide encoding said protein-drug conjugate under conditions that allow expression of said protein-drug conjugate; (b) optionally isolating the protein-drug conjugate produced in step (a).

88. 88. A protein-drug conjugate produced or obtainable by the method of claim 86 or 87.

89. 88. A container or injection device comprising an antigen-binding protein according to any one of claims 1 to 20 and 85, an isolated polynucleotide according to claim 21, a vector according to claim 22, or a protein-drug conjugate according to any one of claims 25 to 79 and 88.

90. 100. A method for imaging skeletal muscle in a subject in need thereof, said method comprising introducing into the body of said subject an antigen binding protein of any one of claims 1 to 20 and 85, wherein said antigen binding protein is conjugated to a detectable biosensor or radioisotope.

91. 91. The method of claim 90, wherein the radioisotope comprises a radionuclide.

92. 92. The method of claim 90 or 91, wherein the antigen binding protein conjugated to a detectable biosensor or radioisotope is introduced to the subject via intramuscular, intravenous, or subcutaneous administration.

93. 86. A method for causing internalization of a small molecule by a muscle fiber, comprising contacting said muscle fiber with an antigen binding protein of any one of claims 1 to 20 and 85, wherein said antigen binding protein is conjugated to a small molecule.

94. 94. The method of claim 93, wherein the small molecule is an androgen, a glucocorticoid, a β2-adrenergic receptor agonist, rapamycin or an analog thereof, a MAPK inhibitor, or a histone deacetylase inhibitor.

95. 95. The method of claim 93 or 94, wherein the small molecule is an androgen.

96. 96. The protein-drug conjugate of claim 95, wherein the androgen is dihydrotestosterone (DHT).

97. 95. The protein-drug conjugate of claim 93 or 94, wherein the small molecule is a glucocorticoid.

98. 98. The protein-drug conjugate of claim 97, wherein the glucocorticoid is budesonide.

99. 94. The method of claim 93, wherein the small molecule comprises a detectable biosensor or a radioisotope.

100. 94. The method of claim 93, wherein the radioisotope comprises a radionuclide.

101. 101. The method of any one of claims 93-100, wherein said contacting comprises administering said antigen binding protein conjugated to said small molecule intramuscularly, intravenously, or subcutaneously in a subject in need thereof.

102. 101. The method of any one of claims 93-100, wherein said contacting comprises culturing said muscle fibers in vitro with said antigen binding protein conjugated to said small molecule.

103. 103. The method of any one of claims 93 to 102, wherein said antigen binding protein is conjugated to said small molecule via a valine-citrulline para-aminobenzylcarbamate (VC-PAB) and / or glutamic acid-valine-citrulline para-aminobenzylcarbamate (EVC-PAB) linker.

104. 100. A method for administering an antigen binding protein according to any one of claims 1 to 20 and 85, an isolated polynucleotide according to claim 21, a vector according to claim 22, or a protein-drug conjugate according to any one of claims 25 to 79 and 88 in a subject in need thereof, said method comprising introducing said antigen binding protein, said polynucleotide, said vector or said protein-drug conjugate into the body of said subject.

105. 105. The method of claim 104, wherein the antigen binding protein, the polynucleotide, the vector, or the protein-drug conjugate is introduced into the subject's body via intramuscular, subcutaneous, or intravenous administration.

106. 87. A method for delivering molecular cargo to skeletal muscle tissues and / or cells in the body in a subject in need thereof, the method comprising administering to said subject a protein-drug conjugate according to any one of claims 25 to 79 and 88 or a pharmaceutical composition according to claim 80.

107. 10. A method for treating, preventing or reducing the likelihood of a skeletal muscle disease or disorder in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of the antigen binding protein of any one of claims 1 to 20 and 85, the isolated polynucleotide of claim 21, the vector of claim 22, the protein-drug conjugate of any one of claims 25 to 79 and 88, or the pharmaceutical composition of claim 80.

108. 108. The method of claim 107, wherein the antigen binding protein, the polynucleotide, the vector, or the protein-drug conjugate is administered via intramuscular, subcutaneous, or intravenous administration.

109. 109. The method of claim 107 or 108, wherein the skeletal muscle disease or disorder is muscular dystrophy, muscular atrophy, inflammatory myopathy, a disease of the peripheral nerve, a disease of the neuromuscular junction, a metabolic disease of muscle, central core disease, hyperthyroid myopathy, congenital myotonia, myotubular myopathy, nemaline myopathy, congenital paramyotonia, periodic paralysis-hypokalemia-hyperkalemia, centronuclear myopathy, distal Laing myopathy, myofibrillar myopathy, or a disease or disorder disclosed in Tables 1-3.

110. 110. The method of claim 109, wherein the muscular dystrophy is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), congenital muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, myotonic muscular dystrophy, or oculopharyngeal muscular dystrophy.

111. 110. The method of claim 109, wherein the muscle atrophy is spinal muscular atrophy, or muscle atrophy induced by cancer cachexia, disuse, heart failure, chronic obstructive pulmonary disease, or chronic infection.

112. 112. The method of claim 111, wherein the spinal muscular atrophy is amyotrophic lateral sclerosis (ALS), infantile progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, or adult spinal muscular atrophy.

113. 110. The method of claim 109, wherein the inflammatory myopathy is dermatomyositis, polymyositis, or inclusion body myositis.

114. 110. The method of claim 109, wherein the peripheral nerve disease is Charcot-Marie-Tooth disease, Dejerine-Sottas disease, or Friedreich's ataxia.

115. 110. The method of claim 109, wherein the neuromuscular junction disease is myasthenia gravis, Lambert-Eaton syndrome, or botulism.

116. 110. The method of claim 109, wherein the muscle metabolic disorder is acid maltase deficiency, carnitine deficiency, carnitine palmityltransferase deficiency, debranching enzyme deficiency, lactate dehydrogenase deficiency, mitochondrial myopathy, myoadenylate deaminase deficiency, phosphorylase deficiency, phosphofructokinase deficiency, or phosphoglycerate kinase deficiency.

117. 117. The method of any one of claims 107 to 116, further comprising administering to the subject an additional treatment.

118. 118. The method of claim 117, wherein the additional treatment comprises physical exercise.

119. 118. The method of claim 117, wherein the additional treatment comprises administering testosterone and / or glucocorticoids.

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