Anti-ACVR2A antibodies and uses thereof

Abstract

Anti-ACVR2A antibodies or antigen-binding fragments thereof and their use for inhibiting or antagonizing ACVR2A. The antibodies and antigen-binding fragments may be used in therapeutic methods for treating ACVR2A or ACVR2A ligand-related diseases or disorders, which diseases or disorders are ameliorated or improved by inhibition of ACVR2A.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to International Application No. PCT / CN2021 / 116485, filed September 3, 2021, the disclosure of which is incorporated herein by reference in its entirety.

[0002] Sequence Listing This application contains a computer-readable sequence listing submitted herewith in XML file format, the entire contents of which are incorporated herein by reference in their entirety. The sequence listing XML file submitted herewith is entitled "14668-008-228_seqlist.xml", was created on August 27, 2022, and is 91,313 bytes in size.

[0003] 1.Technical Field Provided herein are molecules capable of binding to ACVR2A, pharmaceutical compositions comprising same, and uses thereof. [Background technology]

[0004] 2.Background technology Activin receptor type 2A (ACVR2A) is a receptor that mediates the functions of activin, among other biological activities. Activin is a dimeric growth and differentiation factor that belongs to the transforming growth factor-β (TGF-β) superfamily of structurally related signaling proteins. Activin signals through a heteromeric complex of receptor serine kinases, including type I and type II receptors, all of which are transmembrane proteins composed of a ligand-binding extracellular domain with a cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with serine / threonine specificity. Type I receptors are essential for signal transduction; type II receptors are required for ligand binding and phosphorylation of the type I receptor. While the type II receptor ACVR2A has been implicated in various disease states, there is a need in the art for improved antibody therapies targeting ACVR2A. Summary of the Invention

[0005] 3. Summary of the Invention In one aspect, provided herein is an antibody or antigen-binding fragment thereof that selectively binds to ACVR2A. In some embodiments, the antibody provided herein binds to ACVR2A more than ACVR2B. In some embodiments, the affinity of the antibody or antigen-binding fragment provided herein for ACVR2A is at least 10-fold greater than its affinity for ACVR2B. The present disclosure provides methods of using ACVR2A-binding proteins. In some embodiments, the ACVR2A-binding protein can inhibit or block the binding of ACVR2A to ACVR2A ligands, such as activin A, activin B, GDF8, and GDF11. In some embodiments, the antibody or antigen-binding fragment provided herein comprises: (i) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 1, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2; (ii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 3, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2; (iii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 4, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2; (iv) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 5, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 6; (v) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 6; (vi) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 8, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 6; (vii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 9, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2; (viii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 10, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2; (ix) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 11, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2; (x) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2; (xi) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 13, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2; (xii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 14; (xiii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 15; (xiv) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2; (xv) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 16; (xvi) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 17; (xvii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 18; (xviii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 19; (xix) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 20; (xx) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 21; (xxi) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 22; (xxii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 23; (xxiii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 24; (xxiv) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 6; (xxv) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 25; (xxvi) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 26; (xxvii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 27; (xxviii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 28; (xxix) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 29; (xxx) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 11, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 30; (xxxi) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 31; (xxxii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 32; (xxxiii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 33; (xxxiv) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 9, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 34; (xxxv) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 11, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 35; (xxxvi) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 11, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 36; (xxxvii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 11, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 37; (xxxviii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 38; (xxxix) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 39; (xxxx) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 40; or (xxxxi) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 9, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 41.

[0006] In some embodiments, the antibodies or antigen-binding fragments provided herein comprise: (i) HCDR1 comprises the amino acid sequence of SEQ ID NO: 42, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (ii) HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; or (iii) HCDR1 comprises the amino acid sequence of SEQ ID NO: 49, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (iv) HCDR1 comprises the amino acid sequence of SEQ ID NO: 50, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 52, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 53, or (v) HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 52, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 53, or (vi) HCDR1 comprises the amino acid sequence of SEQ ID NO: 49, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 52, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 53; or (vii) HCDR1 comprises the amino acid sequence of SEQ ID NO: 54, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; or (viii) HCDR1 comprises the amino acid sequence of SEQ ID NO: 55, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; or (ix) HCDR1 comprises the amino acid sequence of SEQ ID NO: 56, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (x) HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xi) HCDR1 comprises the amino acid sequence of SEQ ID NO: 58, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; or (xii) HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 59, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xiii) HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 60, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xiv) HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xv) HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 61, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; or (xvi) HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 62, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; or (xvii) HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 63, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xviii) HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 52, LCDR2 comprises the amino acid sequence of SEQ ID NO: 82, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xix) HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 64, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; or (xx) HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 65, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xxi) HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 66, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; or (xxii) HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 59, LCDR2 comprises the amino acid sequence of SEQ ID NO: 67, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; or (xxiii) HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 59, LCDR2 comprises the amino acid sequence of SEQ ID NO: 68, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xxiv) HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 52, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 53, or (xxv) HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 59, LCDR2 comprises the amino acid sequence of SEQ ID NO: 69, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xxvi) HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 59, LCDR2 comprises the amino acid sequence of SEQ ID NO: 70, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xxvii) HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 71, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xxviii) HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 72, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xxix) HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 73, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xxx) HCDR1 comprises the amino acid sequence of SEQ ID NO: 56, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 74, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xxxi) HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 75, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xxxii) HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 67, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xxxiii) HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 68, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xxxiv) HCDR1 comprises the amino acid sequence of SEQ ID NO: 54, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 76, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; or (xxxv) HCDR1 comprises the amino acid sequence of SEQ ID NO: 56, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 77, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; or (xxxvi) HCDR1 comprises the amino acid sequence of SEQ ID NO: 56, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 78, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xxxvii) HCDR1 comprises the amino acid sequence of SEQ ID NO: 56, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 79, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; or (xxxviii) HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 69, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xxxix) HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 80, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xxxx) HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 70, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47, or (xxxxi) HCDR1 comprises the amino acid sequence of SEQ ID NO: 54, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 81, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47.

[0007] In some embodiments, the antibodies or antigen-binding fragments provided herein comprise: (i) a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: 2; (ii) a VH comprising the amino acid sequence of SEQ ID NO: 3 and a VL comprising the amino acid sequence of SEQ ID NO: 2; (iii) VH comprising the amino acid sequence of SEQ ID NO: 4 and VL comprising the amino acid sequence of SEQ ID NO: 2; (iv) VH comprising the amino acid sequence of SEQ ID NO: 5 and VL comprising the amino acid sequence of SEQ ID NO: 6; (v) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 6; (vi) a VH comprising the amino acid sequence of SEQ ID NO: 8 and a VL comprising the amino acid sequence of SEQ ID NO: 6; (vii) a VH comprising the amino acid sequence of SEQ ID NO: 9 and a VL comprising the amino acid sequence of SEQ ID NO: 2; (viii) VH comprising the amino acid sequence of SEQ ID NO: 10 and VL comprising the amino acid sequence of SEQ ID NO: 2; (ix) a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 2; (x) a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 2; (xi) a VH comprising the amino acid sequence of SEQ ID NO: 13 and a VL comprising the amino acid sequence of SEQ ID NO: 2; (xii) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 14; (xiii) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 15; (xiv) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 2; (xv) VH comprising the amino acid sequence of SEQ ID NO: 12 and VL comprising the amino acid sequence of SEQ ID NO: 16; (xvi) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 17; (xvii) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 18; (xviii) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 19; (xix) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 20; (xx) VH comprising the amino acid sequence of SEQ ID NO: 12 and VL comprising the amino acid sequence of SEQ ID NO: 21; (xxi) a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 22; (xxii) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 23; (xxiii) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 24; (xxiv) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 6; (xxv) VH comprising the amino acid sequence of SEQ ID NO: 12 and VL comprising the amino acid sequence of SEQ ID NO: 25; (xxvi) VH comprising the amino acid sequence of SEQ ID NO: 12 and VL comprising the amino acid sequence of SEQ ID NO: 26; (xxvii) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 27; (xxviii) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 28; (xxix) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 29; (xxx) VH comprising the amino acid sequence of SEQ ID NO: 11 and VL comprising the amino acid sequence of SEQ ID NO: 30; (xxxi) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 31; (xxxii) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 32; (xxxiii) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 33; (xxxiv) VH comprising the amino acid sequence of SEQ ID NO: 9 and VL comprising the amino acid sequence of SEQ ID NO: 34; (xxxv) VH comprising the amino acid sequence of SEQ ID NO: 11 and VL comprising the amino acid sequence of SEQ ID NO: 35; (xxxvi) VH comprising the amino acid sequence of SEQ ID NO: 11 and VL comprising the amino acid sequence of SEQ ID NO: 36; (xxxvii) VH comprising the amino acid sequence of SEQ ID NO: 11 and VL comprising the amino acid sequence of SEQ ID NO: 37; (xxxviii) VH comprising the amino acid sequence of SEQ ID NO: 12 and VL comprising the amino acid sequence of SEQ ID NO: 38; (xxxix) VH comprising the amino acid sequence of SEQ ID NO: 12 and VL comprising the amino acid sequence of SEQ ID NO: 39; (xxxx) a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 40; or (xxxxi) VH comprising the amino acid sequence of SEQ ID NO: 9 and VL comprising the amino acid sequence of SEQ ID NO: 41.

[0008] In some embodiments, the antibodies provided herein are IgG. In some embodiments, the antibodies are humanized antibodies.

[0009] In some embodiments, the antibody or antigen-binding fragment thereof is genetically fused or chemically conjugated to the agent.

[0010] In another aspect, provided herein are nucleic acid molecules encoding the antibodies or antigen-binding fragments provided herein.

[0011] In another aspect, provided herein is a vector comprising a nucleic acid molecule encoding an antibody or antigen-binding fragment provided herein.

[0012] In yet another aspect, provided herein is a host cell transformed with a vector encoding the antibody or antigen-binding fragment provided herein.

[0013] In yet another aspect, provided herein is a composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment provided herein, a nucleic acid molecule, or a vector encoding an antibody or antigen-binding fragment provided herein, and a pharmaceutically acceptable excipient.

[0014] In yet another aspect, provided herein is a method of treating a disease or disorder in a subject, the method comprising administering a composition provided herein to the subject. In some embodiments, the method further comprises administering a second agent to the subject. In some embodiments, the disease or disorder is associated with ACVR2A. In some embodiments, the disease or disorder is associated with ACVR2A ligands, including activins (e.g., activin A, activin B, activin AB, activin C, activin AC, and activin E), growth / differentiation factors (GDFs, such as GDF1, GDF3, GDF5, GDF6, GDF7, GDF8, GDF10, and GDF11), and bone morphogenetic proteins (BMPs, such as BMP2, BMP4, BMP6, BMP7, BMP8a, BMP8b, BMP9, and BMP10).

[0015] The method according to any one of claims 11 to 13, wherein the disease or disorder is associated with ACVR2A.

[0016] In some embodiments, the disease or disorder is a musculoskeletal disease or disorder. In some embodiments, the musculoskeletal disease or disorder is selected from the group consisting of anemia, muscle atrophy, spinal muscular atrophy, and cancer cachexia. In some embodiments, the disease or disorder is an age-related condition selected from the group consisting of sarcopenia, skin atrophy, muscle wasting, brain atrophy, atherosclerosis, arteriosclerosis, emphysema, osteoporosis, osteoarthritis, immunodeficiency, hypertension, dementia, Huntington's disease, Alzheimer's disease, cataracts, age-related macular degeneration, prostate cancer, stroke, reduced life expectancy, frailty, memory loss, wrinkles, renal dysfunction, and age-related hearing loss. In some embodiments, the disease or disorder is a metabolic disorder selected from the group consisting of type II diabetes, metabolic syndrome, hyperglycemia, nonalcoholic steatohepatitis (NASH), and obesity. In some embodiments, the disease or disorder is selected from the group consisting of acute and / or chronic kidney disease or renal failure, liver fibrosis or cirrhosis, pulmonary fibrosis, pulmonary arterial hypertension, cancer, renal fibrosis, Parkinson's disease, amyotrophic lateral sclerosis (ALS), brain atrophy, dementia and anemia, cachexia, sarcoma, bone loss, hi some embodiments, the disease or disorder is cancer, including ovarian cancer, breast cancer, esophageal cancer, head and neck cancer, lung cancer, melanoma, multiple myeloma, colon cancer, hepatocellular carcinoma, pancreatic cancer, endometrial cancer, and gastrointestinal cancer.

[0017] In yet another aspect, provided herein is a method of inhibiting or antagonizing ACVR2A in a cell, the method comprising contacting the cell with a composition provided herein. [Brief explanation of the drawings]

[0018] 4. Brief description of the drawings [Figure 1A] Figures 1A-1D show activin A competitive ELISA assays of ACVR2A hits. Anti-ACVR2A hits from the CDRL1 and CDRL2 random mutation phage display library bind to ACVR2A and block the interaction between activin A and ACVR2A. Figure 1A: Anti-ACVR2A Fab hits from the CDRL1 mutation library. [Figure 1B]Figures 1A-1D show activin A competitive ELISA assays of ACVR2A hits. Anti-ACVR2A hits from the CDRL1 and CDRL2 random mutation phage display library bind to ACVR2A and block the interaction between activin A and ACVR2A. Figure 1B: Anti-ACVR2A Fab hits from the CDRL2 mutation library. [Figure 1C] Figures 1A-1D show activin A competitive ELISA assays of ACVR2A hits. Anti-ACVR2A hits from the CDRL1 and CDRL2 random mutation phage display library bind to ACVR2A and block the interaction between activin A and ACVR2A. Figure 1C: Anti-ACVR2A IgG hits from the CDRL1 and CDRL2 mutation library. [Figure 1D] Figures 1A-1D show activin A competitive ELISA assays of ACVR2A hits. Anti-ACVR2A hits from the CDRL1 and CDRL2 random mutation phage display library bind to ACVR2A and block the interaction between activin A and ACVR2A. Figure 1D: Anti-ACVR2A IgG hits generated by the CDR shuffling method. [Figure 2A] Figures 2A-D show phospho-Smad-dependent reporter gene assays of ACVR2A hits. The ACVR2B knockout stable cell line HEK293T-B1 was transfected with the CAGA-12 luciferase reporter plasmid and incubated overnight with the IgG hits and activin A to test luciferase signaling. Figure 2A: Hits J, 21047, 21155, 21169, 21341, 21343, 21366, and 275 inhibited activin A-induced phospho-Smad-dependent signaling. [Figure 2B]Figures 2A-2D show phospho-Smad-dependent reporter gene assays of ACVR2A hits. The ACVR2B knockout stable cell line HEK293T-B1 was transfected with the CAGA-12 luciferase reporter plasmid and incubated overnight with the IgG hits and activin A to test luciferase signaling. Figures 2B and 2C show that the CDR-shuffled IgG hits NGS-1, NGS-2, NGS-3, NGS-4, NGS-5, 6401, 6403, 3351, 3352, 3353, 3354, and 3355 inhibited activin A-induced phospho-Smad-dependent signaling. [Figure 2C] Figures 2A-2D show phospho-Smad-dependent reporter gene assays of ACVR2A hits. The ACVR2B knockout stable cell line HEK293T-B1 was transfected with the CAGA-12 luciferase reporter plasmid and incubated overnight with the IgG hits and activin A to test luciferase signaling. Figures 2B and 2C show that the CDR-shuffled IgG hits NGS-1, NGS-2, NGS-3, NGS-4, NGS-5, 6401, 6403, 3351, 3352, 3353, 3354, and 3355 inhibited activin A-induced phospho-Smad-dependent signaling. [Figure 2D] Figures 2A-D show phospho-Smad-dependent reporter gene assays of ACVR2A hits. The ACVR2B knockout stable cell line HEK293T-B1 was transfected with the CAGA-12 luciferase reporter plasmid and tested for luciferase signaling after overnight incubation with IgG hits and activin A. Figure 2D: Hits J, 275, 21155, 21169, 21341, 21343, 21366, and 6401 inhibited GDF8-induced phospho-Smad-dependent signaling. [Figure 3]Phospho-Smad3 inhibition by IgG hits in C2C12 cells. The level of Smad3 phosphorylation in satellite cells C2C12 treated for 30 minutes in the presence of activin A (50 ng / ml) alone (PBS) and in combination with ACVE2A Ab hits was quantified using an HTRF protocol. Hits J, 21155, 21169, 21341, 275, and 6401 reduced phospho-Smad3 levels induced by activin A. [Figure 4A] As shown in Figures 4A-4D, ACVR2A Ab increased body and muscle weight in mice. Naive SCID mice were treated with 20 mg / kg of ACVR2A Ab LA01 once a week for 28 days. Figure 4A: Body weight change growth curves are presented as mean ± SEM (n = 8). Ab LA01 treatment significantly increased body weight. [Figure 4B] As shown in Figures 4A-4D, ACVR2A Ab increased body and muscle weight in mice. Naive SCID mice were treated with 20 mg / kg of ACVR2A Ab LA01 once a week for 28 days. Figure 4B: Tibialis anterior muscle weight increased with Ab LA01 treatment. [Figure 4C] As shown in Figures 4A-4D, ACVR2A Ab increased body and muscle weight in mice. Naive SCID mice were treated with 20 mg / kg of ACVR2A Ab LA01 once a week for 28 days. Figure 4C: Changes in inguinal adipose tissue weight. [Figure 4D] As shown in Figures 4A-4D, ACVR2A Ab increased body and muscle weight in mice. Naive SCID mice were treated with 20 mg / kg of ACVR2A Ab LA01 once a week for 28 days. Figure 4D: Changes in epididymal adipose tissue weight. *, P<0.05 vs. isotype control; **, P<0.01 vs. control; ***, P<0.001 vs. control (Student's t-test). [Figure 5A]As shown in Figures 5A-5C, ACVR2A Ab increased body and muscle weight in wild-type mice. C57BL / 6 mice were treated with 10 mg / kg of ACVR2A Ab LA01 twice weekly for 6 weeks. Figure 5A: Body weight change growth curves are presented as mean ± SEM (n = 8). [Figure 5B] As shown in Figures 5A-5C, ACVR2A Ab increased body and muscle weight in wild-type mice. C57BL / 6 mice were treated with 10 mg / kg of ACVR2A Ab LA01 twice weekly for 6 weeks. Figure 5B: Ab LA01 increased tibialis anterior muscle weight. [Figure 5C] As shown in Figures 5A-5C, ACVR2A Ab increased body and muscle weight in wild-type mice. C57BL / 6 mice were treated with 10 mg / kg of ACVR2A Ab LA01 twice weekly for 6 weeks. Figure 5C: Ab LA01 increased gastrocnemius muscle weight change. *, P<0.05 vs. isotype control; **, P<0.01 vs. control; ***, P<0.001 vs. control (Student's t-test). [Figure 6A] As shown in Figures 6A-6G, ACVR2A Ab promotes red blood cell formation. C57BL / 6 mice were treated with 10 mg / kg of ACVR2A Ab LA01 and / or ACVR2B Trap ACE-536 twice weekly for 2 weeks. After 7 days of treatment, ACVR2B Trap ACE-536 alone or in combination with ACVR2A Ab LA01 increased red blood cell count (Figure 6A), hemoglobin (Figure 6B), and hematocrit (Figure 6C). In contrast, 7 days of treatment with Ab LA01 alone had little effect on red blood cell maturation (Figures 6A, 6B, and 6C). However, 7 days of treatment with Ab LA01 significantly increased reticulocyte count. [Figure 6B]As shown in Figures 6A-6G, ACVR2A Ab promotes red blood cell formation. C57BL / 6 mice were treated with 10 mg / kg of ACVR2A Ab LA01 and / or ACVR2B Trap ACE-536 twice weekly for 2 weeks. After 7 days of treatment, ACVR2B Trap ACE-536 alone or in combination with ACVR2A Ab LA01 increased red blood cell count (Figure 6A), hemoglobin (Figure 6B), and hematocrit (Figure 6C). In contrast, 7 days of treatment with Ab LA01 alone had little effect on red blood cell maturation (Figures 6A, 6B, and 6C). However, 7 days of treatment with Ab LA01 significantly increased reticulocyte count. [Figure 6C] As shown in Figures 6A-6G, ACVR2A Ab promotes red blood cell formation. C57BL / 6 mice were treated with 10 mg / kg of ACVR2A Ab LA01 and / or ACVR2B Trap ACE-536 twice weekly for 2 weeks. After 7 days of treatment, ACVR2B Trap ACE-536 alone or in combination with ACVR2A Ab LA01 increased red blood cell count (Figure 6A), hemoglobin (Figure 6B), and hematocrit (Figure 6C). In contrast, 7 days of treatment with Ab LA01 alone had little effect on red blood cell maturation (Figures 6A, 6B, and 6C). However, 7 days of treatment with Ab LA01 significantly increased reticulocyte count. [Figure 6D] As shown in Figures 6A-6G, ACVR2A Ab promotes red blood cell formation. C57BL / 6 mice were treated with 10 mg / kg of ACVR2A Ab LA01 and / or ACVR2B Trap ACE-536 twice weekly for 2 weeks. After 7 days of treatment, ACVR2B Trap ACE-536 alone or in combination with ACVR2A Ab LA01 increased red blood cell count (Figure 6A), hemoglobin (Figure 6B), and hematocrit (Figure 6C). In contrast, 7 days of treatment with Ab LA01 alone had little effect on red blood cell maturation (Figures 6A, 6B, and 6C). However, 7 days of treatment with Ab LA01 significantly increased reticulocyte count. [Figure 6E]As shown in Figures 6A-6G, ACVR2A Abs promote red blood cell hematopoiesis. C57BL / 6 mice were treated with 10 mg / kg of ACVR2A Ab LA01 and / or ACVR2B Trap ACE-536 twice weekly for 2 weeks. After 14 days of treatment, Ab LA01 promoted hematopoiesis similar to ACE-536, including red blood cell count (Figure 6E), hemoglobin (Figure 6F), and hematocrit (Figure 6G). Combination treatment with Ab LA01 and ACE-536 was more effective in hematopoiesis than either single agent treatment (Figures 6E-6G). Mean ± SEM is shown. *, P<0.05 vs. isotype control; **, P<0.01 vs. control; ***, P<0.001 vs. control; ****, P<0.0001 vs. control (one-way ANOVA test). [Figure 6F] As shown in Figures 6A-6G, ACVR2A Abs promote red blood cell hematopoiesis. C57BL / 6 mice were treated with 10 mg / kg of ACVR2A Ab LA01 and / or ACVR2B Trap ACE-536 twice weekly for 2 weeks. After 14 days of treatment, Ab LA01 promoted hematopoiesis similar to ACE-536, including red blood cell count (Figure 6E), hemoglobin (Figure 6F), and hematocrit (Figure 6G). Combination treatment with Ab LA01 and ACE-536 was more effective in hematopoiesis than either single agent treatment (Figures 6E-6G). Mean ± SEM is shown. *, P<0.05 vs. isotype control; **, P<0.01 vs. control; ***, P<0.001 vs. control; ****, P<0.0001 vs. control (one-way ANOVA test). [Figure 6G]As shown in Figures 6A-6G, ACVR2A Abs promote red blood cell hematopoiesis. C57BL / 6 mice were treated with 10 mg / kg of ACVR2A Ab LA01 and / or ACVR2B Trap ACE-536 twice weekly for 2 weeks. After 14 days of treatment, Ab LA01 promoted hematopoiesis similar to ACE-536, including red blood cell count (Figure 6E), hemoglobin (Figure 6F), and hematocrit (Figure 6G). Combination treatment with Ab LA01 and ACE-536 was more effective in hematopoiesis than either single agent treatment (Figures 6E-6G). Mean ± SEM is shown. *, P<0.05 vs. isotype control; **, P<0.01 vs. control; ***, P<0.001 vs. control; ****, P<0.0001 vs. control (one-way ANOVA test). [Figure 7A] As shown in Figures 7A-7E, ACVR2A Ab attenuates CC14-induced liver fibrosis in a mouse model. Liver fibrosis was induced in 6- to 8-week-old C57 / BL6 mice by intraperitoneal injection of CC14 dissolved in corn oil at a 1:10 ratio at 1 mL / kg twice weekly for 5 weeks. Mice were treated subcutaneously with ACVR2A Ab LA01 or an isotype control antibody at a dose of 20 mg / kg once weekly for 5 weeks. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed after 2 weeks of Ab LA01 treatment. At the end of the study, livers were stained with hematoxylin-eosin (HE) and Masson's trichrome to evaluate fibrosis, inflammation, and hepatitis lesions and analyzed using the Knodell Histology Activity Index (HAI) system. Collagen 3 (Col3) mRNA was analyzed by real-time PCR assay. FIG. 7A: Ab LA01 significantly increased body weight compared to isotype control Ab from days 13 to 35. [Figure 7B]As shown in Figures 7A-7E, ACVR2A Ab attenuates CC14-induced liver fibrosis in a mouse model. Liver fibrosis was induced in 6- to 8-week-old C57 / BL6 mice by intraperitoneal injection of CC14 dissolved in corn oil at a 1:10 ratio at 1 mL / kg twice weekly for 5 weeks. Mice were treated subcutaneously with ACVR2A Ab LA01 or an isotype control antibody at a dose of 20 mg / kg once weekly for 5 weeks. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed after 2 weeks of Ab LA01 treatment. At the end of the study, livers were stained with hematoxylin-eosin (HE) and Masson's trichrome to evaluate fibrosis, inflammation, and hepatitis lesions and analyzed using the Knodell Histology Activity Index (HAI) system. Collagen 3 (Col3) mRNA was analyzed by real-time PCR assay. FIG. 7B: Two-week treatment with Ab LA01 reduced serum ALT and AST levels in a CC14-induced liver fibrosis model. [Figure 7C] As shown in Figures 7A-7E, ACVR2A Ab attenuates CC14-induced liver fibrosis in a mouse model. Liver fibrosis was induced in 6- to 8-week-old C57 / BL6 mice by intraperitoneal injection of CC14 dissolved in corn oil at a 1:10 ratio at 1 mL / kg twice weekly for 5 weeks. Mice were treated subcutaneously with ACVR2A Ab LA01 or an isotype control antibody at a dose of 20 mg / kg once weekly for 5 weeks. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed after 2 weeks of Ab LA01 treatment. At the end of the study, livers were stained with hematoxylin-eosin (HE) and Masson's trichrome to evaluate fibrosis, inflammation, and hepatitis lesions and analyzed using the Knodell Histology Activity Index (HAI) system. Collagen 3 (Col3) mRNA was analyzed by real-time PCR assay. FIG. 7C: Hepatic Col3 expression was decreased after 5 weeks of treatment with Ab LA01. [Figure 7D]As shown in Figures 7A-7E, ACVR2A Ab attenuates CC14-induced liver fibrosis in a mouse model. Liver fibrosis was induced in 6- to 8-week-old C57 / BL6 mice by intraperitoneal injection of CC14 dissolved in corn oil at a 1:10 ratio at 1 mL / kg twice weekly for 5 weeks. Mice were treated subcutaneously with ACVR2A Ab LA01 or an isotype control antibody at a dose of 20 mg / kg once weekly for 5 weeks. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed after 2 weeks of Ab LA01 treatment. At the end of the study, livers were stained with hematoxylin-eosin (HE) and Masson's trichrome to evaluate fibrosis, inflammation, and hepatitis lesions and analyzed using the Knodell Histology Activity Index (HAI) system. Collagen 3 (Col3) mRNA was analyzed by real-time PCR assay. Figure 7D: Histological analysis of the liver. Liver fibrosis, portal inflammation, and hepatitis lesion scores demonstrated that Ab LA01 attenuated CC14-induced liver fibrosis and liver injury. [Figure 7E]As shown in Figures 7A-7E, ACVR2A Ab attenuates CC14-induced liver fibrosis in a mouse model. Liver fibrosis was induced in 6- to 8-week-old C57 / BL6 mice by intraperitoneal injection of CC14 dissolved in corn oil at a 1:10 ratio at 1 mL / kg twice weekly for 5 weeks. Mice were treated subcutaneously with ACVR2A Ab LA01 or an isotype control antibody at a dose of 20 mg / kg once weekly for 5 weeks. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed after 2 weeks of Ab LA01 treatment. At the end of the study, livers were stained with hematoxylin-eosin (HE) and Masson's trichrome to evaluate fibrosis, inflammation, and hepatitis lesions and analyzed using the Knodell Histology Activity Index (HAI) system. Collagen 3 (Col3) mRNA was analyzed by real-time PCR assay. Figure 7E: Ab LA01 promoted erythropoiesis in a CC14-induced liver fibrosis model. RBC counts, hemoglobin concentrations, and hematocrit values ​​increased after 24 days of treatment with Ab LA01. Mean ± SEM is shown. *, P<0.05 vs. isotype control; **, P<0.01 vs. control; ***, P<0.001 vs. control; ****, P<0.0001 vs. control (one-way ANOVA test). [Figure 8A] As shown in Figures 8A-8F, ACVR2A Ab attenuates liver fibrosis in the HFD (high-fat diet)-CC14 NASH model. Diet-induced obese (DIO) C57 / BL6 mice aged 18-19 weeks were fed an HFD and treated with low-dose CC14 (25% CC14, 0.5 ml / kg) to induce NASH. Mice were treated with ACVR2A Ab LA01 at 4 mg / kg or 20 mg / kg twice weekly (SC) for 4 weeks. The FXR agonist obeticholic acid (OCA) was used as a positive control at 30 mpk poqd. Figure 8A: ACVR2A Ab LA01 treatment increased mouse body weight compared to the isotype control group. [Figure 8B]As shown in Figures 8A-8F, ACVR2A Ab attenuates liver fibrosis in the HFD (high-fat diet)-CC14 NASH model. Diet-induced obese (DIO) C57 / BL6 mice aged 18-19 weeks were fed an HFD and treated with low-dose CC14 (25% CC14, 0.5 ml / kg) to induce NASH. Mice were treated with ACVR2A Ab LA01 at 4 mg / kg or 20 mg / kg twice weekly (SC) for 4 weeks. The FXR agonist obeticholic acid (OCA) was used as a positive control at 30 mpk poqd. Figures 8B and 8C: LA01 treatment at 20 mg / kg reduced liver fibrosis scores and Sirius Red staining signals. [Figure 8C] As shown in Figures 8A-8F, ACVR2A Ab attenuates liver fibrosis in the HFD (high-fat diet)-CC14 NASH model. Diet-induced obese (DIO) C57 / BL6 mice aged 18-19 weeks were fed an HFD and treated with low-dose CC14 (25% CC14, 0.5 ml / kg) to induce NASH. Mice were treated with ACVR2A Ab LA01 at 4 mg / kg or 20 mg / kg twice weekly (SC) for 4 weeks. The FXR agonist obeticholic acid (OCA) was used as a positive control at 30 mpk poqd. Figures 8B and 8C: LA01 treatment at 20 mg / kg reduced liver fibrosis scores and Sirius Red staining signals. [Figure 8D] As shown in Figures 8A-8F, ACVR2A Ab attenuates liver fibrosis in the HFD (high-fat diet)-CC14 NASH model. 18-19-week-old diet-induced obese (DIO) C57 / BL6 mice were fed an HFD and treated with low-dose CC14 (25% CC14, 0.5 ml / kg) to induce NASH. Mice were treated with ACVR2A Ab LA01 at 4 mg / kg or 20 mg / kg twice weekly (SC) for 4 weeks. The FXR agonist obeticholic acid (OCA) was used as a positive control at 30 mpk poqd. Figures 8D and 8E: Liver collagen gene expression (Col3al) and liver aSMA were decreased in the 20 mg / kg LA01-treated group. [Figure 8E]As shown in Figures 8A-8F, ACVR2A Ab attenuates liver fibrosis in the HFD (high-fat diet)-CC14 NASH model. 18-19-week-old diet-induced obese (DIO) C57 / BL6 mice were fed an HFD and treated with low-dose CC14 (25% CC14, 0.5 ml / kg) to induce NASH. Mice were treated with ACVR2A Ab LA01 at 4 mg / kg or 20 mg / kg twice weekly (SC) for 4 weeks. The FXR agonist obeticholic acid (OCA) was used as a positive control at 30 mpk poqd. Figures 8D and 8E: Liver collagen gene expression (Col3al) and liver aSMA were decreased in the 20 mg / kg LA01-treated group. [Figure 8F] As shown in Figures 8A-8F, ACVR2A Ab attenuates liver fibrosis in the HFD (high-fat diet)-CC14 NASH model. 18-19-week-old diet-induced obese (DIO) C57 / BL6 mice were fed an HFD and treated with low-dose CC14 (25% CC14, 0.5 ml / kg) to induce NASH. Mice were treated with ACVR2A Ab LA01 at 4 mg / kg or 20 mg / kg twice weekly (SC) for 4 weeks. The FXR agonist obeticholic acid (OCA) was used as a positive control at 30 mpk poqd. Figure 8F: LA01 treatment increased liver weight. Mean ± SEM is shown. *, P < 0.05 vs. isotype control; **, P < 0.01 vs. control; ***, P < 0.001 vs. control (one-way ANOVA test). [Figure 9A] As shown in Figures 9A and 9B, ACVR2A Ab LA01 inhibits CT26 tumor growth. Balb / C mice (n=8 per treatment) were inoculated subcutaneously with 0.5x10E6 viable CT26 cells (day 5) and treated twice weekly subcutaneously (SC) with PBS, 10 mg / kg anti-PD-L1 antibody 10F.9G2 intraperitoneally (IP), or 10 mg / kg 10F.9G2 (IP) + 10 mg / kg ACVR2A Ab LA01. Figure 9A: Effect of LA01 on tumor growth. [Figure 9B]As shown in Figures 9A and 9B, ACVR2A Ab LA01 inhibits CT26 tumor growth. Balb / C mice (n=8 per treatment) were subcutaneously inoculated with 0.5x10E6 viable CT26 cells (day 5) and then treated twice weekly subcutaneously (SC) with PBS, 10 mg / kg anti-PD-L1 antibody 10F.9G2 intraperitoneally (IP), or 10 mg / kg 10F.9G2 (IP) plus 10 mg / kg ACVR2A Ab LA01. Figure 9B: Individual tumor volumes for each mouse on day 14. Anti-PD-L1 antibody treatment alone had no effect; in contrast, the combination of ACVR2A Ab LA01 and PD-L1 antibody produced an anti-tumor effect. Mean ± SEM is shown. **, P<0.01 (one-way ANOVA test). [Figure 10] ACVR2A Ab LA01 inhibits LLC tumor growth in combination with PD-L1 Ab. C57 / BL6 mice inoculated intramuscularly (in the hind leg) with 5x10E5 LLC cells were treated with PBS, 10mg / kg PD-L1 Ab FAZ053 intravenously (IV) twice weekly, or a combination of PD-L1 Ab and ACVR2A Ab: 10mg / kg FAZ053 IV + 10mg / kg ACVR2A Ab SC twice weekly. Single-agent PD-L1 Ab treatment had little effect on tumor growth (Group 2, T / C=0.62, p=0.04), whereas the combination of ACVR2A Ab LA01 and PD-L1 antibody significantly inhibited tumor growth compared to the control group (Group 3, T / C=0.41, p<0.01). [Figure 11A] As shown in Figures 11A-11I, ACVR2A Ab LA01 inhibits LLC tumor growth in combination with carboplatin. C57 / BL6 mice bearing LLC tumors were treated with vehicle control, carboplatin, or a combination of carboplatin and ACVR2A Ab. Figure 11A: The combination of ACVR2A Ab LA01 and carboplatin inhibited tumor growth more dramatically than carboplatin alone. [Figure 11B]As shown in Figures 11A-11I, ACVR2A Ab LA01 inhibits LLC tumor growth in combination with carboplatin. C57 / BL6 mice bearing LLC tumors were treated with vehicle control, carboplatin, or a combination of carboplatin and ACVR2A Ab. Figure 11B: At individual tumor volumes in each group, the combination of ACVR2A Ab LA01 enhanced the antitumor effect of carboplatin. [Figure 11C] As shown in Figures 11A-11I, ACVR2A Ab LA01 inhibits LLC tumor growth in combination with carboplatin. C57 / BL6 mice bearing LLC tumors were treated with vehicle control, carboplatin, or a combination of carboplatin and ACVR2A Ab. Figures 11C, 11D, and 11E show the percentages of CD8+ effector T cells (Teff), Foxp3+ regulatory T cells (Treg), and the ratio of Teff to Treg in tumors from different groups. [Figure 11D] As shown in Figures 11A-11I, ACVR2A Ab LA01 inhibits LLC tumor growth in combination with carboplatin. C57 / BL6 mice bearing LLC tumors were treated with vehicle control, carboplatin, or a combination of carboplatin and ACVR2A Ab. Figures 11C, 11D, and 11E show the percentages of CD8+ effector T cells (Teff), Foxp3+ regulatory T cells (Treg), and the ratio of Teff to Treg in tumors from different groups. [Figure 11E] As shown in Figures 11A-11I, ACVR2A Ab LA01 inhibits LLC tumor growth in combination with carboplatin. C57 / BL6 mice bearing LLC tumors were treated with vehicle control, carboplatin, or a combination of carboplatin and ACVR2A Ab. Figures 11C, 11D, and 11E show the percentages of CD8+ effector T cells (Teff), Foxp3+ regulatory T cells (Treg), and the ratio of Teff to Treg in tumors from different groups. [Figure 11F]As shown in Figures 11A-11I, ACVR2A Ab LA01 inhibits LLC tumor growth in combination with carboplatin. C57 / BL6 mice bearing LLC tumors were treated with vehicle control, carboplatin, or a combination of carboplatin and ACVR2A Ab. Figure 11F: The ratio of Teff to Treg negatively correlated with tumor volume (R-squared = 0.30, p-value = 0.0054). [Figure 11G] As shown in Figures 11A-11I, ACVR2A Ab LA01 inhibits LLC tumor growth in combination with carboplatin. C57 / BL6 mice bearing LLC tumors were treated with vehicle control, carboplatin, or the combination of carboplatin and ACVR2A Ab. Figures 11G, 11H, and 11I: M1 phenotype macrophages, M2 phenotype macrophages, and M1 / M2 ratios in different groups. The M1 / M2 ratio was significantly increased in the combination group. Mean ± SEM is shown. *, P<0.05; **, P<0.01; ***, P<0.001; ****, p<0.0001; ns, not significant (two-tailed t-test). [Figure 11H] As shown in Figures 11A-11I, ACVR2A Ab LA01 inhibits LLC tumor growth in combination with carboplatin. C57 / BL6 mice bearing LLC tumors were treated with vehicle control, carboplatin, or the combination of carboplatin and ACVR2A Ab. Figures 11G, 11H, and 11I: M1 phenotype macrophages, M2 phenotype macrophages, and M1 / M2 ratios in different groups. The M1 / M2 ratio was significantly increased in the combination group. Mean ± SEM is shown. *, P<0.05; **, P<0.01; ***, P<0.001; ****, p<0.0001; ns, not significant (two-tailed t-test). [Figure 11I]As shown in Figures 11A-11I, ACVR2A Ab LA01 inhibits LLC tumor growth in combination with carboplatin. C57 / BL6 mice bearing LLC tumors were treated with vehicle control, carboplatin, or the combination of carboplatin and ACVR2A Ab. Figures 11G, 11H, and 11I: M1 phenotype macrophages, M2 phenotype macrophages, and M1 / M2 ratios in different groups. The M1 / M2 ratio was significantly increased in the combination group. Mean ± SEM is shown. *, P<0.05; **, P<0.01; ***, P<0.001; ****, p<0.0001; ns, not significant (two-tailed t-test). [Figure 12A] As shown in Figures 12A-12F, ACVR2A Ab LA01 attenuated carboplatin-induced anemia. Complete blood count results showed a decrease in white blood cells (WBC) (Figure 12A), neutrophils (NEUT) (Figure 12B), and platelets (PLT) (Figure 12C) after carboplatin treatment, and ACVR2A Ab treatment significantly increased PLT counts. [Figure 12B] As shown in Figures 12A-12F, ACVR2A Ab LA01 attenuated carboplatin-induced anemia. Complete blood count results showed a decrease in white blood cells (WBC) (Figure 12A), neutrophils (NEUT) (Figure 12B), and platelets (PLT) (Figure 12C) after carboplatin treatment, and ACVR2A Ab treatment significantly increased PLT counts. [Figure 12C] As shown in Figures 12A-12F, ACVR2A Ab LA01 attenuated carboplatin-induced anemia. Complete blood count results showed a decrease in white blood cells (WBC) (Figure 12A), neutrophils (NEUT) (Figure 12B), and platelets (PLT) (Figure 12C) after carboplatin treatment, and ACVR2A Ab treatment significantly increased PLT counts. [Figure 12D] As shown in Figures 12A-12F, ACVR2A Ab LA01 attenuated carboplatin-induced anemia. Figures 12D, 12E, and 12F: Red blood cells (RBC), hemoglobin (HGB), and hematocrit (HCT) changes in different groups. *, P<0.05; ***, P<0.001; ****, p<0.0001 (one-way ANOVA test). [Figure 12E] As shown in Figures 12A-12F, ACVR2A Ab LA01 attenuated carboplatin-induced anemia. Figures 12D, 12E, and 12F: Red blood cells (RBC), hemoglobin (HGB), and hematocrit (HCT) changes in different groups. *, P<0.05; ***, P<0.001; ****, p<0.0001 (one-way ANOVA test). [Figure 12F] As shown in Figures 12A-12F, ACVR2A Ab LA01 attenuated carboplatin-induced anemia. Figures 12D, 12E, and 12F: Red blood cells (RBC), hemoglobin (HGB), and hematocrit (HCT) changes in different groups. *, P<0.05; ***, P<0.001; ****, p<0.0001 (one-way ANOVA test). [Figure 13A] As shown in Figures 13A-13D, ACVR2A Ab inhibited tumor growth in the CDX mouse model of ovarian cancer. Figure 13A: TOV-21G cells secreted high levels of activin A into the culture medium compared with other ovarian cancer cells. [Figure 13B] As shown in Figures 13A-13D, ACVR2A Ab inhibited tumor growth in the ovarian cancer CDX mouse model. Figure 13B: Effect of Ab LA01 on tumor growth. Six- to eight-week-old female Balb / C nude mice were subcutaneously inoculated with 3 x 10E6 viable TOV-21G cells in 0.1 ml of PBS into the right flank. ACVR2A Ab LA01 single-agent treatment significantly inhibited tumor growth compared to the control group (p<0.001). [Figure 13C] As shown in Figures 13A-13D, ACVR2A Ab inhibited tumor growth in the CDX mouse model of ovarian cancer. Figures 13C and 13D: Immunophenotypic analysis of tumor-infiltrating lymphocytes (TILs). More lymphocytes were found to infiltrate tumors in the LA01 Ab-treated group. The numbers of total NK cells (CD45+CD3-CD49+) and activated NK cells (CD69+ or NKG2D+) in the tumors were elevated in the LA01 Ab-treated group compared with the control group (p=0.0108, p=0.0076, and p=0.0244, respectively) (Figure 13C). [Figure 13D] As shown in Figures 13A-13D, ACVR2A Ab inhibited tumor growth in the CDX mouse model of ovarian cancer. Figures 13C and 13D: Immunophenotypic analysis of tumor-infiltrating lymphocytes (TILs). More lymphocytes were found to infiltrate tumors in the LA01 Ab-treated group. The numbers of total NK cells (CD45+CD3-CD49+) and activated NK cells (CD69+ or NKG2D+) in tumors were elevated in the LA01 Ab-treated group compared with the control group (p=0.0108, p=0.0076, and p=0.0244, respectively) (Figure 13C). Similarly, more macrophages were present in the LA01 Ab-treated tumors (p=0.00341) (Figure 13D). DETAILED DESCRIPTION OF THE INVENTION

[0019] 5. MODE FOR CARRYING OUT THE INVENTION The present disclosure is based in part on novel antibodies that bind to ACVR2A and their superior properties.

[0020] 5.1.Definition The techniques and procedures described or referenced herein include those that are generally well understood and / or commonly used by those of skill in the art using conventional methodologies, such as, for example, widely utilized methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual (3rd ed. 2001); Current Protocols in Molecular Biology (Ausubel et al., eds., 2003); Therapeutic Monoclonal Antibodies: From Bench to Clinic (An ed. 2009); Monoclonal Antibodies: Methods and Protocols (Albitar ed. 2010); and Antibody Engineering Vols 1 and 2 (Kontermann and Dubel eds., 2nd ed. 2010). Unless otherwise defined herein, technical and scientific terms used herein have the meanings commonly understood by those of skill in the art. For purposes of interpreting this specification, the following explanations of terms apply, and whenever appropriate, terms used in the singular also include the plural and vice versa. In the event that any description of a term conflicts with any document incorporated herein by reference, the description of the term set forth below shall control.

[0021] The terms "antibody," "immunoglobulin," or "Ig" are used interchangeably herein and are used in the broadest sense, specifically encompassing, for example, monoclonal antibodies (including agonist, antagonist, neutralizing, full-length, or intact monoclonal antibodies), antibody compositions with polyepitopic or monoepitopic specificity, polyclonal or univalent antibodies, multivalent antibodies, multispecific antibodies formed from at least two intact antibodies (e.g., bispecific antibodies, so long as they exhibit the desired biological activity), single-chain antibodies, and fragments thereof (e.g., domain antibodies), as described below. Antibodies may be human, humanized, chimeric, and / or affinity matured, as well as antibodies derived from other species, e.g., mouse, rabbit, llama, etc. The term "antibody" is intended to include polypeptide products of B cells within the immunoglobulin class of polypeptides capable of binding to a specific molecular antigen and composed of two identical pairs of polypeptide chains, each pair having one heavy chain (approximately 50-70 kDa) and one light chain (approximately 25 kDa), with the amino-terminal portion of each chain containing a variable region of about 100 to about 130 or more amino acids, and the carboxy-terminal portion of each chain containing a constant region. See, e.g., Antibody Engineering (Borrebaeck ed., 2nd ed. 1995); and Kuby, Immunology (3rd ed. 1997). Antibody also refers to portions of antibody heavy or light chain polypeptides, including synthetic antibodies, recombinantly produced antibodies, antibodies including those from camelid species (e.g., llamas or alpacas) or humanized variants thereof, intrabodies, anti-idiotypic (anti-Id) antibodies, and functional fragments (e.g., antigen-binding fragments) of any of the above, which retain some or all of the binding activity of the antibody from which the fragment is derived. Non-limiting examples of functional fragments (e.g., antigen-binding fragments) include single-chain Fvs (scFv) (including, e.g., monospecific, bispecific, etc.), Fab fragments, F(ab') fragments, F(ab)2 fragments, F(ab')2 fragments, disulfide-bridged Fvs (dsFv), Fd fragments, Fv fragments, diabodies, triabodies, tetrabodies, and minibodies.In particular, antibodies provided herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, such as molecules containing an antigen-binding domain or site that binds to an antigen (e.g., one or more CDRs of an antibody). Such antibody fragments can be found, for example, in Harlow and Lane, Antibodies: A Laboratory Manual (1989); Mol, Biology and Biotechnology: A Comprehensive Desk Reference (Myers ed., 1995); Huston et al., 1993, Cell Biophysics 22:189-224; Pluckthun and Skerra, 1989, Meth. Enzymol. 178:497-515; and Day, Advanced Immunochemistry (2d ed. 1990). The antibodies provided herein can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgAI, and IgA2) of immunoglobulin molecule. The antibodies can be agonist or antagonist antibodies. The antibodies can be neither agonist nor antagonist.

[0022] An "antigen" is a structure to which an antibody can selectively bind. A target antigen can be a polypeptide, carbohydrate, nucleic acid, lipid, hapten, or other naturally occurring or synthetic compound. In some embodiments, the target antigen is a polypeptide. In certain embodiments, the antigen is associated with a cell, e.g., present on or within a cell.

[0023] An "intact" antibody is one that comprises an antigen-binding site as well as a CL and at least heavy chain constant regions CH1, CH2, and CH3. The constant region may comprise a human constant region or an amino acid sequence variant thereof. In certain embodiments, an intact antibody has one or more effector functions.

[0024] The terms "binding" or "binding" refer to interactions between molecules, including, for example, forming a complex. The interaction can be a non-covalent interaction, including, for example, hydrogen bonding, ionic bonding, hydrophobic interactions, and / or van der Waals interactions. A complex can also include the association of two or more molecules held together by covalent or non-covalent bonds, interactions, or forces. The strength of all non-covalent interactions between a single antigen-binding site on an antibody and a single epitope of a target molecule, such as an antigen, is the affinity of the antibody or functional fragment for that epitope. The association rate (k on ) to the dissociation rate (k off ) ratio (k off / k on ) is the dissociation constant K D and is inversely proportional to affinity. D The lower the value, the higher the affinity of the antibody. D The value of k varies for different complexes of antibody and antigen. on and k off The dissociation constant K of the antibodies provided herein depends on both D can be determined using any of the methods provided herein or any other method known to those skilled in the art. The affinity at one binding site does not always reflect the true strength of the interaction between an antibody and an antigen. When a complex antigen containing multiple repeated antigenic determinants (e.g., a multivalent antigen) contacts an antibody containing multiple binding sites, the interaction between the antibody and the antigen at one site increases the probability of a reaction at a second site. The strength of such multiple interactions between a multivalent antibody and an antigen is called avidity.

[0025] In connection with the binding molecules described herein, terms such as "binds to," "specifically binds to," and similar terms are also used interchangeably herein to refer to binding molecules of an antigen-binding domain that specifically binds to an antigen, such as a polypeptide. Binding molecules or antigen-binding domains that bind or specifically bind to an antigen can be identified, for example, by immunoassays, Octet®, Biacore®, or other techniques known to those of skill in the art. In some embodiments, a binding molecule or antigen-binding domain binds to or specifically binds to an antigen if it binds to the antigen with higher affinity than any cross-reactive antigens, as determined using experimental techniques such as enzyme-linked immunosorbent assay (ELISA). Typically, a specific or selective response is at least two times the background signal or noise and may exceed 10 times the background. See, e.g., Fundamental Immunology 332-36 (Paul ed., 2d ed. 1989) for a discussion of binding specificity. In certain embodiments, the extent of binding of a binding molecule or antigen-binding domain to a "non-target" protein is less than about 10% of the binding of the binding molecule or antigen-binding domain to its specific target antigen, as determined, for example, by fluorescence-activated cell sorting (FACS) analysis. Binding molecules or antigen-binding domains that bind to an antigen include those that can bind to the antigen with sufficient affinity so that the binding molecule is useful, for example, as a therapeutic and / or diagnostic agent in targeting the antigen. In certain embodiments, a binding molecule or antigen-binding domain that binds to an antigen has a dissociation constant (K) of less than or equal to 1 μM, 800 nM, 600 nM, 550 nM, 500 nM, 300 nM, 250 nM, 100 nM, 50 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, or 0.1 nM. D In certain embodiments, the binding molecule or antigen-binding domain binds to an epitope of an antigen that is conserved among antigens from different species.

[0026] In certain embodiments, binding molecules or antigen-binding domains can comprise "chimeric" sequences in which a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, and the remainder of the chain is identical to or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (see U.S. Pat. No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81:6851-55). Chimeric sequences may also include humanized sequences.

[0027] In certain embodiments, a binding molecule or antigen-binding domain can comprise a portion of a "humanized" form of a non-human (e.g., camelid, murine, non-human primate) antibody containing sequences from a human immunoglobulin (e.g., recipient antibody), in which native CDR residues are replaced by residues from a corresponding CDR of a non-human species (e.g., donor antibody) such as camelid, mouse, rat, rabbit, or non-human primate having the desired specificity, affinity, and capacity. In some instances, one or more FR region residues of the human immunoglobulin sequence are replaced by corresponding non-human residues. Furthermore, humanized antibodies can comprise residues that are not found in the recipient antibody or the donor antibody. These modifications are made to further refine antibody performance. A humanized antibody heavy or light chain can comprise substantially all of at least one or more variable regions, in which all or substantially all of the CDRs correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. In certain embodiments, a humanized antibody comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature 321:522-25 (1986); Riechmann et al., Nature 332:323-29 (1988); Presta, Curr. Op. Struct. Biol. 2:593-96 (1992); Carter et al., Proc. Natl. Acad. Sci. USA 89:4285-89 (1992); U.S. Patent Nos. 6,800,738; 6,719,971; 6,639,055; 6,407,213; and 6,054,297.

[0028] In certain embodiments, a binding molecule or antigen-binding domain can comprise a portion of a "fully human antibody" or "human antibody," which terms are used interchangeably herein and refer to an antibody comprising a human variable region and, for example, a human constant region. The binding molecule can comprise antibody sequences. In specific embodiments, the term refers to an antibody comprising variable and constant regions of human origin. A "fully human" antibody can also, in certain embodiments, encompass an antibody that binds a polypeptide and is encoded by a nucleic acid sequence that is a naturally occurring somatic variant of a human germline immunoglobulin nucleic acid sequence. The term "fully human antibody" includes antibodies having variable and constant regions corresponding to human germline immunoglobulin sequences as described by Kabat et al. (See Kabat et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDapartment of Health and Human Services, NIH Publication No. 91-3242). A "human antibody" is one that has an amino acid sequence that corresponds to that of an antibody produced by a human and / or has been produced using any of the techniques for producing human antibodies. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues. Human antibodies can be produced using a variety of techniques known in the art, including phage display libraries (Hoogenboom and Winter, J. Mol. Biol. 227:381 (1991); Marks et al., J. Mol. Biol. 222:581 (1991)) and yeast display libraries (Chao et al., Nature Protocols 1:755-68 (2006)).Also available for preparing human monoclonal antibodies are methods described by Cole et al., Monoclonal Antibodies and Cancer Therapy 77 (1985); Boemer et al., J. Immunol. 147(1):86-95 (1991); and van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001). Human antibodies can be prepared by administering antigen to transgenic animals, e.g., mice, that have been modified to produce such antibodies in response to antigen challenge, but whose endogenous gene loci have been disabled (see, e.g., Akobovits, Curr. Opin. Biotechnol. 6(5):561-66 (1995); Bruggemann and Taussing, Curr. Opin. Biotechnol. 8(4):455-58 (1997); and U.S. Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE™ technology). See also, e.g., Li et al., Proc. Natl. Acad. Sci. USA 103:3557-62 (2006), regarding human antibodies generated via human B-cell hybridoma technology.

[0029] In certain embodiments, a binding molecule or antigen-binding domain may comprise a portion of a "recombinant human antibody," which phrase includes human antibodies prepared, expressed, generated, or isolated by recombinant means, such as 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 or a cow) that is transgenic and / or transchromosomal for human immunoglobulin genes (see, e.g., Taylor, LD et al., Nucl. Acids Res. 20:6287-6295 (1992)), or antibodies prepared, expressed, generated, or isolated by any other means involving splicing of human immunoglobulin gene sequences into other DNA sequences. Such recombinant human antibodies can have variable and constant regions derived from human germline immunoglobulin sequences (see Kabat, E.A. et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDapartment of Health and Human Services, NIH Publication No. 91-3242). However, in certain embodiments, such recombinant human antibodies have been subjected to in vitro mutagenesis (or, when animals transgenic for human Ig sequences are used, 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 exist within the human antibody germline repertoire in vivo.

[0030] In certain embodiments, a binding molecule or antigen-binding domain can comprise a portion of a "monoclonal antibody," a term used herein to refer to an antibody obtained from a population of substantially homogeneous antibodies, e.g., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts, or well-known post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation, or asparagine or glutamine deamidation, and each monoclonal antibody typically recognizes a single epitope on an antigen. In specific embodiments, a "monoclonal antibody," as used herein, is an antibody produced by a single hybridoma or other cell. The term "monoclonal" is not limited to any particular method for producing the antibody. For example, monoclonal antibodies useful in the present disclosure may be prepared by the hybridoma method first described by Kohler et al., Nature 256:495 (1975), or may be produced using recombinant DNA methods in bacterial or eukaryotic animal or plant cells (see, e.g., U.S. Pat. No. 4,816,567). "Monoclonal antibodies" may also be isolated from phage antibody libraries using, for example, the techniques described in Clackson et al., Nature 352:624-28 (1991) and Marks et al., J. Mol. Biol. 222:581-97 (1991). Other methods for preparation of clonal cell lines and the monoclonal antibodies expressed thereby are well known in the art. See, for example, Short Protocols in Molecular Biology (Ausubel et al., eds., 5th ed. 2002).

[0031] A typical four-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. In the case of IgG, the four-chain unit generally measures approximately 150,000 daltons. Each L chain is linked to an H chain by one covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. Each H and L chain also has regularly spaced intrachain disulfide bridges. Each H chain has a variable domain (VH) at its N-terminus, followed by three constant domains (CH) for each of the α and γ chains, and four CH domains for the μ and ε isotypes. Each L chain has a variable domain (VL) at its N-terminus, followed by a constant domain (CL) at its other end. The VL is aligned with the VH, and the CL is aligned with the first constant domain (CH1) of the heavy chain. Specific amino acid residues are believed to form an interface between the light-chain variable domain and the heavy-chain variable domain. The pairing of VH and VL together forms a single antigen-binding site. The structure and properties of different classes of antibodies are described, for example, in Basic and Clinical Immunology 71 (Stites et al., eds., 8th ed. 1994); and Immunobiology (Janeway et al., eds., 5th ed. 1995). th ed. 2001).

[0032] The term "Fab" or "Fab region" refers to the antibody region that binds to an antigen. Conventional IgGs typically contain two Fab regions, each located in one of the two arms of the Y-shaped IgG structure. Each Fab region typically consists of one variable region and one constant region from each of the heavy and light chains. More specifically, the variable and constant regions of the heavy chain in the Fab region are the VH and CH1 regions, and the variable and constant regions of the light chain in the Fab region are the VL and CL regions. The VH, CH1, VL, and CL regions in the Fab region can be arranged in various ways to confer antigen-binding capability according to the present disclosure. For example, as in the Fab region of a conventional IgG, the VH and CH1 regions can be on one polypeptide, while the VL and CL regions can be on separate polypeptides. Alternatively, the VH, CH1, VL, and CL regions can all be on the same polypeptide, or they can be oriented in different orders, as described in more detail in the following sections.

[0033] The terms "variable region," "variable domain," "V region," or "V domain" refer to the portion of an antibody light or heavy chain that is generally located at the amino terminus of the light or heavy chain, approximately 120-130 amino acids in length in the heavy chain and approximately 100-110 amino acids in the light chain, and that is used in the binding and specificity of each particular antibody for its particular antigen. The variable region of a heavy chain may be referred to as "VH." The variable region of a light chain may be referred to as "VL." The term "variable" refers to the fact that certain segments of the variable region differ extensively in sequence among antibodies. The V region mediates antigen binding and defines the specificity of a particular antibody for its particular antigen. However, variability is not evenly distributed across the 110-amino acid span of the variable region. Instead, V regions consist of less variable (e.g., relatively invariant) stretches of approximately 15-30 amino acids called framework regions (FRs) separated by shorter regions of greater variability (e.g., extreme variability) called "hypervariable regions," each approximately 9-12 amino acids in length. Each heavy-chain and light-chain variable region contains four FRs, primarily in a β-sheet configuration, connected by three hypervariable regions that form loops and, in some cases, form part of a β-sheet structure. The hypervariable regions in each chain are held together in close proximity by the FRs and, together with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of the antibody (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest (5th ed. 1991)). The constant regions are not directly involved in binding the antibody to the antigen, but exhibit various effector functions (e.g., antibody participation in antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC)). The sequences of the variable regions vary significantly among different antibodies. In a specific embodiment, the variable regions are human variable regions.

[0034] The terms "variable region residue numbering according to Kabat" or "amino acid position numbering as in Kabat," and variations thereof, refer to the numbering system used for the heavy or light chain variable regions of the antibody compilation in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or CDR of the variable domain. For example, a heavy chain variable domain may contain a single amino acid insertion after residue 52 (residue 52a according to Kabat) and three inserted residues after residue 82 (e.g., residues 82a, 82b, and 82c according to Kabat). The Kabat numbering of residues may be determined for a given antibody by alignment of the antibody's sequence with a "standard" Kabat-numbered sequence at the regions of homology. The Kabat numbering system is generally used when referring to residues in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., supra). The "EU numbering system" or "EU index" is generally used when referring to residues in the immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra). "EU index as in Kabat" refers to the residue numbering of the human IgG1 EU antibody. Other numbering systems are described, for example, by AbM, Chothia, Contact, IMGT, and AHon.

[0035] The term "heavy chain," when used in reference to an antibody, refers to a polypeptide chain of approximately 50 to 70 kDa, the amino-terminal portion of which contains a variable region of approximately 120 to 130 or more amino acids, and the carboxy-terminal portion of which contains a constant region. The constant region can be one of five different types (e.g., isotypes), called alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ), based on the amino acid sequence of the heavy chain constant region. Different heavy chains vary in size, with α, δ, and γ containing approximately 450 amino acids, and μ and ε containing approximately 550 amino acids. When combined with light chains, these different types of heavy chains give rise to five well-known classes (e.g., isotypes) of antibodies: IgA, IgD, IgE, IgG, and IgM, each of which contains four subclasses of IgG: IgG1, IgG2, IgG3, and IgG4.

[0036] The term "light chain," when used in reference to an antibody, refers to a polypeptide chain of about 25 kDa, the amino-terminal portion of which contains a variable region of about 100 to about 110 or more amino acids, and the carboxy-terminal portion of which contains a constant region. The approximate length of a light chain is 211 to 217 amino acids. There are two different types, called kappa (K) or lambda (λ), based on the amino acid sequence of the constant domain.

[0037] As used herein, the terms "hypervariable region," "HVR," "complementarity-determining region," and "CDR" are used interchangeably. "CDR" refers to one of the three hypervariable regions (H1, H2, or H3) in the non-framework region of an immunoglobulin (Ig or antibody) VH β-sheet framework, or one of the three hypervariable regions (L1, L2, or L3) in the non-framework region of an antibody VL β-sheet framework. CDR1, CDR2, and CDR3 in a VH domain are also referred to as HCDR1, HCDR2, and HCDR3, respectively. CDR1, CDR2, and CDR3 in a VL domain are also referred to as LCDR1, LCDR2, and LCDR3, respectively. Thus, CDRs are variable region sequences interspersed within framework region sequences.

[0038] CDR region is well known to those skilled in the art and is defined by a well-known numbering system.For example, Kabat complementarity determining region (CDR) is the most commonly used one based on sequence variability (see, for example, Kabat et al., supra; Nick Deschacht et al., J Immunol 2010;184:5696-5704).Chothia instead refers to the position of structural loop (see, for example, Chothia and Lesk, J.Mol.Biol.196:901-17(1987)). The terminus of the Chothia CDR-H1 loop, when numbered using the Kabat numbering convention, varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertion at H35A and H35B; if neither 35A nor 35B is present, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34). The AbM hypervariable regions represent a compromise between the Kabat CDRs and the Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software (see, e.g., Antibody Engineering Vol. 2 (Kontermann and Dubel eds., 2nd ed. 2010)). The "contact" hypervariable regions are based on an analysis of available complex crystal structures. Another universal numbering system that has been developed and widely adopted is the ImMunoGeneTics (IMGT) Information System® (Lafranc et al., Dev. Comp. Immunol. 27(1):55-77(2003)). IMGT is an integrated information system specialized for immunoglobulins (IGs), T cell receptors (TCRs), and major histocompatibility complexes (MHCs) of humans and other vertebrates. As used herein, CDRs are referred to both with respect to amino acid sequence and position within the light or heavy chain.Because the "locations" of CDRs within the structure of immunoglobulin variable domains are conserved across species and reside in structures called loops, CDR and framework residues are readily identified by using a numbering system that aligns variable domain sequences according to structural features. This information can be used when grafting and replacing CDR residues from one species' immunoglobulin onto an acceptor framework, typically from a human antibody. An additional numbering system (AHon) has been developed by Honegger and Pluckthun, J. Mol. Biol. 309:657-70 (2001). For example, the correspondence between numbering systems, including the Kabat numbering system, and the IMGT-specific numbering system is well known to those skilled in the art (see, e.g., Kabat, supra; Chothia and Lesk, supra; Martin, supra; Lefranc et al., supra). Residues from each of these hypervariable regions or CDRs are illustrated in Table 1 below.

[0039] [Table 1]

[0040] [Table 2]

[0041] The boundaries of a given CDR may vary depending on the scheme used for identification. Thus, unless otherwise specified, the terms "CDR" and "complementarity-determining region" of a given antibody or region thereof (e.g., variable region), as well as individual CDRs of an antibody or region thereof (e.g., CDR-H1, CDR-H2), should be understood to encompass the complementarity-determining regions defined by any of the known schemes described hereinabove. In some cases, a scheme for identifying one or more specific CDRs is specified, such as CDRs defined by the IMGT, Kabat, Chothia, or Contact methods. In other cases, the specific amino acid sequences of the CDRs are given. Note that CDR regions may also be defined by a combination of various numbering systems, for example, a combination of the Kabat and Chothia numbering systems, or a combination of the Kabat and IMGT numbering systems. Thus, terms such as "CDR1 described in a particular VH" include, but are not limited to, any CDR1 defined by the exemplary CDR numbering systems described above. Given a variable region (eg, VH or VL), one skilled in the art will understand that the CDRs within the region can be defined by different numbering systems or combinations thereof.

[0042] The hypervariable regions may comprise "extended hypervariable regions" such as: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in VL, and 26-35 or 26-35A (H1), 50-65 or 49-65 (H2), and 93-102, 94-102, or 95-102 (H3) in VH.

[0043] The term "constant region" or "constant domain" refers to the carboxy-terminal portions of the light and heavy chains that are not directly involved in binding an antibody to an antigen but exhibit various effector functions, such as interaction with Fc receptors. This term refers to the portion of an immunoglobulin molecule that has a more conserved amino acid sequence compared to other portions of the immunoglobulin, i.e., the variable region, which contains the antigen-binding site. The constant region may contain the CH1, CH2, and CH3 regions of the heavy chain and the CL region of the light chain.

[0044] The term "framework" or "FR" refers to variable region residues that flank the CDRs. FR residues are present, for example, in chimeric, humanized, human, domain antibodies, diabodies, linear antibodies, and bispecific antibodies. FR residues are variable domain residues other than hypervariable region or CDR residues.

[0045] The term "Fc region" herein is used to define the C-terminal region of an immunoglobulin heavy chain, including, for example, native-sequence Fc regions, recombinant Fc regions, and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain can vary, the human IgG heavy chain Fc region is often defined to stretch from the amino acid residue at position Cys226, or from Pro230, to the carboxyl terminus. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) can be removed, for example, during antibody production or purification, or by recombinantly engineering the nucleic acid encoding the antibody heavy chain. Thus, an intact antibody composition can include antibody populations in which all K447 residues have been removed, antibody populations in which the K447 residue has not been removed, and antibody populations having a mixture of antibodies with and without the K447 residue. A "functional Fc region" possesses the "effector functions" of a native-sequence Fc region. Exemplary "effector functions" include C1q binding; CDC; Fc receptor binding; ADCC; phagocytosis; and down-regulation of cell surface receptors (e.g., B cell receptors). Such effector functions generally require that the Fc region be combined with a binding region or domain (e.g., an antibody variable region or domain) and can be assessed using a variety of assays known to those of skill in the art. A "variant Fc region" comprises an amino acid sequence that differs from that of a native-sequence Fc region by at least one amino acid modification (e.g., substitution, addition, or deletion). In certain embodiments, the variant Fc region has at least one amino acid substitution compared to the native-sequence Fc region or the Fc region of a parent polypeptide, e.g., about 1 to about 10 amino acid substitutions, or about 1 to about 5 amino acid substitutions in the native-sequence Fc region or the Fc region of a parent polypeptide. The variant Fc region herein can have at least about 80% homology to a native sequence Fc region and / or the Fc region of a parent polypeptide, or at least about 90% homology thereto, for example, at least about 95% homology thereto.

[0046] As used herein, "epitope" is a term used in the art and refers to a localized region of an antigen to which a binding molecule (e.g., an antibody) can specifically bind. An epitope can be a linear epitope, a conformational epitope, a non-linear epitope, or a discontinuous epitope. In the case of a polypeptide antigen, for example, an epitope can be consecutive amino acids of a polypeptide (a "linear" epitope), or an epitope can include amino acids from two or more non-contiguous regions of a polypeptide (a "conformational," "non-linear," or "discontinuous" epitope). In general, it will be understood by those skilled in the art that a linear epitope may or may not depend on secondary, tertiary, or quaternary structure. For example, in some embodiments, a binding molecule binds to a group of amino acids, regardless of whether it is folded in the native three-dimensional protein structure. In other embodiments, the binding molecule requires the amino acid residues that make up the epitope to exhibit a particular conformation (eg, a bend, twist, turn, or fold) in order to recognize and bind to the epitope.

[0047] "Percent (%) amino acid sequence identity" and "homology" with respect to peptide, polypeptide, or antibody sequences are defined as the percentage of amino acid residues in a candidate sequence that are identical with amino acid residues in a particular peptide or polypeptide sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in a variety of ways that are within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN™ (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0048] The term "specificity" refers to the selective recognition of an antigen-binding protein for a specific epitope of an antigen. For example, natural antibodies are monospecific. As used herein, the term "multispecific" indicates that an antigen-binding protein has two or more antigen-binding sites, at least two of which bind to different antigens. As used herein, "bispecific" means that an antigen-binding protein has two different antigen-binding specificities. As used herein, the term "monospecific" antibody refers to an antigen-binding protein that has one or more binding sites, each of which binds to the same antigen.

[0049] As used herein, the term "valent" refers to the presence of a specific number of binding sites in an antigen-binding protein. For example, a natural or full-length antibody has two binding sites and is bivalent. Thus, the terms "trivalent," "tetravalent," "pentavalent," and "hexavalent" refer to the presence of two, three, four, five, and six binding sites in an antigen-binding protein, respectively.

[0050] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. Polymers may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acids. These terms also encompass amino acid polymers that have been modified, either naturally or by intervention, such as disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification. Also included within this definition are polypeptides containing one or more analogs of an amino acid, including, but not limited to, unnatural amino acids, as well as other modifications known in the art. Polypeptides of the present disclosure may be based on antibodies or other members of the immunoglobulin superfamily, and it is understood that in certain embodiments, a "polypeptide" can occur as a single chain or as two or more associated chains.

[0051] "Polynucleotide" or "nucleic acid," as used interchangeably herein, refers to a polymer of nucleotides of any length, including DNA and RNA. Nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction. Polynucleotides may also include modified nucleotides, such as methylated nucleotides and their analogs. "Oligonucleotide," as used herein, generally refers to short, generally single-stranded, synthetic polynucleotides generally, but not necessarily, less than about 200 nucleotides in length. The terms "oligonucleotide" and "polynucleotide" are not mutually exclusive. The above description of polynucleotides is equally and fully applicable to oligonucleotides. Cells producing the binding molecules of the present disclosure can include parent hybridoma cells, as well as bacterial and eukaryotic host cells into which nucleic acid encoding the antibody has been introduced. Unless otherwise specified, the left-hand end of any single-stranded polynucleotide sequence disclosed herein is the 5' end, and the left-hand direction of a double-stranded polynucleotide sequence is referred to as the 5' direction. The direction of 5' to 3' addition of a nascent RNA transcript is referred to as the transcription direction, and the region of the sequence on the DNA strand that is 5' to the 5' end of the RNA transcript and has the same sequence as the RNA transcript is referred to as the "upstream sequence." The region of the sequence on the DNA strand that is 3' to the 3' end of the RNA transcript and has the same sequence as the RNA transcript is referred to as the "downstream sequence."

[0052] An "isolated nucleic acid" is a nucleic acid, e.g., RNA, DNA, or mixed nucleic acid, that has been substantially separated from other genomic DNA sequences and proteins or complexes (such as ribosomes and polymerases) that naturally accompany it in its native sequence. An "isolated" nucleic acid molecule is one that is separated from other nucleic acid molecules that are present in the nucleic acid molecule's natural source. Furthermore, an "isolated" nucleic acid molecule (e.g., a cDNA molecule) can be substantially free of other cellular material or culture medium if produced by recombinant techniques, or can be substantially free of chemical precursors or other chemicals if chemically synthesized. In specific embodiments, one or more nucleic acid molecules encoding an antibody described herein are isolated or purified. This term encompasses a nucleic acid sequence that has been removed from its naturally occurring environment, including recombinant or cloned DNA isolates and chemically synthesized analogs or analogs biologically synthesized in heterologous systems. A substantially pure molecule can include a molecule in isolated form. Specifically, an "isolated" nucleic acid molecule encoding an antibody described herein is a nucleic acid molecule that has been identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the environment in which it is produced.

[0053] Unless otherwise specified, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. The phrase nucleotide sequence encoding a protein or RNA may also include introns, to the extent that a nucleotide sequence that encodes a protein may, in some versions, contain introns.

[0054] The term "control sequences" refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism. Control sequences that are suitable for prokaryotes include, for example, a promoter, optionally an operator sequence, and a ribosome binding site. Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.

[0055] As used herein, the term "operably linked" and similar phrases (e.g., genetically fused), when used with reference to nucleic acids or amino acids, refer to the operable linkage of nucleic acid sequences or amino acid sequences, respectively, placed in a functional relationship to each other. For example, operably linked promoters, enhancer elements, open reading frames, 5' and 3' UTRs, and terminator sequences result in the correct production of a nucleic acid molecule (e.g., RNA). In some embodiments, operably linked nucleic acid elements result in the transcription of the open reading frame and ultimately the production of a polypeptide (i.e., expression of the open reading frame). As another example, an operably linked peptide is one in which functional domains are positioned at an appropriate distance from each other to confer the intended function of each domain.

[0056] The term "vector" refers to a substance used to carry or contain a nucleic acid sequence, including, for example, a nucleic acid sequence encoding a binding molecule (e.g., an antibody) described herein, for introducing a nucleic acid sequence into a host cell. Vectors applicable for use include, for example, expression vectors, plasmids, phage vectors, viral vectors, episomes, and artificial chromosomes, which may contain a selection sequence or marker operable for stable integration into a host cell chromosome. Furthermore, a vector may contain one or more selectable marker genes and appropriate expression control sequences. Selectable marker genes that may be included provide, for example, resistance to antibiotics or toxins, complement auxotrophic deficiencies, or supply critical nutrients not present in the culture medium. Expression control sequences may include constitutive and inducible promoters, transcription enhancers, transcription terminators, and the like, which are well known in the art. When two or more nucleic acid molecules (e.g., both antibody heavy and light chains or antibody VH and VL) are to be co-expressed, both nucleic acid molecules can be inserted, for example, into a single expression vector or into separate expression vectors. For single vector expression, the encoding nucleic acids can be operably linked to one common expression control sequence, or can be linked to different expression control sequences, such as one inducible promoter and one constitutive promoter. Introduction of nucleic acid molecules into host cells can be confirmed using methods well known in the art. Such methods include, for example, nucleic acid analysis, such as Northern blot or polymerase chain reaction (PCR) amplification of mRNA, immunoblotting for expression of gene products, or other suitable analytical methods for testing expression of the introduced nucleic acid sequence or its corresponding gene product. It will be understood by those skilled in the art that the nucleic acid molecule will be expressed in an amount sufficient to produce the desired product, and it will further be understood that expression levels can be optimized to obtain sufficient expression using methods well known in the art.

[0057] As used herein, the term "host" refers to an animal, such as a mammal (e.g., a human).

[0058] The term "host cell," as used herein, refers to the particular subject cell that can be transfected with a nucleic acid molecule and the progeny or potential progeny of such a cell. The progeny of such a cell may not be identical to the parent cell transfected with the nucleic acid molecule due to mutations or environmental influences that may occur in succeeding generations or integration of the nucleic acid molecule into the host cell genome.

[0059] As used herein, the terms "transfected" or "transformed" or "transduced" refer to the process by which exogenous nucleic acid is transferred or incorporated into a host cell. A "transfected" or "transformed" or "transduced" cell is one that has been transfected, transformed or transduced with exogenous nucleic acid. The cell includes the primary subject cell and its progeny.

[0060] As used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of a federal or state government, or listed in the United States Pharmacopoeia, the European Pharmacopoeia, or other generally recognized pharmacopoeias for use in animals, and more particularly in humans.

[0061] "Excipient" means a pharmaceutically acceptable material, composition, or vehicle (e.g., a liquid or solid filler, diluent, solvent, or encapsulating material). Excipients include, for example, encapsulating materials or additives such as absorption enhancers, antioxidants, binders, buffers, carriers, coating agents, colorants, diluents, disintegrants, emulsifiers, bulking agents, fillers, flavoring agents, humectants, lubricants, fragrances, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizing agents, wetting agents, and mixtures thereof. The term "excipient" can also refer to a diluent, adjuvant (e.g., Freund's adjuvant (complete or incomplete)), or vehicle.

[0062] In some embodiments, the excipient is a pharmaceutically acceptable excipient. Examples of pharmaceutically acceptable excipients include buffers (e.g., phosphate, citric acid, and other organic acids); antioxidants including ascorbic acid; low molecular weight (e.g., less than about 10 amino acid residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or non-ionic surfactants such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™. Other examples of pharmaceutically acceptable excipients are described in Remington and Gennaro, Remington's Pharmaceutical Sciences (18th ed. 1990).

[0063] In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation, suitable for use in contact with the tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit / risk ratio. See, e.g., Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009. In some embodiments, a pharmaceutically acceptable excipient is nontoxic to cells or mammals exposed to it at the dosages and concentrations employed. In some embodiments, the pharmaceutically acceptable excipient is an aqueous pH buffered solution.

[0064] In some embodiments, pharmaceutical excipients are sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.). Water is an exemplary excipient when the composition (e.g., pharmaceutical composition) is administered intravenously. Saline and aqueous dextrose and glycerol solutions can also be used as liquid excipients, particularly for injectable solutions. Pharmaceutical excipients can also be starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. The compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, and the like. Oral composition containing formulations can include standard excipients such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc.

[0065] The compositions containing the pharmaceutical compound may contain the binding molecule (eg, antibody), eg, in isolated or purified form, together with a suitable amount of excipients.

[0066] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of an antibody, or therapeutic molecule, or pharmaceutical composition comprising an agent and antibody, provided herein, sufficient to bring about a desired result.

[0067] The terms "subject" and "patient" may be used interchangeably. As used herein, in certain embodiments, a subject is a mammal, such as a non-primate or a primate (e.g., a human). In specific embodiments, a subject is a human. In one embodiment, a subject is a mammal (e.g., a human) diagnosed with a disease or disorder. In another embodiment, a subject is a mammal, e.g., a human, at risk of developing a disease or disorder.

[0068] "Administering" or "administration" refers to the act of injecting or otherwise physically delivering a substance present outside the body to a patient, such as by mucosal, intradermal, intravenous, intramuscular delivery, and / or any other physical delivery method described herein or known in the art.

[0069] As used herein, the terms "treat," "treatment," and "treating" refer to a reduction or amelioration of the progression, severity, and / or duration of a disease or condition resulting from the administration of one or more therapies. Treatment may be determined by assessing whether there has been a reduction, alleviation, and / or mitigation of one or more symptoms associated with the underlying disease, such that an improvement is observed in a patient, even though the patient may still be suffering from the underlying disease. The term "treat" includes both management and amelioration of disease. The terms "manage," "managing," and "management" refer to a beneficial effect that a subject experiences from a treatment that does not necessarily result in a cure of the disease.

[0070] The terms "prevent," "preventing," and "prevention" refer to reducing the likelihood of the occurrence (or recurrence) of a disease, disorder, condition, or associated symptom (e.g., diabetes or cancer).

[0071] As used herein, "delaying" the onset of cancer means postponing, preventing, slowing, retarding, stabilizing, and / or postponing the onset of the disease. This delay can be of varying lengths of time, depending on the history of the disease and / or the individual being treated. As will be apparent to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. A method for "delaying" the onset of cancer is one that reduces the probability of disease onset in a given time frame and / or reduces the extent of disease in a given time frame compared to the absence of the method. Such comparisons are typically based on clinical trials using a statistically significant number of individuals. The onset of cancer can be detectable using standard methods, including, but not limited to, computerized axial tomography (CAT scan), magnetic resonance imaging (MRI), abdominal ultrasound, coagulation tests, arteriography, or biopsy. Onset can also refer to the progression of cancer, which may be undetectable initially, and includes onset, recurrence, and onset.

[0072] As used herein, "ACVR2A-associated disease or disorder" refers to a disease or disorder involving cells or tissues in which ACVR2A is expressed or overexpressed. In some embodiments, an ACVR2A-associated disease or disorder involves cells in which ACVR2A is aberrantly expressed. In other embodiments, an ACVR2A-associated disease or disorder involves cells in which ACVR2A is deficient in at least one of its activities.

[0073] As used herein, "ACVR2A ligand-associated disease or disorder" refers to a disease or disorder involving cells or tissues in which one or more of the ACVR2A ligands are expressed or overexpressed, including activins (such as activin A, activin B, activin AB, activin C, activin AC, and activin E), growth / differentiation factors (GDFs such as GDF1, GDF3, GDF5, GDF6, GDF7, GDF8, GDF10, and GDF11), and bone morphogenetic proteins (BMPs such as BMP2, BMP4, BMP6, BMP7, BMP8a, BMP8b, BMP9, and BMP10). In some embodiments, the ACVR2A ligand-associated disease or disorder involves cells in which one or more of the ACVR2A ligands are abnormally expressed. In other embodiments, the ACVR2A ligand-associated disease or disorder involves cells in which one or more of the ACVR2A ligands are deficient in at least one of their activities. In other embodiments, the ACVR2A ligand-associated disease or disorder involves one or more ACVR2A ligands whose protein levels in serum, plasma, or blood are abnormal.

[0074] The terms "about" and "approximately" mean within 20%, within 15%, within 10%, within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2%, within 1%, or less of a given value or range.

[0075] As used in this disclosure and claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0076] Whenever an embodiment is described herein using the term "comprising," it is understood that other similar embodiments described in terms of "consisting of" and / or "consisting essentially of" are also provided. Whenever an embodiment is described herein with the phrase "consisting essentially of," it is also understood that other similar embodiments described in terms of "consisting of" are also provided.

[0077] The term "between" when used in phrases such as "between A and B" or "between A and B" refers to a range that includes both A and B.

[0078] The term "and / or" as used herein in phrases such as "A and / or B" is intended to include both A and B; A or B; A alone; and B alone. Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A alone; B alone; and C alone.

[0079] 5.2.ACVR2A binding molecules 5.2.1. Antibodies that bind to ACVR2A In one aspect, provided herein is an antibody capable of binding to ACVR2A. ACVR2A is a receptor that mediates the function of activin, a member of the transforming growth factor-β (TGF-β) superfamily involved in diverse biological processes. ACVR2A is a transmembrane serine-threonine kinase receptor that mediates signal transduction by forming heterodimeric complexes with various combinations of type I and type II receptors and ligands in a cell-specific manner. The type II receptor is primarily involved in ligand binding and contains an extracellular ligand-binding domain, a transmembrane domain, and a cytoplasmic serine-threonine kinase domain. The nucleic acid and amino acid sequences of ACVR2A are known (see GCID:GC02P 147844, HGNC:173, NCBI Entrez Gene:92, Ensembl:ENSG00000121989, OMIM®:102581, and UniProtKB / Swiss-Prot:P27037). In some embodiments, the antibody provided herein binds to human ACVR2A. In some embodiments, the anti-ACVR2A antibodies provided herein modulate one or more ACVR2A activities. In some embodiments, the anti-ACVR2A antibodies provided herein are antagonistic antibodies.

[0080] In one embodiment, an antibody according to the present disclosure is an ACVR2A antagonist with no or low agonist activity. In another embodiment, an antibody or functional fragment comprising an antigen-binding portion binds to the target protein ACVR2A and reduces activin A binding to ACVR2A to basal levels. In one aspect of this embodiment, the antibody or functional fragment reduces the amount of activin A bound to ACVR2A. In a further aspect of this embodiment, the antibody or functional fragment completely prevents activin A from binding to ACVR2A. In a further embodiment, the antibody or functional fragment inhibits Smad activation. An antibody that inhibits one or more of these ACVR2A functional properties (e.g., biochemical, immunochemical, cellular, physiological, or other biological activities, etc.) as determined according to methodologies known in the art and described herein is understood to be associated with a statistically significant decrease in the particular activity compared to that seen in the absence of the antibody (e.g., or in the presence of a control antibody of irrelevant specificity). In some embodiments, antibodies that inhibit ACVR2A activity result in a statistically significant decrease in the measured parameter of at least 10%, at least 50%, 80%, or 90%, and in certain embodiments, antibodies of the present disclosure can inhibit greater than 95%, 98%, or 99% of ACVR2A functional activity.

[0081] In one embodiment, an antibody of the present disclosure does not cross-react with ACVR2A-related proteins, more specifically, does not cross-react with human ACVR2B (NP-001607.1, GI:4501897). In one embodiment, an antibody of the present disclosure binds to ACVR2A but not ACVR2B. In one embodiment, an antibody of the present disclosure binds to ACVR2A with 10-fold greater affinity than it binds to ACVR2B. In one embodiment, an antibody of the present disclosure binds to ACVR2A with 20-fold greater affinity than it binds to ACVR2B. In one embodiment, an antibody of the present disclosure binds to ACVR2A with 30-fold greater affinity than it binds to ACVR2B. In one embodiment, an antibody of the present disclosure binds to ACVR2A with 40-fold greater affinity than it binds to ACVR2B. In one embodiment, an antibody of the present disclosure binds to ACVR2A with 50-fold greater affinity than it binds to ACVR2B. In one embodiment, an antibody of the present disclosure binds to ACVR2A with 60-fold greater affinity than it binds to ACVR2B. In one embodiment, an antibody of the present disclosure binds to ACVR2A with 70-fold greater affinity than it binds to ACVR2B. In one embodiment, an antibody of the present disclosure binds to ACVR2A with 80-fold greater affinity than it binds to ACVR2B. In one embodiment, an antibody of the present disclosure binds to ACVR2A with 90-fold greater affinity than it binds to ACVR2B. In one embodiment, an antibody of the present disclosure binds to ACVR2A with 100-fold greater affinity than it binds to ACVR2B. In one embodiment, an antibody of the present disclosure binds to ACVR2A with more than 100-fold greater affinity than it binds to ACVR2B, for example, 500-fold or 1000-fold greater affinity.

[0082] In some embodiments, the anti-ACVR2A antibodies provided herein have a cytotoxicity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, 0.01 nM, or ≦0.001 nM (e.g., 10 -8 M or less, e.g. 10 -8 M~10 -13 M, e.g. 10 -9 M~10 -13 Dissociation constant (K D) binds to ACVR2A (e.g., human ACVR2A). Various methods of measuring binding affinity are known in the art, including, for example, by RIA performed using the Fab version of the antibody of interest and its antigen (Chen et al., 1999, J. Mol Biol 293:865-81); by biolayer interferometry (BLI) or surface plasmon resonance (SPR) assays by Octet®, for example, using the Octet® Red 96 system, or by Biacore®, for example, using a Biacore® TM-2000 or Biacore® TM-3000, any of which can be used for purposes of the present disclosure. The "on rate" or "rate of association" or "association rate" or "k" may also be determined using the same biolayer interferometry (BLI) or surface plasmon resonance (SPR) techniques described above, for example, using an Octet® Red 96, Biacore® TM-3000, or Biacore® TM-8000 system.

[0083] In some embodiments, the anti-ACVR2A antibodies provided herein are those described in Section 7, below. Accordingly, in some embodiments, the antibodies provided herein comprise one or more CDR sequences of any one of SEQ ID NOS: 1-41. CDR sequences can be determined according to well-known numbering systems. In some embodiments, the CDRs are according to the IMGT numbering system. In some embodiments, the CDRs are according to the Kabat numbering system. In some embodiments, the CDRs are according to the AbM numbering system. In other embodiments, the CDRs are according to the Chothia numbering system. In other embodiments, the CDRs are according to the Contact numbering system. In some embodiments, the anti-ACVR2A antibodies are humanized. In some embodiments, the anti-ACVR2A antibodies comprise an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0084] In some embodiments, the anti-ACVR2A antibodies provided herein comprise HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 1. In some embodiments, the anti-ACVR2A antibodies provided herein comprise HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 3. In some embodiments, the anti-ACVR2A antibodies provided herein comprise HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 4. In some embodiments, the anti-ACVR2A antibodies provided herein comprise HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 5. In some embodiments, the anti-ACVR2A antibodies provided herein comprise HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7. In some embodiments, the anti-ACVR2A antibodies provided herein comprise HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 8. In some embodiments, the anti-ACVR2A antibodies provided herein comprise HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 9. In some embodiments, the anti-ACVR2A antibodies provided herein comprise HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 10. In some embodiments, the anti-ACVR2A antibodies provided herein comprise HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 11. In some embodiments, the anti-ACVR2A antibodies provided herein comprise HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12. In some embodiments, the anti-ACVR2A antibodies provided herein comprise HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 13. CDR sequences can be determined according to any well-known numbering system or combination thereof. In some embodiments, the CDRs are according to the IMGT numbering system. In some embodiments, the CDRs are according to the Kabat numbering system. In some embodiments, the CDRs are according to the AbM numbering system. In other embodiments, the CDRs are according to the Chothia numbering system. In other embodiments, the CDRs are according to the Contact numbering system.

[0085] In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 6. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 14. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 15. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 16. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 17. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 18. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 19. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 20. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 21. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 22. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 23. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 24. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 25.In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 26. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 27. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 28. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 29. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 30. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 31. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 32. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 33. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 34. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 35. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 36. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 37. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 38. In some embodiments, the anti-ACVR2A antibodies provided herein comprise an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 39.In some embodiments, the anti-ACVR2A antibodies provided herein comprise LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 40. In some embodiments, the anti-ACVR2A antibodies provided herein comprise LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 41. The CDR sequences can be determined according to any well-known numbering system or a combination thereof. In some embodiments, the CDRs are according to the IMGT numbering system. In some embodiments, the CDRs are according to the Kabat numbering system. In some embodiments, the CDRs are according to the AbM numbering system. In other embodiments, the CDRs are according to the Chothia numbering system. In other embodiments, the CDRs are according to the Contact numbering system.

[0086] In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 1, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 3, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 4, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 5, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 6. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 6. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 8, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 6. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 9, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 10, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 11, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 13, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 14. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 15. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 16. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 17. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 18. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 19.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO:7, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO:20. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO:12, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO:21. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO:12, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO:22. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO:7, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO:23. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO:7, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO:24. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO:7, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO:6. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO:12, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO:25. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO:12, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO:26. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO:7, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO:27.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 28. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 29. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 11, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 30. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 31. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 32. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 33. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 9, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 34. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 11, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 35. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 11, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 36.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 11, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 37. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 38. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 39. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 40. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise an HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 9, and an LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 41. CDR sequences can be determined according to any known numbering system or combination thereof. In some embodiments, the CDRs are numbered according to IMGT numbering. In some embodiments, the CDRs are numbered according to Kabat numbering. In some embodiments, the CDRs are numbered according to AbM numbering. In other embodiments, the CDRs are numbered according to Chothia numbering. In other embodiments, the CDRs are numbered according to Contact numbering.

[0087] In other embodiments, provided herein is an antibody that binds to ACVR2A, which has: (i) an HCDR1 comprising an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any of SEQ ID NOs: 42, 48, 49, 50, 54, 55, 56, 57, and 58; (iii) an HCDR2 comprising an amino acid sequence having 5%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 44; (iv) an HCDR3 comprising an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 45, 5 (v) an LCDR1 comprising an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to any of SEQ ID NOs: 46, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, and 82; and / or (vi) an LCDR3 comprising an amino acid sequence having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to either of SEQ ID NOs: 47 and 53. In some embodiments, the anti-ACVR2A antibody is humanized.In some embodiments, the anti-ACVR2A antibody comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0088] In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 42, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 49, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 50, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 52, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 53. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 52, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 53.In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 49, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 52, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 53. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 54, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 55, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 56, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47.In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 58, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 59, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 60, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 61, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47.In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 62, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 63, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 52, LCDR2 comprises the amino acid sequence of SEQ ID NO: 82, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 64, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 65, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47.In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 66, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 59, LCDR2 comprises the amino acid sequence of SEQ ID NO: 67, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 59, LCDR2 comprises the amino acid sequence of SEQ ID NO: 68, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 52, LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 53. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 59, LCDR2 comprises the amino acid sequence of SEQ ID NO: 69, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47.In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 59, LCDR2 comprises the amino acid sequence of SEQ ID NO: 70, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 71, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 72, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. ... and LCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 73, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibody or antigen-binding fragment provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 56, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 74, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibody or antigen-binding fragment provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 75, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 67, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 68, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47.In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 54, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 76, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 56, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 77, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 56, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 78, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 56, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 79, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 69, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47.In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 80, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 70, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some specific embodiments, in the antibodies or antigen-binding fragments provided herein, HCDR1 comprises the amino acid sequence of SEQ ID NO: 54, HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, LCDR2 comprises the amino acid sequence of SEQ ID NO: 81, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 47.

[0089] In some embodiments, the antibody further comprises one or more framework regions of SEQ ID NOs: 1-41. In some embodiments, the antibodies provided herein are humanized antibodies. The framework regions described herein are determined based on the boundaries of the CDR numbering system. In other words, when CDRs are determined by, for example, Kabat, IMGT, or Chothia, the framework regions are the amino acid residues surrounding the CDRs in the variable region in the following format from N-terminus to C-terminus: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. For example, FR1 is defined as the amino acid residues N-terminal to the CDR1 amino acid residues as defined, for example, by the Kabat numbering system, the IMGT numbering system, or the Chothia numbering system; FR2 is defined as the amino acid residues between the CDR1 amino acid residues and the CDR2 amino acid residues as defined, for example, by the Kabat numbering system, the IMGT numbering system, or the Chothia numbering system; FR3 is defined as the amino acid residues between the CDR2 amino acid residues and the CDR3 amino acid residues as defined, for example, by the Kabat numbering system, the IMGT numbering system, or the Chothia numbering system; and FR4 is defined as the amino acid residues C-terminal to the CDR3 amino acid residues as defined, for example, by the Kabat numbering system, the IMGT numbering system, or the Chothia numbering system.

[0090] In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 3 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 4 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 5 and a VL comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 8 and a VL comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 9 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 10 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 13 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 14.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 18. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 21. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 23. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 24. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 6.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 25. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 26. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 27. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 28. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 29. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 31. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 32. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 33. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 9 and a VL comprising the amino acid sequence of SEQ ID NO: 34. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 36.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 37. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 38. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 39. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 40. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH comprising the amino acid sequence of SEQ ID NO: 9 and a VL comprising the amino acid sequence of SEQ ID NO: 41.

[0091] In certain embodiments, the antibodies or antigen-binding fragments thereof described herein comprise an amino acid sequence that has a certain percent identity compared to any of the antibodies provided herein, for example, those described in Section 7 below.

[0092] The determination of percent identity between two sequences, e.g., amino acid sequences or nucleic acid sequences, can be accomplished using a mathematical algorithm. A non-limiting example of a mathematical algorithm utilized for comparing two sequences is the algorithm of Karlin and Altschul, Proc. Natl. Acad. Sci. USA 87:2264-2268 (1990), modified as in Karlin and Altschul, Proc. Natl. Acad. Sci. USA 90:5873-5877 (1993). Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul et al., J. Mol. Biol. 215:403 (1990). BLAST nucleotide searches can be performed, for example, using the NBLAST nucleotide program parameters set to score=100 and word length=12 to obtain nucleotide sequences homologous to the nucleic acid molecules described herein. BLAST protein searches can be performed using the XBLAST program parameters set, for example, to a score of 50 and word length of 3, to obtain amino acid sequences homologous to the protein molecules described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., Nucleic Acids Res. 25:3389-3402 (1997). Alternatively, PSI BLAST can be used to perform an iterated search that detects distant relationships between molecules (Id.). When utilizing BLAST, Gapped BLAST, and PSI Blast programs, the default program parameters for the respective programs (e.g., XBLAST and NBLAST) can be used (see, e.g., the National Center for Biotechnology Information (NCBI) World Wide Web at ncbi.nlm.nih.gov). Another non-limiting example of a mathematical algorithm utilized for sequence comparison is the algorithm of Myers and Miller, CABIOS 4:11-17 (1998).Such an algorithm is incorporated into the ALIGN program (version 2.0), which is part of the GCG sequence alignment software package. When utilizing the ALIGN program to compare amino acid sequences, a PAM 120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. When calculating percent identity, typically only exact matches are counted.

[0093] In some embodiments, the antibodies provided herein contain substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence, but an anti-ACVR2A antibody comprising that sequence retains the ability to bind to ACVR2A. In some embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the reference amino acid sequence. In some embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). Optionally, the anti-ACVR2A antibodies provided herein include post-translational modifications of the reference sequence.

[0094] In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:1, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:3, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:2.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:4, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:5, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:6.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:7, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:6. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:8, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:6.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:9, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 10, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:2.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 11, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 12, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:2.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 13, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:7, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:14.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:7, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:15. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:7, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:2. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 12, and a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 16.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 7, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 17. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:7, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:18.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:7, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:19. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:7, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:20.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 12, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 21. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 12, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 22.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 7, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 23. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:7, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:24.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:7, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:6. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 12, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:25.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 12, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:26. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:7, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:27.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:7, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:28. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:7, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:29. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 11, and at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 30. and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 7. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 31. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 7, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 32.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 7, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 33. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:9, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:34.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 11, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 35. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 11, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 36.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 11, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 37. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 12, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 38.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 12, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 39. In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 12, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:40.In some embodiments, the antibodies or antigen-binding fragments provided herein comprise a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 9, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 41. In all of the above embodiments, the antibodies bind to ACVR2A.

[0095] In some embodiments, functional epitopes can be mapped, for example, by combinatorial alanine scanning, to identify amino acids in the ACVR2A protein required for interaction with the anti-ACVR2A antibodies provided herein. In some embodiments, the epitope may be identified using the three-dimensional structure and crystal structure of an anti-ACVR2A antibody bound to ACVR2A. In some embodiments, the present disclosure provides antibodies that specifically bind to the same epitope as any of the anti-ACVR2A antibodies provided herein. For example, in some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 3 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 4 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 5 and a VL comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 8 and a VL comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 9 and a VL comprising the amino acid sequence of SEQ ID NO: 2.In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 10 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 13 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 18.In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 21. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 23. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 24. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 25. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 26.In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 27. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 28. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 29. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 31. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 32. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 33. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 9 and a VL comprising the amino acid sequence of SEQ ID NO: 34. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 35.In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 36. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 37. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 38. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 39. In some embodiments, the antibodies or antigen-binding fragments provided herein bind to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 40. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 9 and a VL comprising the amino acid sequence of SEQ ID NO: 41.

[0096] In some embodiments, provided herein are anti-ACVR2A antibodies or antigen-binding fragments thereof that specifically bind to ACVR2A in competition with any one of the anti-ACVR2A antibodies described herein. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 3 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 4 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 5 and a VL comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:7 and a VL comprising the amino acid sequence of SEQ ID NO:6. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:8 and a VL comprising the amino acid sequence of SEQ ID NO:6. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:9 and a VL comprising the amino acid sequence of SEQ ID NO:2. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:10 and a VL comprising the amino acid sequence of SEQ ID NO:2.In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 13 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the antibody or antigen-binding fragment provided herein specifically binds to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 18.In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 19. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 21. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 23. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 24. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 25. In some embodiments, the antibody or antigen-binding fragment provided herein specifically binds to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 26.In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 27. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 28. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 29. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 31. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 32. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 33. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 9 and a VL comprising the amino acid sequence of SEQ ID NO: 34. In some embodiments, the antibody or antigen-binding fragment provided herein specifically binds to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 35.In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 36. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 37. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 38. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 39. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 40. In some embodiments, the antibodies or antigen-binding fragments provided herein specifically bind to ACVR2A competitively with an anti-ACVR2A antibody comprising a VH comprising the amino acid sequence of SEQ ID NO: 9 and a VL comprising the amino acid sequence of SEQ ID NO: 41.

[0097] In some embodiments, provided herein is an ACVR2A binding protein comprising any one of the anti-ACVR2A antibodies described above. In some embodiments, the ACVR2A binding protein is a monoclonal antibody, including a murine antibody, a chimeric antibody, a humanized antibody, or a human antibody. In some embodiments, the anti-ACVR2A antibody is an antibody fragment, e.g., an scFv. In some embodiments, the ACVR2A binding protein is a fusion protein comprising an anti-ACVR2A antibody provided herein. In other embodiments, the ACVR2A binding protein is a multispecific antibody comprising an anti-ACVR2A antibody provided herein. Other exemplary ACVR2A binding molecules are described in more detail in the following sections.

[0098] In some embodiments, an anti-ACVR2A antibody or antigen binding protein according to any of the above embodiments may incorporate any of the features, alone or in combination, as described in Sections 5.2.2-5.2.6, below.

[0099] 5.2.2. Antibody fragments As used herein, the term "antibody" also includes various antibody fragments thereof. Antibodies provided herein include, but are not limited to, immunoglobulin molecules and immunologically active portions of immunoglobulin molecules. The immunoglobulin molecules provided herein can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) of immunoglobulin molecules. In some embodiments, the antibody is an IgG antibody. In some embodiments, the IgG antibody is an IgG1 antibody. In some embodiments, the IgG antibody is an IgG2, IgG3, or IgG4 antibody.

[0100] Antibody variants and derivatives include functional fragments of antibodies that retain the ability to bind antigen.Exemplary functional fragments include Fab fragments (e.g., antibody fragments containing an antigen-binding domain and comprising a light chain and a portion of a heavy chain bridged by a disulfide bond); Fab' (e.g., antibody fragments containing a single antigen-binding domain comprising a Fab and an additional portion of the heavy chain through the hinge region); F(ab')2 (e.g., two Fab' molecules linked by an interchain disulfide bond in the hinge region of the heavy chain; the Fab' molecules may be directed against the same or different epitopes); bispecific Fab (e.g., an Fab having two antigen-binding domains, Fab molecules, each of which may be directed against a different epitope; single chains comprising variable regions, also known as scFvs (e.g., the variable antigen-binding determining regions of a single light and heavy chain of an antibody linked together by a chain, e.g., 10-25 amino acids); disulfide-linked Fvs, or dsFvs (e.g., the variable antigen-binding determining regions of a single light and heavy chain of an antibody linked together by a disulfide bond); camelized VHs (e.g., the variable antigen-binding determining regions of a single heavy chain of an antibody, in which some amino acids of the VH interface are those found in the heavy chain of a naturally occurring camelid antibody). binding determining regions); bispecific scFvs (e.g., scFv or dsFv molecules having two antigen-binding domains, each of which may be directed against a different epitope); diabodies (e.g., dimerized scFvs formed when the VH domain of a first scFv assembles with the VL domain of a second scFv and the VL domain of the first scFv assembles with the VH domain of the second scFv; the two antigen-binding regions of the diabody may be directed against the same or different epitopes); These include diabodies (e.g., trimerizing scFvs, which are formed in a manner similar to diabodies, but with three antigen-binding domains generated in a single complex; the three antigen-binding domains may be directed to the same or different epitopes); and tetrabodies (e.g., tetramerizing scFvs, which are formed in a manner similar to diabodies, but with four antigen-binding domains generated in a single complex; the four antigen-binding domains may be directed to the same or different epitopes).

[0101] Various techniques have been developed for producing antibody fragments. Traditionally, these fragments were derived via proteolytic digestion of intact antibodies (see, e.g., Morimoto et al., 1992, J. Biochem. Biophys. Methods 24:107-17; and Brennan et al., 1985, Science 229:81-83). However, these fragments can now be produced directly by recombinant host cells. For example, Fab, Fv, and scFv antibody fragments can all be expressed in and secreted from E. coli or yeast cells, thereby allowing the facile production of large amounts of these fragments. Antibody fragments can be isolated from the antibody phage libraries described above. Alternatively, Fab'-SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab')2 fragments (Carter et al., 1992, Bio / Technology 10:163-67). According to another approach, F(ab')2 fragments can be isolated directly from recombinant host cell culture. Fab and F(ab')2 fragments with extended in vivo half-lives containing salvage receptor-binding epitope residues are described, for example, in U.S. Pat. No. 5,869,046. Other techniques for the production of antibody fragments will be apparent to those skilled in the art. In certain embodiments, the antibody is a single-chain Fv fragment (scFv) (see, e.g., WO 93 / 16185; U.S. Pat. Nos. 5,571,894 and 5,587,458). Fvs and scFvs have intact combining sites that lack constant regions; therefore, they may be suitable for reduced nonspecific binding during in vivo use. scFv fusion proteins may be constructed to provide fusion of an effector protein at either the amino or carboxy terminus of the scFv (see, e.g., Borrebaeck, ed., supra). An antibody fragment may also be a "linear antibody," e.g., as described in the references cited above. Such linear antibodies may be monospecific or multispecific, e.g., bispecific.

[0102] 5.2.3. Antibody Variants In some embodiments, amino acid sequence modification of the antibodies that bind to ACVR2A described herein is contemplated. For example, it may be desirable to optimize the binding affinity and / or other biological properties of the antibody (including, but not limited to, specificity, thermal stability, expression level, effector function, glycosylation, reduced immunogenicity, or solubility). Thus, in addition to the antibodies that bind to ACVR2A described herein, it is contemplated that variants of the antibodies that bind to ACVR2A described herein can be prepared. For example, antibody variants can be prepared by introducing appropriate nucleotide changes into the encoding DNA and / or by synthesis of the desired antibody or polypeptide. Those skilled in the art will understand that amino acid changes may alter post-translational processing of the antibody.

[0103] chemical modification In some embodiments, the antibodies provided herein are chemically modified, for example, by the covalent attachment of any type of molecule to the antibody. Antibody derivatives may include antibodies chemically modified by, for example, glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, or conjugation to one or more immunoglobulin domains (e.g., Fc or portions of Fc). Any of a number of chemical modifications can be made by known techniques, including, but not limited to, specific chemical cleavage, acetylation, formulation, metabolic synthesis of tunicamycin, etc. Additionally, the antibody may contain one or more non-classical amino acids.

[0104] In some embodiments, the antibodies provided herein are modified to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to an antibody can be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites are created or removed.

[0105] When the antibodies provided herein are fused to an Fc region, the carbohydrate attached thereto can be modified. Natural antibodies produced by mammalian cells typically contain branched, biantennary oligosaccharides that are generally attached by an N-linkage to Asn297 in the CH2 domain of the Fc region. See, for example, Wright et al., TIBTECH 15:26-32 (1997). The oligosaccharides may include various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose attached to the GlcNAc in the "stem" of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharides in the binding molecules provided herein can be made to generate variants with specific improved properties.

[0106] In other embodiments, when an antibody provided herein is fused to an Fc region, the antibody variant provided herein may have a carbohydrate structure lacking fucose attached (directly or indirectly) to the Fc region. For example, the amount of fucose in such an antibody may be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose in the glycan at Asn297 relative to the sum of all glycostructures (e.g., complex, hybrid, and high-mannose structures) attached to Asn297, as measured by MALDI-TOF mass spectrometry, for example, as described in WO 2008 / 077546. Asn297 refers to an asparagine residue located at approximately position 297 (EU numbering of Fc region residues) in the Fc region. However, Asn297 may also be located approximately ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, depending on minor sequence variations in the antibody. Such fucosylation variants may have improved ADCC function. See, e.g., U.S. Patent Application Publication Nos. 2003 / 0157108 and 2004 / 0093621. Examples of publications relating to "defucosylated" or "fucose-deficient" antibody variants include U.S. Patent Application Publication Nos. 2003 / 0157108; WO 2000 / 61739; WO 2001 / 29246; U.S. Patent Application Publication Nos. 2003 / 0115614; 2002 / 0164328; 2004 / 0093621; and U.S. Patent Application Publication Nos. 2004 / 0115614 and 2002 / 0164328. 32140; 2004 / 0110704; 2004 / 0110282; 2004 / 0109865; WO 2003 / 085119; 2003 / 084570; 2005 / 035586; 2005 / 035778; 2005 / 053742; 2002 / 031140; Okazaki et al., J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al., Biotech. Bioeng. 87:614 (2004).Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells, which are deficient in protein fucosylation (Ripka et al., Arch. Biochem. Biophys. 249:533-545 (1986); U.S. Patent Application Publication No. 2003 / 0157108; and WO 2004 / 056312), and alpha-1,6-fucosyltransferase gene FUT8 knockout CHO cells (see, e.g., Yamane-Ohnuki et al., Biotech. Bioeng. 87:614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and WO 2003 / 085107).

[0107] The binding molecules, including antibodies, provided herein further provide bisected oligosaccharides, for example, where a biantennary oligosaccharide attached to the Fc region is bisected by GlcNAc. Such variants may have reduced fucosylation and / or improved ADCC function. Examples of such variants are described, for example, in WO 2003 / 011878 (Jean-Mairet et al.); U.S. Pat. No. 6,602,684 (Umana et al.); and U.S. Pat. No. 2005 / 0123546 (Umana et al.). Variants having at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such variants may have improved CDC function. Such variants are described, for example, in WO 1997 / 30087; WO 1998 / 58964; and WO 1999 / 22764.

[0108] In the present antibodies and molecules comprising an Fc region, one or more amino acid modifications may be introduced into the Fc region, thereby generating an Fc region variant. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) containing an amino acid modification (e.g., a substitution) at one or more amino acid positions.

[0109] In some embodiments, the present application contemplates variants that retain some, but not all, effector functions, making them desirable candidates for uses in which the half-life of the binding molecule in vivo is important, but certain effector functions (such as complement and ADCC) are unnecessary or deleterious. In vitro and / or in vivo cytotoxicity assays can be performed to confirm reduced / depleted CDC and / or ADCC activity. For example, Fc receptor (FcR) binding assays can be performed to ensure that the binding molecule lacks FcγR binding (and thus likely lacks ADCC activity) but retains FcRn binding ability. Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest are described in U.S. Pat. No. 5,500,362 (e.g., Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); U.S. Pat. No. 5,821,337 (Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assay methods may be used (e.g., the ACTI™ non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA); and CytoTox 96® non-radioactive cytotoxicity assay (Promega, Madison, WI). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model (e.g., as described in Clynes et al.). (See, e.g., WO 2006 / 029879 and WO 2005 / 100402 for examples of CDC binding assays.) A Clq binding assay may also be performed to confirm that the antibody is unable to bind Clq and therefore lacks CDC activity. See, e.g., the Clq and C3c binding ELISAs in WO 2006 / 029879 and WO 2005 / 100402.To assess complement activation, a CDC assay may be performed (see, e.g., Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and MJ Glennie, Blood 103:2738-2743 (2004)). Determination of FcRn binding and in vivo clearance / half-life can also be performed using methods known in the art (see, e.g., Petkova, SB et al., Int'l. Immunol. 18(12):1759-1769 (2006)).

[0110] Binding molecules with reduced effector function include those with substitutions at one or more of Fc region residues 238, 265, 269, 270, 297, 327, and 329 (U.S. Patent No. 6,737,056). Such Fc variants include Fc variants with substitutions at two or more of amino acid positions 265, 269, 270, 297, and 327, including the so-called "DANA" Fc variant with substitutions of residues 265 and 297 to alanine (U.S. Patent No. 7,332,581).

[0111] Certain variants have been described that have improved or diminished binding to FcRs (see, e.g., U.S. Pat. No. 6,737,056; WO 2004 / 056312; and Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001)).

[0112] In some embodiments, the variants comprise an Fc region having one or more amino acid substitutions that improve ADCC, e.g., substitutions at positions 298, 333, and / or 334 (EU numbering of residues) of the Fc region. In some embodiments, the modifications are made in the Fc region and result in altered (i.e., either improved or decreased) Clq binding and / or complement dependent cytotoxicity (CDC) (e.g., as described in U.S. Pat. No. 6,194,551, WO 99 / 51642, and Idusogie et al., J. Immunol. 164:4178-4184 (2000)).

[0113] Binding molecules with extended half-lives and improved binding to the neonatal Fc receptor (FcRn) (FcRn is involved in the transfer of maternal IgG to the fetus) (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)) have been described in U.S. Patent Application Publication No. 2005 / 0014934 (Hinton et al.). These molecules comprise an Fc region with one or more substitutions therein that improve binding of the Fc region to FcRn. Such Fc variants include those having a substitution at one or more of the following Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, ​​413, 424, or 434, e.g., a substitution at Fc region residue 434 (U.S. Patent No. 7,371,826). See also Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821; and WO 94 / 29351 for other examples of Fc region variants.

[0114] In some embodiments, it may be desirable to generate cysteine ​​engineered antibodies in which one or more residues of an antibody are substituted with cysteine ​​residues. In some embodiments, the substituted residues are present in accessible sites of the antibody. By substituting these residues with cysteine, reactive thiol groups are thereby placed in accessible sites of the antibody, which can be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to generate immunoconjugates, as further described herein.

[0115] Substitutions, deletions, or insertions The variations can be substitutions, deletions, or insertions of one or more codons encoding the antibody or polypeptide, resulting in a change in the amino acid sequence compared to the original antibody or polypeptide. Target sites for substitutional mutagenesis include the CDRs and FRs.

[0116] Amino acid substitutions can result from replacing one amino acid with another amino acid with similar structural and / or chemical properties, e.g., replacing leucine with serine, e.g., conservative amino acid substitutions. Mutations can be introduced into the nucleotide sequences encoding the molecules provided herein using standard techniques known to those of skill in the art, including, for example, site-directed mutagenesis and PCR-mediated mutagenesis, which result in amino acid substitutions. Insertions or deletions can optionally range from about 1 to 5 amino acids. In certain embodiments, substitutions, deletions, or insertions comprise fewer than 25 amino acid substitutions, fewer than 20 amino acid substitutions, fewer than 15 amino acid substitutions, fewer than 10 amino acid substitutions, fewer than 5 amino acid substitutions, fewer than 4 amino acid substitutions, fewer than 3 amino acid substitutions, or fewer than 2 amino acid substitutions compared to the original molecule. In specific embodiments, substitutions are conservative amino acid substitutions at one or more predicted non-essential amino acid residues. Acceptable variations can be determined by systematically inserting, deleting, or substituting amino acids in a sequence and testing the resulting variants for activity exhibited by the parent antibody.

[0117] Amino acid sequence insertions include amino- and / or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing multiple residues, as well as intrasequence insertions of single or multiple amino acid residues. An exemplary terminal insertion is an antibody with an N-terminal methionyl residue.

[0118] Antibodies generated by conservative amino acid substitutions are included in the present disclosure. In conservative amino acid substitutions, an amino acid residue is replaced with an amino acid residue having a side chain with a similar charge. As described above, families of amino acid residues with side chains with similar charges have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Alternatively, mutations can be introduced randomly along all or part of the coding sequence, such as by saturation mutagenesis, and the resulting mutants can be screened for biological activity to identify mutants that retain activity. After mutagenesis, the encoded protein can be expressed and the activity of the protein determined. Conservative substitutions (e.g., within a group of amino acids with similar properties and / or side chains) can be made to maintain or not significantly change properties. Exemplary substitutions are shown in Table 2 below.

[0119] [Table 3]

[0120] Amino acids may be classified according to similarities in the properties of their side chains (see, e.g., Lehninger, Biochemistry 73-75 (2d ed. 1975)): (1) nonpolar: Ala (A), Val (V), Leu (L), Ile (I), Pro (P), Phe (F), Trp (W), Met (M); (2) uncharged polar: Gly (G), Ser (S), Thr (T), Cys (C), Tyr (Y), Asn (N), Gln (Q); (3) acidic: Asp (D), Glu (E); and (4) basic: Lys (K), Arg (R), His (H). Alternatively, naturally occurring residues can be categorized into groups based on common side chain properties: (1) hydrophobic: norleucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that affect chain orientation: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe. For example, any cysteine ​​residue not involved in maintaining the proper conformation of the antibody can also be substituted with another amino acid (such as alanine or serine) to improve the oxidative stability of the molecule and prevent aberrant crosslinking. Non-conservative substitutions involve exchanging a member of one of these classes for another.

[0121] One type of substitutional variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Generally, the resulting variants selected for further testing have modified (e.g., improved) certain biological properties (e.g., increased affinity, decreased immunogenicity) compared to the parent antibody and / or have substantially retained certain biological properties of the parent antibody. An exemplary substitutional variant is an affinity-matured antibody, which may be conveniently generated using phage display-based affinity maturation techniques, such as those described herein. Briefly, one or more CDR residues are mutated, and the variant antibodies are displayed on phage and screened for a particular biological activity (e.g., binding affinity).

[0122] Modifications (e.g., substitutions) may be made in the CDRs, e.g., to improve antibody affinity. Such modifications may be made in CDR "hotspots," i.e., residues encoded by codons that undergo frequent mutation during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and / or in the SDRs (a-CDRs), and the resulting mutant antibodies or fragments thereof are tested for binding affinity. Affinity maturation by constructing and reselecting from a secondary library is described, for example, in Hoogenboom et al., Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some embodiments of affinity maturation, diversity is introduced into the variable genes selected for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity. Another method for introducing diversity involves a CDR-directed approach, in which several CDR residues (e.g., 4-6 residues at a time) are randomized. CDR residues involved in antigen binding may be specifically identified using, for example, alanine scanning mutagenesis or modeling. A more detailed description of affinity maturation is provided in the following sections.

[0123] In some embodiments, substitutions, insertions, or deletions may occur within one or more CDRs, so long as the modifications do not substantially reduce the antibody's ability to bind to the antigen. For example, conservative modifications (e.g., conservative substitutions provided herein) that do not substantially reduce binding affinity may be made in a CDR. In some embodiments of the variant antibody sequences provided herein, each CDR is either unaltered or contains no more than one, two, or three amino acid substitutions.

[0124] A useful method for identifying antibody residues or regions that can be targeted for mutagenesis is called "alanine scanning mutagenesis," as described by Cunningham and Wells, Science, 244:1081-1085 (1989). In this method, target residues or groups (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) are identified and replaced with neutral or negatively charged amino acids (e.g., alanine or polyalanine) to determine whether the interaction between the antibody and antigen is affected. Further substitutions may be introduced at amino acid positions that demonstrate functional sensitivity to the initial substitution. Alternatively, or in addition, a crystal structure of an antigen-antibody complex may be used to identify contact points between the antibody and antigen. Such contact and neighboring residues may be targeted or eliminated as candidates for substitution. Mutants may be screened to determine whether they contain desired properties.

[0125] Amino acid sequence insertions include amino- and / or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues. An example of a terminal insertion is an antibody with an N-terminal methionyl residue. Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g., to ADEPT) or a polypeptide which increases the serum half-life of the antibody.

[0126] Variations can be made using methods known in the art, such as oligonucleotide-mediated (site-directed) mutagenesis, alanine scanning, and PCR mutagenesis. Site-directed mutagenesis (see, e.g., Carter, Biochem J. 237:1-7 (1986); and Zoller et al., Nucl. Acids Res. 10:6487-500 (1982)), cassette mutagenesis (see, e.g., Wells et al., Gene 34:315-23 (1985)), or other known techniques can be performed on cloned DNA to produce antibody variant DNA.

[0127] 5.2.4. In Vitro Affinity Maturation In some embodiments, antibody variants with improved properties, such as affinity, stability, or expression level, compared to the parent antibody can be prepared by in vitro affinity maturation. Similar to natural prototypes, in vitro affinity maturation is based on the principle of mutation and selection. Libraries of antibodies are displayed (e.g., covalently or noncovalently) on the surface of an organism (e.g., phage, bacteria, yeast, or mammalian cells) or in association with the mRNA or DNA that encodes them. Affinity selection of the displayed antibodies allows for the isolation of organisms or complexes that carry the genetic information encoding the antibody. Two or three rounds of mutation and selection using display methods such as phage display typically result in antibody fragments with affinities in the low nanomolar range. Affinity-matured antibodies can have nanomolar or even picomolar affinities for target antigens.

[0128] Phage display is a widespread method for antibody display and selection. Antibodies are displayed on the surface of Fd or M13 bacteriophage as fusions to bacteriophage coat proteins. Selection involves exposing the phage-displayed antibodies to antigen to enable them to bind to their target, a process called "panning." Phage that bind to the antigen are recovered and used to infect bacteria to produce phage for further rounds of selection. For reviews, see, e.g., Hoogenboom, Methods. Mol. Biol. 178:1-37 (2002); and Bradbury and Marks, J. Immunol. Methods 290:29-49 (2004).

[0129] In some embodiments, a mammalian display system may be used.

[0130] Diversity can also be introduced into the CDRs of an antibody library in a targeted manner or through random introduction. The former approach involves sequentially targeting all CDRs of an antibody through high-level or low-level mutagenesis, or by targeting isolated hot spots of somatic hypermutation (see, e.g., Ho et al., J. Biol. Chem. 280:607-17 (2005)), or by targeting residues suspected of affecting affinity for experimental or structural reasons. Diversity can also be introduced by replacing naturally diverse regions through DNA shuffling or similar techniques (see, e.g., Lu et al., J. Biol. Chem. 278:43496-507 (2003); U.S. Patent Nos. 5,565,332 and 6,989,250). Alternative techniques that target hypervariable loops extending into framework region residues (see, e.g., Bond et al., J. Mol. Biol. 348:699-709 (2005)) use loop deletions and insertions in the CDRs or use hybridization-based diversification (see, e.g., U.S. Patent Publication No. 2004 / 0005709). Additional methods for generating diversity in CDRs are disclosed, for example, in U.S. Patent No. 7,985,840. Additional methods that can be used to generate antibody libraries and / or antibody affinity maturation are disclosed, for example, in U.S. Pat. Nos. 8,685,897 and 8,603,930, and U.S. Patent Application Publication Nos. 2014 / 0170705, 2014 / 0094392, 2012 / 0028301, 2011 / 0183855, and 2009 / 0075378, each of which is incorporated herein by reference.

[0131] Screening of libraries can be accomplished by a variety of techniques known in the art, for example, antibodies can be immobilized on solid supports, columns, pins, or cellulose / poly(vinylidene fluoride) membranes / other filters, expressed on host cells immobilized on adsorption plates, or used in cell sorting, or conjugated to biotin for capture on streptavidin-coated beads, or used in any other method for panning display libraries.

[0132] For reviews of in vitro affinity maturation methods, see, e.g., Hoogenboom, Nature Biotechnology 23:1105-16 (2005); Quiroz and Sinclair, Revista Ingeneria Biomedia 4:39-51 (2010); and references therein.

[0133] 5.2.5. Antibody Modification Covalent modifications of antibodies are included within the scope of the present disclosure. Covalent modifications include reacting targeted amino acid residues of the antibody with organic derivatizing agents capable of reacting with selected side chains or the N- or C-terminal residues of the antibody. Other modifications include deamidation of glutaminyl and asparaginyl residues to the corresponding glutamyl and aspartyl residues, respectively, hydroxylation of proline and lysine, phosphorylation of the hydroxyl group of seryl or threonyl residues, methylation of the α-amino groups of lysine, arginine, and histidine side chains (see, e.g., Creighton, Proteins: Structure and Molecular Properties 79-86 (1983)), acetylation of the N-terminal amine, and amidation of any C-terminal carboxyl group.

[0134] Other types of covalent modifications of antibodies included within the scope of the present disclosure include altering the native glycosylation pattern of the antibody or polypeptide, as described above (see, e.g., Beck et al., Curr. Pharm. Biotechnol. 9:482-501 (2008); and Walsh, Drug Discov. Today 15:773-80 (2010)), and linking the antibody to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol (PEG), polypropylene glycol, or polyoxyalkylenes, e.g., in the manner described in U.S. Pat. Nos. 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192; or 4,179,337. Antibodies that bind ACVR2A of the present disclosure may also be genetically fused or conjugated to one or more immunoglobulin constant regions or portions thereof (e.g., Fc) to extend half-life and / or confer known Fc-mediated effector functions.

[0135] The antibodies that bind ACVR2A of the present disclosure may also be modified to form chimeric molecules comprising an antibody that binds ACVR2A fused to another heterologous polypeptide or amino acid sequence, such as an epitope tag (see, e.g., Terpe, Appl. Microbiol. Biotechnol. 60:523-33 (2003)), or the Fc region of an IgG molecule (see, e.g., Aruffo, Antibody Fusion Proteins 221-42 (Chamow and Ashkenazi eds., 1999)).

[0136] Also provided herein are fusion proteins comprising an antibody that binds ACVR2A of the present disclosure and a heterologous polypeptide. In some embodiments, the heterologous polypeptide to which the antibody is genetically fused or chemically conjugated is useful for targeting the antibody to cells that have ACVR2A expressed on their cell surface.

[0137] Also provided herein are panels of antibodies that bind to the ACVR2A antigen. In specific embodiments, the panel of antibodies has different association rates, different dissociation rates, different affinities for the ACVR2A antigen, and / or different specificities for the ACVR2A antigen. In some embodiments, the panel comprises or consists of about 10 to about 1000 or more antibodies. The panel of antibodies can be used in 96-well or 384-well plates, for example, for assays such as ELISA.

[0138] 5.2.6. Other Binding Molecules, Including Antibodies In another aspect, provided herein is a binding molecule comprising the anti-ACVR2A antibody provided herein. In some embodiments, the antibody against ACVR2A provided herein is part of another binding molecule. Exemplary binding molecules of the present disclosure are described herein.

[0139] fusion proteins In various embodiments, the antibodies provided herein can be genetically fused or chemically conjugated to another agent, e.g., a protein-based entity. The antibody can be chemically conjugated to the agent or otherwise non-covalently conjugated to the agent. The agent can be a peptide or an antibody (or fragment thereof).

[0140] Thus, in some embodiments, provided herein are antibodies recombinantly fused or chemically conjugated (covalently or non-covalently conjugated) to a heterologous protein or polypeptide (or fragment thereof, e.g., a polypeptide of about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 amino acids, or more than 500 amino acids) to produce a fusion protein, and uses thereof. In particular, provided herein are fusion proteins comprising an antigen-binding fragment (e.g., CDR1, CDR2, and / or CDR3) of an antibody provided herein and a heterologous protein, polypeptide, or peptide.

[0141] Additionally, the antibodies provided herein can be fused to marker or "tag" sequences, such as peptides, to facilitate purification. In specific embodiments, marker or tag amino acid sequences are hexahistidine peptides, hemagglutinin ("HA") tags, and "FLAG" tags.

[0142] Methods for fusing or conjugating moieties (including polypeptides) to antibodies are known (e.g., Amon et al., Monoclonal Antibodies for Immunotargeting of Drugs in Cancer Therapy, in Monoclonal Antibodies and Cancer Therapy 243-56 (Reisfeld et al., eds., 1985); Hellstrom et al., Antibodies for Drug Delivery, in Controlled Drug Delivery 623-53 (Robinson et al., eds., 2d ed. 1987); Thorpe, Antibody Carriers of Cytotoxic Agents in Cancer Therapy: A Review, in Monoclonal Antibodies: Biological and Clinical Applications 475-506 (Pinchera et al., eds., 1985); Analysis, Results, and Future Prospect of the Therapeutic Use of Radiolabeled Antibodies in Cancer Therapy, in Monoclonal Antibodies for Cancer Detection and Therapy 475-506 (Pinchera et al., eds., 1985)). 303-16 (Baldwin et al., eds., 1985); Thorpe et al. al., Immunol. Rev. 62:119-58 (1982); US Patent No. 5,336,603; US Patent No. 5,622,929; US Patent No. 5,359, No. 046; No. 5,349,053; No. 5,447,851; No. 5,723,125; No. 5,783,181; No. 5,908,626 ; European Patent No. 5,844,095; and European Patent No. 5,112,946; European Patent No. 307,434; European Patent No. 367,166; European Patent No. 394,827; International Publication Nos. 91 / 06570, 96 / 04388, 96 / 22024, 97 / 34631 and 99 / 04813; Ashkenazi et al.,Proc.Natl.Acad.Sci.USA, 88:10535-39 (1991); Traunecker et al., Nature, 331:84-86 (1988); Zheng et al., J. Immunol. 154:5590-600 (1995); and Vil et al., Proc. Natl. Acad. Sci. USA 89:11337-41 (1992).

[0143] Fusion proteins may be generated, for example, through the techniques of gene shuffling, motif shuffling, exon shuffling, and / or codon shuffling (collectively referred to as "DNA shuffling"). DNA shuffling may be used to alter the activities of the antibodies provided herein (e.g., including antibodies with higher affinities and lower dissociation rates) (see, e.g., U.S. Patent Nos. 5,605,793; 5,811,238; 5,830,721; 5,834,252; and 5,837,458; Patten et al., Curr. Opinion Biotechnol. 8:724-33 (1997); Harayama, Trends Biotechnol. 16(2):76-82 (1998); Hansson et al., J. Mol. Biol. 287:265-76 (1999); and Lorenzo and Blasco, Biotechniques 24(2):308-13 (1998)). Antibodies or the encoded antibodies may be modified by subjecting them to random mutagenesis by error-prone PCR, random nucleotide insertion, or other methods prior to recombination. Polynucleotides encoding the antibodies provided herein may be recombined with one or more components, motifs, sections, portions, domains, fragments, etc., of one or more heterologous molecules.

[0144] In some embodiments, an antibody provided herein is conjugated to a second antibody to form an antibody heteroconjugate.

[0145] In various embodiments, the antibody is genetically fused to the agent. Genetic fusion may be achieved by placing a linker (e.g., a polypeptide) between the antibody and the agent. The linker may be a flexible linker.

[0146] In various embodiments, the antibody is genetically conjugated to the therapeutic molecule by using the hinge region to link the antibody to the therapeutic molecule.

[0147] Also provided herein are methods for producing the various fusion proteins provided herein. The various methods described in Section 5.4 can also be utilized to produce the fusion proteins provided herein.

[0148] In specific embodiments, the fusion proteins provided herein are recombinantly expressed. Recombinant expression of the fusion proteins provided herein may require the construction of an expression vector containing a polynucleotide encoding the protein or a fragment thereof. Once a polynucleotide encoding a protein or a fragment thereof provided herein is obtained, a vector for producing the molecule can be produced by recombinant DNA technology using techniques well known in the art. Thus, methods for preparing a protein by expressing a polynucleotide containing an encoding nucleotide sequence are described herein. Methods well known to those skilled in the art can be used to construct expression vectors containing a coding sequence and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. Also provided are replicable vectors containing a nucleotide sequence encoding a fusion protein or a fragment thereof, or a CDR, provided herein, operably linked to a promoter.

[0149] The expression vector can be introduced into a host cell by conventional techniques, and the transfected cells then cultured by conventional techniques to produce a fusion protein provided herein. Accordingly, also provided herein is a host cell containing a polynucleotide encoding a fusion protein provided herein, or a fragment thereof, operably linked to a heterologous promoter.

[0150] A variety of host-expression vector systems may be utilized to express the fusion proteins provided herein. Such host-expression systems represent vehicles in which a coding sequence of interest may be produced and subsequently purified, but also represent cells that, when transformed or transfected with the appropriate nucleotide coding sequence, are capable of expressing the fusion proteins provided herein in situ. These include, but are not limited to, bacteria (e.g., microorganisms such as E. coli and B. subtilis transformed with recombinant bacteriophage DNA, plasmid DNA, or cosmid DNA expression vectors containing the coding sequence); yeast (e.g., Saccharomyces pichia) transformed with recombinant yeast expression vectors containing the coding sequence; Pichia); insect cell systems infected with a recombinant viral expression vector (e.g., baculovirus) containing the coding sequence; plant cell systems infected with a recombinant viral expression vector (e.g., cauliflower mosaic virus, CaMV, tobacco mosaic virus, TMV) or transformed with a recombinant plasmid expression vector (e.g., Ti plasmid) containing the coding sequence; or mammalian cell systems (e.g., COS, CHO, BHK, 293, NS0, and 3T3 cells) harboring a recombinant expression construct containing a promoter derived from the genome of a mammalian cell (e.g., metallothionein promoter) or a promoter derived from a mammalian virus (e.g., adenovirus late promoter; vaccinia virus 7.5K promoter). Examples of suitable vectors include Escherichia coli (Escherichia coli), particularly for expression of whole recombinant antibody molecules. Bacterial cells, such as Escherichia coli (E. coli), or eukaryotic cells can be used to express recombinant fusion proteins. For example, mammalian cells, such as Chinese hamster ovary cells (CHO), in combination with a vector such as the major intermediate-early gene promoter element from human cytomegalovirus, are effective expression systems for antibodies or variants thereof. In specific embodiments, expression of the nucleotide sequence encoding the fusion proteins provided herein is regulated by a constitutive promoter, an inducible promoter, or a tissue-specific promoter.

[0151] In bacterial systems, many expression vectors can be advantageously selected depending on the intended use of the expressed fusion protein. For example, when large quantities of such fusion proteins are to be produced, a vector that directs high-level expression of an easily purified fusion protein product may be desired for the production of pharmaceutical compositions of the fusion protein. Such vectors include, but are not limited to, the E. coli expression vector pUR278 (Ruther et al., EMBO 12:1791 (1983)), in which the coding sequence may be individually ligated into the vector in frame with the lacZ coding region to produce a fusion protein; the pIN vector (Inouye & Inouye, Nucleic Acids Res. 13:3101-3109 (1985); Van Heeke & Schuster, J. Biol. Chem. 24:5503-5509 (1989)); and the like. pGEX vectors can also be used to express foreign polypeptides as fusion proteins with glutathione 5-transferase (GST). Generally, such fusion proteins are soluble and can be easily purified from lysed cells by adsorption and binding to matrix glutathione agarose beads followed by elution in the presence of free glutathione. pGEX vectors are designed to contain thrombin or factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.

[0152] Many viral-based expression systems can be utilized in mammalian host cells. When adenovirus is used as an expression vector, the coding sequence of interest can be ligated into an adenovirus transcription / translation control complex, e.g., the late promoter and tripartite leader sequence. This chimeric gene can then be inserted into the adenovirus genome by in vitro or in vivo recombination. Insertion into non-essential regions of the viral genome (e.g., regions E1 or E3) results in recombinant viruses that are viable and capable of expressing the fusion protein in infected hosts (see, e.g., Logan & Shenk, Proc. Natl. Acad. Sci. USA 8 1:355-359 (1984)). Efficient translation of the inserted coding sequence may be required for efficient translation of the coding sequence. These signals include the ATG initiation codon and adjacent sequences. Furthermore, the initiation codon should be in line with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (see, e.g., Bittner et al., Methods in Enzymol. 153:51-544 (1987)).

[0153] In addition, a host cell strain may be chosen which modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of the protein product may be important for the function of the protein. Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed. To this end, eukaryotic host cells that possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product may be used. Such mammalian host cells include, but are not limited to, CHO, VERY, BHK, Hela, COS, MDCK, 293, 3T3, W138, BT483, Hs578T, HTB2, BT20, and T47D, NS0 (a murine myeloma cell line that does not endogenously produce any immunoglobulin chains), CRL7030, and HsS78Bst cells.

[0154] Stable expression can be utilized for long-term, high-yield production of recombinant proteins. For example, cell lines that stably express fusion proteins can be engineered. Rather than using expression vectors containing viral origins of replication, host cells can be transformed with DNA controlled by appropriate expression control elements (e.g., promoter, enhancer, sequences, transcription terminators, polyadenylation sites, etc.) and a selectable marker. After introduction of the foreign DNA, engineered cells can be grown in an enriched medium for 1-2 days and then switched to a selective medium. The selectable marker in the recombinant plasmid confers resistance to the selection and allows the cells to stably integrate the plasmid into their chromosomes and grow to form foci that can then be cloned and expanded into cell lines. This method can be advantageously used to engineer cell lines that express fusion proteins. Such engineered cell lines can be particularly useful in screening and evaluating compositions that interact directly or indirectly with binding molecules.

[0155] Several selection systems may be used, including but not limited to herpes simplex virus thymidine kinase (Wigler et al., Cell 11:223 (1977)), hypoxanthine guanine phosphoribosyltransferase (Szybalska & Szybalski, Proc. Natl. Acad. Sci. USA 48:202 (1992)), and adenine phosphoribosyltransferase (Lowy et al., Cell 22:8-17 (1980)) genes, which may be used in tk-, hgprt-, or aprt- cells, respectively. Antimetabolite resistance can also be used as the basis of selection for the following genes: dhfr, which confers resistance to methotrexate (Wigler et al., Natl. Acad. Sci. USA 77:357 (1980); O'Hare et al., Proc. Natl. Acad. Sci. USA 78:1527 (1981)); gpt, which confers resistance to mycophenolic acid (Mulligan & Berg, Proc. Natl. Acad. Sci. USA 78:2072 (1981)); neo, which confers resistance to the aminoglycoside G-418 (Wu and Wu, Biotherapy 3:87-95 (1991); Tolstoshev, Ann. Rev. Pharmacol. Toxicol. 32:573-596 (1993); Mulligan, Science 260:926-932 (1993); and Morgan and Anderson, Ann. Rev. Biochem. 62:191-217 (1993); May, TIB TECH 11(5):155-215 (1993); and hygro, which confers resistance to hygromycin (Santerre et al., Gene 30:147 (1984)).Methods commonly known in the field of recombinant DNA technology may be routinely applied to select the desired recombinant clones, and such methods are described, for example, in Ausubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, NY (1993); Kriegler, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY (1990); and Chapters 12 and 13 of Dracopoli et al., (eds.), Current Protocols in Human Genetics, John Wiley & Sons, NY (1994); Colberre-Garapin et al., J. Mol. Biol. 150:1 (1981) (incorporated herein by reference in their entireties).

[0156] The expression level of a fusion protein can be increased by vector amplification (for a review, see Bebbington and Hentschel, "The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells in DNA cloning," Vol. 3 (Academic Press, New York, 1987)). If the marker in the vector system expressing the fusion protein is amplifiable, increasing the level of inhibitor present in the host cell culture increases the copy number of the marker gene. Since the amplified region is associated with the fusion protein gene, production of the fusion protein also increases (Crouse et al., Mol. Cell. Biol. 3:257 (1983)).

[0157] A host cell may be co-transfected with multiple expression vectors provided herein. The vectors may contain identical selectable markers to allow equal expression of each encoded polypeptide. Alternatively, a single vector may be used that can encode and express multiple polypeptides. The coding sequences may comprise cDNA or genomic DNA.

[0158] Once a fusion protein provided herein is produced by recombinant expression, it may be purified by any method known in the art for the purification of polypeptides (e.g., immunoglobulin molecules), such as, for example, chromatography (e.g., ion exchange, affinity, particularly by affinity for a specific antigen after Protein A, sizing column chromatography, and kappa-selective affinity chromatography), centrifugation, differential solubility, or any other standard technique for the purification of proteins. Additionally, the fusion protein molecules provided herein can be fused to heterologous polypeptide sequences described herein or otherwise known in the art to facilitate purification.

[0159] Immunoconjugates In some embodiments, the present disclosure also provides immunoconjugates comprising any of the anti-ACVR2A antibodies described herein conjugated to one or more cytotoxic agents, e.g., chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), or radioactive isotopes.

[0160] In some embodiments, the immunoconjugate is an antibody that binds to a maytansinoid (e.g., U.S. Pat. Nos. 5,208,020, 5,416,064, and EP 0 425 142). 235(B1)); auristatins, e.g., monomethylauristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Pat. Nos. 5,635,483, 5,780,588, and 7,498,298); dolastatins; calicheamicin or its derivatives (see U.S. Pat. Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, and 5,877,296; Hinman et al., Cancer Res. 53:3336-3342 (1993); and Lode et al., Cancer Res. Res. 58:2925-2928 (1998); anthracyclines, such as daunomycin or doxorubicin (Kratz et al., Current Med. Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721 (2005); Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. Chem. Letters 12:1529-1532 (2002); King et al. al., J. Med. Chem. 45:4336-4343 (2002); and U.S. Patent No. 6,630,579); methotrexate; vindesine; taxanes such as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortataxel; trichothecenes; and antibody-drug conjugates (ADCs) conjugated to one or more drugs, including, but not limited to, CC1065.

[0161] In some embodiments, the immunoconjugate is an immunogen selected from, but not limited to, diphtheria A chain, non-binding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolacca americana proteins (PAPI, PAPII, and PAP-S), Momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitors, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and trichothecenes.

[0162] In some embodiments, the immunoconjugate comprises an antibody described herein conjugated to a radioactive atom to form a radioconjugate. A variety of radioisotopes are available for the production of radioconjugates. Examples include At 211 , 1 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 and radioactive isotopes of Lu. When a radioconjugate is used for detection, it may contain a radioactive atom for scintigraphic studies, such as TC99m or 1123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese, or iron.

[0163] Conjugates of antibodies and cytotoxic agents may be prepared using a variety of bifunctional protein coupling agents, such as N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl)hexanediamine), bis-diazonium derivatives (such as bis(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, ricin immunotoxin can be prepared as described in Vitetta et al., Science 238:1098 (1987). Carbon-14 labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugating radionucleotides to antibodies. See WO 94 / 11026.

[0164] The linker may be a "cleavable linker" that facilitates release of the conjugated agent within the cell, although non-cleavable linkers are also contemplated herein. Linkers for use in the conjugates of the present disclosure include, but are not limited to, acid-labile linkers (e.g., hydrazone linkers), disulfide-containing linkers, peptidase-sensitive linkers (e.g., peptide linkers containing the amino acids valine and / or citrulline, such as citrulline-valine or phenylalanine-lysine), photolabile linkers, dimethyl linkers, thioether linkers, or hydrophilic linkers designed to circumvent multidrug transporter-mediated resistance.

[0165] The immunoconjugates or ADCs herein contemplate such conjugates prepared using cross-linking reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, sulfo-SMPB, and SVSB (succinimidyl-(4-vinylsulfone)benzoate), which are commercially available (e.g., from Pierce Biotechnology, Inc., Rockford, Illinois, USA).

[0166] In other embodiments, the antibodies provided herein are, for example, conjugated or recombinantly fused to a diagnostic molecule. Such diagnosis and detection can be achieved, for example, by coupling the antibody to a detectable substance (including, but not limited to, various enzymes (e.g., but not limited to, horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase)); a prosthetic group (such as, but not limited to, streptavidin / biotin or avidin / biotin); a fluorescent material (such as, but not limited to, umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride, or phycoerythrin); a luminescent material (such as, but not limited to, luminol); a bioluminescent material (such as, but not limited to, luciferase, luciferin, or aequorin); or a chemiluminescent material (such as a gamma-, Auger-, beta-, alpha-, or positron-emitting radioisotope of 225Ac).

[0167] Polynucleotides In certain embodiments, the present disclosure provides polynucleotides encoding the antibodies that bind to ACVR2A, and fusion proteins comprising the antibodies that bind to ACVR2A described herein. The polynucleotides of the present disclosure can be in the form of RNA or DNA. DNA includes cDNA, genomic DNA, and synthetic DNA, and can be double-stranded or single-stranded, and if single-stranded, can be the coding strand or non-coding (antisense) strand. In some embodiments, the polynucleotide is in the form of cDNA. In some embodiments, the polynucleotide is a synthetic polynucleotide.

[0168] The present disclosure further relates to variants of the polynucleotides described herein, where the variants encode, for example, fragments, analogs, and / or derivatives of the antibodies that bind to ACVR2A of the present disclosure. In certain embodiments, the present disclosure provides polynucleotides, including polynucleotides having a nucleotide sequence at least about 75% identical, at least about 80% identical, at least about 85% identical, at least about 90% identical, at least about 95% identical, and in some embodiments, at least about 96%, 97%, 98%, or 99% identical to a polynucleotide encoding an antibody that binds to ACVR2A of the present disclosure. As used herein, the phrase "a polynucleotide having a nucleotide sequence that is at least, e.g., 95%, 'identical' to a reference nucleotide sequence" is intended to mean that the nucleotide sequence of the polynucleotide is identical to the reference sequence, except that the polynucleotide sequence may contain up to five point mutations per every 100 nucleotides of the reference nucleotide sequence. In other words, to obtain a polynucleotide having a nucleotide sequence that is at least 95% identical to a reference nucleotide sequence, up to 5% of the nucleotides in the reference sequence can be deleted or substituted with alternative nucleotides, or up to 5% of the total number of nucleotides in the reference sequence can be inserted into the reference sequence. These variations in the reference sequence can occur at the 5' or 3' terminal position of the reference nucleotide sequence, or anywhere between these terminal positions, either individually among the nucleotides in the reference sequence, or in one or more contiguous groups within the reference sequence.

[0169] Polynucleotide variants can contain alterations in coding regions, non-coding regions, or both. In some embodiments, polynucleotide variants contain alterations that produce silent substitutions, additions, or deletions, but do not alter the properties or activities of the encoded polypeptide. In some embodiments, polynucleotide variants contain silent substitutions that do not result in a change in the amino acid sequence of the polypeptide (due to the degeneracy of the genetic code). Polynucleotide variants can be produced for a variety of reasons, such as to optimize codon expression for a particular host (i.e., to change codons in human mRNA to codons preferred by a bacterial host, such as E. coli). In some embodiments, polynucleotide variants contain at least one silent mutation in a non-coding or coding region of the sequence.

[0170] In some embodiments, polynucleotide variants are produced to modulate or alter the expression (or expression level) of an encoded polypeptide. In some embodiments, polynucleotide variants are produced to increase expression of an encoded polypeptide. In some embodiments, polynucleotide variants are produced to decrease expression of an encoded polypeptide. In some embodiments, polynucleotide variants have increased expression of an encoded polypeptide compared to the parent polynucleotide sequence. In some embodiments, polynucleotide variants have decreased expression of an encoded polypeptide compared to the parent polynucleotide sequence.

[0171] Vectors containing the nucleic acid molecules described herein are also provided. In one embodiment, the nucleic acid molecules can be incorporated into a recombinant expression vector. The present disclosure provides recombinant expression vectors containing any of the nucleic acids of the present disclosure. As used herein, the term "recombinant expression vector" refers to a genetically modified oligonucleotide or polynucleotide construct that allows expression of an mRNA, protein, polypeptide, or peptide by a host cell when the construct contains a nucleotide sequence encoding the mRNA, protein, polypeptide, or peptide and the vector is contacted with a cell under conditions sufficient to have the mRNA, protein, polypeptide, or peptide expressed in the cell. The vectors described herein are not naturally occurring in their entirety. However, portions of the vector may be naturally occurring. The described recombinant expression vectors can contain any type of nucleotide, including, but not limited to, DNA and RNA, which can be single-stranded or double-stranded, can be partially synthetic or obtained from natural sources, and can contain natural nucleotides, non-natural nucleotides, or modified nucleotides. The recombinant expression vectors can contain naturally occurring or non-naturally occurring internucleotide linkages, or both types of linkages. The non-naturally occurring or modified nucleotides or internucleotide bonds do not interfere with the transcription or replication of the vector.

[0172] In one embodiment, the recombinant expression vector of the present disclosure can be any suitable recombinant expression vector and can be used to transform or transfect any suitable host. Suitable vectors include vectors designed for propagation and amplification or expression, or both, such as plasmids and viruses. The vector can be selected from the group consisting of the pUC series (Fermentas Life Sciences, Glen Burnie, MD), the pBluescript series (Stratagene, La Jolla, CA), the pET series (Novagen, Madison, WI), the pGEX series (Pharmacia Biotech, Uppsala, Sweden), and the pEX series (Clontech, Palo Alto, CA). Bacteriophage vectors such as λGT10, λGT11, λEMBL4, λNMI149, and λZapII (Stratagene) can be used. Examples of plant expression vectors include pBI01, pBI01.2, pBI121, pBI101.3, and pBIN19 (Clontech). Examples of animal expression vectors include pEUK-C1, pMAM, and pMAMneo (Clontech). The recombinant expression vector may be a viral vector, such as a retroviral vector, for example a gamma retroviral vector.

[0173] In embodiments, recombinant expression vectors are prepared using standard recombinant DNA techniques, e.g., as described in Sambrook et al., supra, and Ausubel et al., supra. Expression vector constructs, whether circular or linear, can be prepared to contain a replication system functional in prokaryotic or eukaryotic host cells. Replication systems can be derived, for example, from ColEl, SV40, 2μ plasmid, λ, bovine papilloma virus, etc.

[0174] Recombinant expression vectors may optionally include regulatory sequences, such as transcriptional and translational initiation and termination codons, that are specific to the type of host (e.g., bacterium, plant, fungus, or animal) into which the vector will be introduced, considering whether the vector is DNA- or RNA-based.

[0175] Recombinant expression vectors can contain one or more marker genes to allow for the selection of transformed or transfected hosts. Marker genes include biocide resistance (e.g., resistance to antibiotics, heavy metals, etc.), complementation in auxotrophic hosts to provide prototrophy. Suitable marker genes for the described expression vectors include, for example, neomycin / G418 resistance gene, histidinol x resistance gene, histidinol resistance gene, tetracycline resistance gene, and ampicillin resistance gene.

[0176] The recombinant expression vector can include a native or non-native promoter operably linked to the nucleotide sequence of the present disclosure. For example, the selection of strong, weak, tissue-specific, inducible, and developmentally specific promoters is within the ordinary skill of one of ordinary skill in the art. Similarly, combining a nucleotide sequence with a promoter is also within the ordinary skill of one of ordinary skill in the art. The promoter can be a non-viral promoter or a viral promoter, such as a cytomegalovirus (CMV) promoter, a RSV promoter, an SV40 promoter, or a promoter found in the long terminal repeat of murine stem cell virus.

[0177] Recombinant expression vectors can be designed for either transient expression, stable expression, or both, and can be made for constitutive or inducible expression.

[0178] Additionally, recombinant expression vectors can be engineered to contain a suicide gene. As used herein, the term "suicide gene" refers to a gene that causes the death of a cell that expresses the suicide gene. A suicide gene can be a gene that confers sensitivity to an agent, e.g., a drug, on the cell in which the gene is expressed, causing the cell to die when contacted or exposed to the agent. Suicide genes are known in the art and include, for example, herpes simplex virus (HSV) thymidine kinase (TK) gene, cytosine deaminase, purine nucleoside phosphorylase, and nitroreductase.

[0179] In certain embodiments, the polynucleotide is isolated. In certain embodiments, the polynucleotide is substantially pure.

[0180] Host cells containing the nucleic acid molecules described herein are also provided. Host cells can be any cell containing heterologous nucleic acid. The heterologous nucleic acid can be a vector (e.g., an expression vector). For example, host cells can be cells from any organism that are selected, modified, transformed, propagated, used, or manipulated in any way for the cellular production of a substance, e.g., the cellular expression of a gene, DNA or RNA sequence, protein, or enzyme. An appropriate host can be determined. For example, host cells can be selected based on the vector backbone and the desired result. By way of example, plasmids or cosmids can be introduced into prokaryotic host cells for replication of some types of vectors. Bacterial cells, such as, but not limited to, DH5α, JM109, and KCB, SURE® competent cells, and SOLOPACK Gold cells, can be used as host cells for vector replication and / or expression. Additionally, bacterial cells, such as E. coli LE392, can be used as host cells for phage viruses. Eukaryotic cells that can be used as host cells include, but are not limited to, yeast (e.g., YPH499, YPH500, and YPH501), insect, and mammalian cells. Examples of mammalian eukaryotic host cells for replication and / or expression of vectors include, but are not limited to, HeLa, NIH3T3, Jurkat, 293, COS, Saos, PC12, SP2 / 0 (American Type Culture Collection (ATCC), Manassas, VA, CRL-1581), NS0 (European Collection of Cell Cultures (ECACC), Salisbury, Wiltshire, UK, ECACC No. 85110503), FO (ATCC CRL-1646), and Ag653 (ATCC CRL-1580) mouse cell lines. An exemplary human myeloma cell line is U266 (ATCC CRL-TIB-196). Other useful cell lines include those derived from Chinese hamster ovary (CHO) cells, such as CHO-K1SV (Lonza Biologies, Walkersville, MD), CHO-K1 (ATCC CRL-61) or DG44.

[0181] 5.4. Antibody Preparation and Production Methods Methods for preparing antibodies have been described. See, for example, Els Pardon et al., Nature Protocol, 9(3):674 (2014). Antibodies (e.g., scFv fragments) may be obtained using methods known in the art, for example, by immunizing a Camelidae species (e.g., a camel or a llama) and obtaining hybridomas therefrom, or by cloning a library of antibodies using molecular biology techniques known in the art and then selecting individual clones from the unselected library by ELISA, or by using phage display.

[0182] Antibodies provided herein can be produced by culturing cells transformed or transfected with vectors containing antibody-encoding nucleic acids. Polynucleotide sequences encoding polypeptide components of antibodies of the present disclosure can be obtained using standard recombinant techniques. Desired polynucleotide sequences can be isolated and sequenced from antibody-producing cells (such as hybridoma cells or B cells). Alternatively, polynucleotides can be synthesized using a nucleotide synthesizer or PCR technology. Once obtained, the polypeptide-encoding sequence is inserted into a recombinant vector capable of replicating and expressing heterologous polynucleotides in host cells. Many vectors available and known in the art can be used for the purposes of the present disclosure. The selection of an appropriate vector depends primarily on the size of the nucleic acid to be inserted into the vector and the particular host cell to be transformed with the vector. Suitable host cells for expressing antibodies of the present disclosure include prokaryotes such as archaebacteria and eubacteria, including gram-negative or gram-positive organisms, eukaryotic microorganisms such as filamentous fungi or yeast, invertebrate cells such as insect cells or plant cells, and vertebrate cells such as mammalian host cell lines. Host cells are transformed with the above-described expression vectors and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences. Antibodies produced by the host cells are purified using standard protein purification methods known in the art.

[0183] Methods for antibody production, including vector construction, expression, and purification, are further described in Pluckthun et al., Antibody Engineering: Producing antibodies in Escherichia coli: From PCR to fermentation 203-52 (McCafferty et al., eds., 1996); Kwong and Rader, E. coli Expression and Purification of Fab Antibody Fragments, in Current Protocols in Protein Science (2009); Tachibana and Takekoshi, Production of Antibody Fab Fragments in Escherichia coli, in Antibody Expression and Production (Al-Rubeai ed., 2011); and Therapeutic Monoclonal Antibodies: From Bench to Clinic (An ed., 2009).

[0184] It is, of course, contemplated that anti-ACVR2A antibodies may be prepared using alternative methods known in the art. For example, the appropriate amino acid sequence, or portions thereof, may be produced by direct peptide synthesis using solid-phase techniques (see, e.g., Stewart et al., Solid-Phase Peptide Synthesis (1969); and Merrifield, J. Am. Chem. Soc. 85:2149-54 (1963)). In vitro protein synthesis may be performed using manual techniques or by automation. Various portions of the anti-ACVR2A antibody may be chemically synthesized separately and combined using chemical or enzymatic methods to produce the desired anti-ACVR2A antibody. Alternatively, antibodies may be purified from cells or body fluids (such as milk) of transgenic animals engineered to express the antibody, as disclosed, for example, in U.S. Patent Nos. 5,545,807 and 5,827,690.

[0185] Polyclonal antibodies Polyclonal antibodies are generally raised in animals by multiple subcutaneous (sc) or intraperitoneal (ip) injections of the relevant antigen and an adjuvant. A protein that is immunogenic in the species being immunized, such as keyhole limpet hemocyanin (KLH), serum albumin, bovine thyroglobulin, or soybean trypsin inhibitor, is conjugated with a bifunctional or derivatizing agent, such as maleimidobenzoyl sulfosuccinimide ester (conjugation via cysteine ​​residues), N-hydroxysuccinimide (conjugation via lysine residues), glutaraldehyde, succinic anhydride, SOCl, or R. 1 N=C=NR, where R and R 1 It may be useful to conjugate the relevant antigen using adjuvants such as (wherein each is independently a lower alkyl group). Examples of adjuvants that can be used include Freund's complete adjuvant and MPL-TDM adjuvant (monophosphoryl lipid A, synthetic trehalose dicorynomycolate). The immunization protocol may be selected by one skilled in the art without undue experimentation.

[0186] For example, animals are immunized against the antigen, immunogenic conjugate, or derivative by combining, for example, 100 μg or 5 μg of protein or conjugate (for rabbits or mice, respectively) with 3 volumes of Freund's complete adjuvant and injecting the solution intradermally at multiple sites. One month later, the animals are boosted with 1 / 5 to 1 / 10 of the original amount of peptide or conjugate in Freund's complete adjuvant by subcutaneous injection at multiple sites. Seven to 14 days later, the animals are bled and the serum is assayed for antibody titer. Animals are boosted until the titer plateaus.

[0187] Conjugates can also be made in recombinant cell culture as protein fusions. Additionally, aggregating agents such as alum are suitable for enhancing the immune response.

[0188] Monoclonal antibodies Monoclonal antibodies are obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for naturally occurring mutations and / or post-translational modifications (e.g., isomerization, amidation) that may be present in minor amounts. Thus, the modifier "monoclonal" indicates the character of the antibody as not being a mixture of discrete antibodies.

[0189] For example, monoclonal antibodies may be made using the hybridoma method first described by Kohler et al., Nature, 256:495 (1975), or may be made by recombinant DNA methods (U.S. Pat. No. 4,816,567).

[0190] In a further embodiment, antibodies can be isolated from antibody phage libraries generated using the techniques described in McCafferty et al., Nature, 348:552-554 (1990), Clackson et al., Nature, 352:624-628 (1991), and Marks et al., J. Mol. Biol., 222:581-597 (1991). Subsequent publications describe the production of high affinity (nM range) human antibodies by chain shuffling (Marks et al., Bio / Technology, 10:779-783 (1992)), and combinatorial infection and in vivo recombination as strategies for constructing very large phage libraries (Waterhouse et al., Nucl. Acids Res., 21:2265-2266 (1993)). Therefore, these techniques are viable alternatives to traditional monoclonal antibody hybridoma techniques for the isolation of monoclonal antibodies.

[0191] The DNA can also be modified, for example, by substituting the coding sequence (U.S. Pat. No. 4,816,567; Morrison, et al., Proc. Natl. Acad. Sci. USA, 81:6851 (1984)) or by covalently joining to the coding sequence all or part of the coding sequence of a non-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted to create a chimeric bivalent antibody containing one antigen-binding site with specificity for an antigen and another antigen-binding site with specificity for a different antigen.

[0192] Chimeric or hybrid antibodies can also be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate.

[0193] Recombinant production in prokaryotic cells Polynucleic acid sequences encoding antibodies of the present disclosure can be obtained using standard recombinant techniques. The desired polynucleic acid sequence can be isolated and sequenced from antibody-producing cells, such as hybridoma cells. Alternatively, polynucleotides can be synthesized using a nucleotide synthesizer or PCR technology. Once obtained, the polypeptide-encoding sequence is inserted into a recombinant vector capable of replicating and expressing heterologous polynucleotides in a prokaryotic host. Many vectors available and known in the art can be used for the purposes of the present disclosure. The selection of an appropriate vector depends primarily on the size of the nucleic acid to be inserted into the vector and the specific host cell to be transformed with the vector. Each vector contains various components, depending on its function (amplification or expression of the heterologous polynucleotide, or both) and its compatibility with the specific host cell in which it resides. Vector components generally include, but are not limited to, an origin of replication, a selectable marker gene, a promoter, a ribosome binding site (RBS), a signal sequence, the heterologous nucleic acid insert, and a transcription termination sequence.

[0194] Generally, plasmid vectors containing replicon and control sequences derived from species compatible with the host cell are used in connection with these hosts. The vector ordinarily carries a replication site, as well as marking sequences that are capable of providing phenotypic selection in transformed cells. For example, E. coli is typically transformed using pBR322, a plasmid derived from an E. coli species. Examples of pBR322 derivatives used to express specific antibodies are described in detail in Carter et al., U.S. Patent No. 5,648,237.

[0195] Additionally, phage vectors containing replicon and control sequences compatible with the host microorganism can be used as transforming vectors in connection with these hosts. For example, bacteriophages such as GEM™-11 may be utilized to generate recombinant vectors that can be used to transform susceptible host cells such as E. coli LE392.

[0196] The expression vector of the present application may contain two or more promoter-cistron pairs, each encoding a polypeptide component. A promoter is a non-translated regulatory sequence located upstream (5') of a cistron that controls its expression. Prokaryotic promoters are typically divided into two classes: inducible and constitutive. An inducible promoter is a promoter that initiates increased transcription levels of the cistron under its control in response to changes in culture conditions, such as the presence or absence of a nutrient or a change in temperature.

[0197] Numerous promoters recognized by a variety of potential host cells are well known. The promoter of choice can be operably linked to the cistron DNA encoding the antibody by removing the promoter from the source DNA via restriction enzyme digestion and inserting the isolated promoter sequence into the vector of the present application. Both the native promoter sequence and many heterologous promoters can be used to direct amplification and / or expression of the target gene. In some embodiments, heterologous promoters are utilized because they generally allow for greater transcription and higher yields of the expressed target gene compared to the native target polypeptide promoter.

[0198] Promoters suitable for use in prokaryotic hosts include the PhoA promoter, the galactamase and lactose promoter systems, the tryptophan (trp) promoter system, and hybrid promoters such as the tac or trc promoter. However, other promoters functional in bacteria (e.g., other known bacterial promoters or phage promoters) are similarly suitable. Their nucleic acid sequences have been published, allowing one skilled in the art to operably ligate them to a cistron encoding a target peptide using linkers or adapters (Siebenlist et al., Cell 20:269 (1980)) and to provide any required restriction sites.

[0199] In one embodiment, each cistron in a recombinant vector contains a secretory signal sequence component that directs translocation of an expressed polypeptide across a membrane. Generally, the signal sequence may be a component of the vector, or it may be a part of the target polypeptide DNA that is inserted into the vector. The signal sequence selected for purposes of the present invention should be one that is recognized and processed (i.e., cleaved by a signal peptidase) by the host cell. For prokaryotic host cells that do not recognize and process the signal sequence native to the heterologous polypeptide, the signal sequence can be substituted by a prokaryotic signal sequence selected from the group consisting of, for example, alkaline phosphatase, penicillinase, Ipp, or heat-stable enterotoxin II (STII) leaders, LamB, PhoE, PelB, OmpA, and MBP.

[0200] In some embodiments, production of antibodies according to the present disclosure can occur in the cytoplasm of the host cell and therefore does not require the presence of a secretory signal sequence within each cistron. - The strains provide cytoplasmic conditions favorable for disulfide bond formation, thereby allowing proper folding and assembly of the expressed protein subunits.

[0201] Suitable prokaryotic host cells for expressing the antibodies of the present disclosure include archaebacteria and eubacteria, such as gram-negative or gram-positive bacteria. Examples of useful bacteria include Escherichia (e.g., E. coli), Bacillus (e.g., B. subtilis), Enterobacteria, Pseudomonas species (e.g., P. aeruginosa), Salmonella typhimurium, Serratia marcescens, Klebsiella, Proteus, Shigella, Rhizobia, Vitreoscilla, or Paracoccus. In some embodiments, gram-negative cells are used. In one embodiment, Escherichia coli (E. coli) cells are used as hosts. Examples of E. coli (E. coli) strains include the W3110 strain (Bachmann, Cellular and Molecular Biology, vol. 2 (Washington, DC: American Society for Microbiology, 1987), pp. 1190-1219; ATCC Deposit No. 27,325) and its derivatives, which have the genotype W3110 AfhuA (AtonA) ptr3 lac Iq lacL8 AompT A (nmpc-fepE) degP41 kan RExamples of suitable strains include strain 33D3 (U.S. Pat. No. 5,639,635). Other strains and their derivatives, such as E. coli 294 (ATCC 31,446), E. coli B, E. coli 1776 (ATCC 31,537), and E. coli RV308 (ATCC 31,608), are also suitable. These examples are illustrative and not limiting. Methods for constructing derivatives of any of the above-mentioned bacteria with defined genotypes are known in the art and are described, for example, in Bass et al., Proteins, 8:309-314 (1990). Generally, it is necessary to select an appropriate bacterium taking into account the replication ability of the replicon in the bacterial cell. For example, E. coli, Serratia, or Salmonella species can be suitably used as hosts when well-known plasmids such as pBR322, pBR325, pACYC177, or pKN410 are used to supply the replicon.

[0202] Typically, the host cell should secrete minimal amounts of proteolytic enzymes, and it may be desirable to incorporate additional protease inhibitors into the cell culture.

[0203] Host cells are ...

Claims

1. An antibody or antigen-binding fragment thereof that binds to ACVR2A, wherein the affinity of the antibody or antigen-binding fragment for ACVR2A is at least 10 times greater than its affinity for ACVR2B, and the antibody or antigen-binding fragment has one of the following: (i) heavy chain complementarity determining region 1 (HCDR1), heavy chain complementarity determining region 2 (HCDR2), and heavy chain complementarity determining region 3 (HCDR3) set forth in SEQ ID NO: 1, and light chain complementarity determining region 1 (LCDR1), light chain complementarity determining region 2 (LCDR2), and light chain complementarity determining region 3 (LCDR3) set forth in SEQ ID NO: 2; (ii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 3, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2; (iii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 4, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2; (iv) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 5, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 6; (v) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 6; (vi) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 8, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 6; (vii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 9, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2; (viii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 10, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2; (ix) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 11, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2; (x) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2; (xi) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 13, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2; (xii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 14; (xiii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 15; (xiv) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 2; (xv) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 16; (xvi) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 17; (xvii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 18; (xviii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 19; (xix) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 20; (xx) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 21; (xxi) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 22; (xxii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 23; (xxiii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 24; (xxiv) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 6; (xxv) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 25; (xxvi) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 26; (xxvii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 27; (xxviii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 28; (xxix) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 29; (xxx) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 11, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 30; (xxxi) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 31; (xxxii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 32; (xxxiii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 33; (xxxiv) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 9, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 34; (xxxv) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 11, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 35; (xxxvi) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 11, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 36; (xxxvii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 11, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 37; (xxxviii) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 38; (xxxix) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 39; (xxxx) HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 12, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO: 40; or (xxxxi) An antibody or antigen-binding fragment thereof comprising HCDR1, HCDR2, and HCDR3 set forth in SEQ ID NO: 9, and LCDR1, LCDR2, and LCDR3 set forth in SEQ ID NO:

41.

2. 2. The antibody or antigen-binding fragment of claim 1, (i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 42, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 49, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 50, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 52, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 53; (v) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 52, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 53; (vi) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 49, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 52, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 53; (vii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 54, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (viii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 55, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (ix) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 56, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (x) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (xi) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 58, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (xii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 59, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (xiii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 60, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (xiv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (xv) the HCDR1 comprises the amino acid sequence of SEQ ID NO:57, the HCDR2 comprises the amino acid sequence of SEQ ID NO:43, the HCDR3 comprises the amino acid sequence of SEQ ID NO:44, the LCDR1 comprises the amino acid sequence of SEQ ID NO:61, the LCDR2 comprises the amino acid sequence of SEQ ID NO:46, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:47; (xvi) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 62, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (xvii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 63, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (xviii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 52, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 82, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (xix) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 64, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (xx) the HCDR1 comprises the amino acid sequence of SEQ ID NO:57, the HCDR2 comprises the amino acid sequence of SEQ ID NO:43, the HCDR3 comprises the amino acid sequence of SEQ ID NO:44, the LCDR1 comprises the amino acid sequence of SEQ ID NO:45, the LCDR2 comprises the amino acid sequence of SEQ ID NO:65, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:47; (xxi) the HCDR1 comprises the amino acid sequence of SEQ ID NO:57, the HCDR2 comprises the amino acid sequence of SEQ ID NO:43, the HCDR3 comprises the amino acid sequence of SEQ ID NO:44, the LCDR1 comprises the amino acid sequence of SEQ ID NO:45, the LCDR2 comprises the amino acid sequence of SEQ ID NO:66, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:47; (xxii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 59, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 67, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (xxiii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 59, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 68, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (xxiv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 52, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 46, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 53; (xxv) the HCDR1 comprises the amino acid sequence of SEQ ID NO:57, the HCDR2 comprises the amino acid sequence of SEQ ID NO:43, the HCDR3 comprises the amino acid sequence of SEQ ID NO:44, the LCDR1 comprises the amino acid sequence of SEQ ID NO:59, the LCDR2 comprises the amino acid sequence of SEQ ID NO:69, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:47; (xxvi) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 57, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 59, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 70, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (xxvii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 71, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (xxviii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 72, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (xxix) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 73, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (xxx) the HCDR1 comprises the amino acid sequence of SEQ ID NO:56, the HCDR2 comprises the amino acid sequence of SEQ ID NO:43, the HCDR3 comprises the amino acid sequence of SEQ ID NO:44, the LCDR1 comprises the amino acid sequence of SEQ ID NO:45, the LCDR2 comprises the amino acid sequence of SEQ ID NO:74, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:47; (xxxi) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 75, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (xxxii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 67, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (xxxiii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 48, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 68, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 47; (xxxiv) the HCDR1 comprises the amino acid sequence of SEQ ID NO:54, the HCDR2 comprises the amino acid sequence of SEQ ID NO:43, the HCDR3 comprises the amino acid sequence of SEQ ID NO:44, the LCDR1 comprises the amino acid sequence of SEQ ID NO:45, the LCDR2 comprises the amino acid sequence of SEQ ID NO:76, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:47; (xxxv) the HCDR1 comprises the amino acid sequence of SEQ ID NO:56, the HCDR2 comprises the amino acid sequence of SEQ ID NO:43, the HCDR3 comprises the amino acid sequence of SEQ ID NO:44, the LCDR1 comprises the amino acid sequence of SEQ ID NO:45, the LCDR2 comprises the amino acid sequence of SEQ ID NO:77, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:47; (xxxvi) the HCDR1 comprises the amino acid sequence of SEQ ID NO:56, the HCDR2 comprises the amino acid sequence of SEQ ID NO:43, the HCDR3 comprises the amino acid sequence of SEQ ID NO:44, the LCDR1 comprises the amino acid sequence of SEQ ID NO:45, the LCDR2 comprises the amino acid sequence of SEQ ID NO:78, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:47; (xxxvii) the HCDR1 comprises the amino acid sequence of SEQ ID NO:56, the HCDR2 comprises the amino acid sequence of SEQ ID NO:43, the HCDR3 comprises the amino acid sequence of SEQ ID NO:44, the LCDR1 comprises the amino acid sequence of SEQ ID NO:45, the LCDR2 comprises the amino acid sequence of SEQ ID NO:79, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:47; (xxxviii) the HCDR1 comprises the amino acid sequence of SEQ ID NO:57, the HCDR2 comprises the amino acid sequence of SEQ ID NO:43, the HCDR3 comprises the amino acid sequence of SEQ ID NO:44, the LCDR1 comprises the amino acid sequence of SEQ ID NO:45, the LCDR2 comprises the amino acid sequence of SEQ ID NO:69, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:47; (xxxix) the HCDR1 comprises the amino acid sequence of SEQ ID NO:57, the HCDR2 comprises the amino acid sequence of SEQ ID NO:43, the HCDR3 comprises the amino acid sequence of SEQ ID NO:44, the LCDR1 comprises the amino acid sequence of SEQ ID NO:45, the LCDR2 comprises the amino acid sequence of SEQ ID NO:80, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:47; (xxxx) the HCDR1 comprises the amino acid sequence of SEQ ID NO:57, the HCDR2 comprises the amino acid sequence of SEQ ID NO:43, the HCDR3 comprises the amino acid sequence of SEQ ID NO:44, the LCDR1 comprises the amino acid sequence of SEQ ID NO:45, the LCDR2 comprises the amino acid sequence of SEQ ID NO:70, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:47; or (xxxxi) An antibody or antigen-binding fragment, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 54, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 43, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 45, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 81, and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

47.

3. 3. The antibody or antigen-binding fragment of claim 1 or 2, (i) a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: 2; (ii) a VH comprising the amino acid sequence of SEQ ID NO: 3 and a VL comprising the amino acid sequence of SEQ ID NO: 2; (iii) VH comprising the amino acid sequence of SEQ ID NO: 4 and VL comprising the amino acid sequence of SEQ ID NO: 2; (iv) VH comprising the amino acid sequence of SEQ ID NO: 5 and VL comprising the amino acid sequence of SEQ ID NO: 6; (v) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 6; (vi) VH comprising the amino acid sequence of SEQ ID NO: 8 and VL comprising the amino acid sequence of SEQ ID NO: 6; (vii) VH comprising the amino acid sequence of SEQ ID NO: 9 and VL comprising the amino acid sequence of SEQ ID NO: 2; (viii) VH comprising the amino acid sequence of SEQ ID NO: 10 and VL comprising the amino acid sequence of SEQ ID NO: 2; (ix) a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 2; (x) a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 2; (xi) a VH comprising the amino acid sequence of SEQ ID NO: 13 and a VL comprising the amino acid sequence of SEQ ID NO: 2; (xii) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 14; (xiii) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 15; (xiv) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 2; (xv) VH comprising the amino acid sequence of SEQ ID NO: 12 and VL comprising the amino acid sequence of SEQ ID NO: 16; (xvi) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 17; (xvii) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 18; (xviii) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 19; (xix) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 20; (xx) a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 21; (xxi) a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 22; (xxii) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 23; (xxiii) a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 24; (xxiv) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 6; (xxv) a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 25; (xxvi) a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 26; (xxvii) VH comprising the amino acid sequence of SEQ ID NO: 7 and VL comprising the amino acid sequence of SEQ ID NO: 27; (xxviii) a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 28; (xxix) a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 29; (xxx) a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 30; (xxxi) a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 31; (xxxii) a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 32; (xxxiii) a VH comprising the amino acid sequence of SEQ ID NO: 7 and a VL comprising the amino acid sequence of SEQ ID NO: 33; (xxxiv) a VH comprising the amino acid sequence of SEQ ID NO: 9 and a VL comprising the amino acid sequence of SEQ ID NO: 34; (xxxv) a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 35; (xxxvi) a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 36; (xxxvii) a VH comprising the amino acid sequence of SEQ ID NO: 11 and a VL comprising the amino acid sequence of SEQ ID NO: 37; (xxxviii) VH comprising the amino acid sequence of SEQ ID NO: 12 and VL comprising the amino acid sequence of SEQ ID NO: 38; (xxxix) a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 39; (xxxx) a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 40; or (xxxxi) An antibody or antigen-binding fragment comprising a VH comprising the amino acid sequence of SEQ ID NO: 9 and a VL comprising the amino acid sequence of SEQ ID NO:

41.

4. The antibody or antigen-binding fragment of any one of claims 1 to 3, wherein the antibody is an IgG.

5. The antibody or antigen-binding fragment of any one of claims 1 to 4, wherein the antibody is a human antibody.

6. The antibody or antigen-binding fragment thereof of any one of claims 1 to 5, wherein the antibody or antigen-binding fragment thereof is genetically fused or chemically conjugated to an agent.

7. A nucleic acid molecule encoding the antibody or antigen-binding fragment of any one of claims 1 to 6.

8. A vector comprising the nucleic acid molecule of claim 7.

9. A host cell transformed with the vector of claim 8.

10. A composition comprising a therapeutically effective amount of the antibody or antigen-binding fragment of any one of claims 1 to 6, the nucleic acid molecule of claim 7, or the vector of claim 8, and a pharmaceutically acceptable excipient.

11. 11. The composition of claim 10 for use in the manufacture of a medicament for treating a disease or disorder in a subject, wherein the medicament is administered to the subject.

12. The disease or disorder is (1) ACVR2A-related; (2) associated with an ACVR2A ligand; and / or (3) related to activin A, activin B, GDF8 or GDF11; A composition for use according to claim 11.

13. The disease or disorder is (1) A musculoskeletal disease or disorder, optionally wherein the musculoskeletal disease or disorder is selected from the group consisting of muscular atrophy, spinal muscular atrophy, and cancer cachexia; (2) an age-related condition selected from the group consisting of sarcopenia, skin atrophy, muscle wasting, brain atrophy, atherosclerosis, arteriosclerosis, emphysema, osteoporosis, osteoarthritis, immune deficiency, hypertension, dementia, Huntington's disease, Alzheimer's disease, cataracts, age-related macular degeneration, prostate cancer, stroke, shortened life expectancy, frailty, memory loss, wrinkles, renal dysfunction, and age-related hearing loss; (3) A metabolic disorder selected from the group consisting of type II diabetes, metabolic syndrome, hyperglycemia, NASH, and obesity; (4) selected from the group consisting of acute and / or chronic kidney disease or renal failure, liver fibrosis or cirrhosis, pulmonary fibrosis, pulmonary arterial hypertension, renal fibrosis, Parkinson's disease, ALS, brain atrophy, dementia cachexia, cancer, and cancer treatment-induced bone loss; (5) The cancer is selected from the group consisting of sarcoma, ovarian cancer, breast cancer, esophageal cancer, head and neck cancer, lung cancer, melanoma, multiple myeloma, colorectal cancer, hepatocellular carcinoma, pancreatic cancer, endometrial cancer, and gastrointestinal cancer; or (6) Anemia A composition for use according to claim 11.

14. The composition for use according to any one of claims 11 to 13, wherein a second agent is further administered to the subject.

15. The second agent (1) an ACVR2B antagonist, optionally wherein the ACVR2B antagonist is the ACVR2B extracellular domain fusion protein luspatercept; (2) an anti-PD-L1 antibody; or (3) a chemotherapeutic agent, optionally wherein the chemotherapeutic agent is carboplatin; 15. A composition for use according to claim 14.

16. 11. A method of inhibiting or antagonizing ACVR2A in a cell, comprising contacting the cell with the composition of claim 10.

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