Anti-acvr1 antibodies and uses thereof

The method of claim 33, wherein the antibody has one or more properties selected from the group consisting of:

• (a) is a fully human monoclonal antibody;
• (b) binds to human ACVR1 extracellular domain fused to an Fc (e.g., SEQ ID NO:
• 339) at 25° C. with a dissociation constant (KD)) of less than 60 nM, less than 12 nM, less than less than 2 nM, less than 1 nM, or less than 0.5 nM as measured in a surface plasmon resonance assay;
• (c) binds to human ACVR1 extracellular domain fused to mFc (SEQ ID NO:
• 339) at 37° C.with a dissociation constant (KD)) of less than 150 nM, less than 15 nM, less than less than 5 nM, less than 1.5 nM, or less than 1 nM as measured in a surface plasmon resonance assay;
• (d) binds to human ACVRI extracellular domain fused to myc-myc-hexahistag (e.g., SEQ ID NO:
• 338) at 25° C. with a KD of less than 300 nM, less than 150 nM, less than 25 nM, less than 10 nM, less than 5 nM, less than 3 nM or less than 2 nM as measured in a surface plasmon resonance assay;
• (e) binds to human ACVR1 extracellular domain fused to myc-myc-hexahistag (e.g., SEQ ID NO:
• 338) at 37° C. with a KD of less than 500 nM, less than 50 nM, less than 25 nM, less than 10 nM, as measured in a surface plasmon resonance assay;
• (f) does not bind mouse ACVRI or binds to mouse ACVR1 extracellular domain fused to myc-myc-hexahistag (e.g., SEQ ID NO:
• 340) at 25° C. with a KD of greater than 500 nM, as measured in a surface plasmon resonance assay;
• (g) does not bind mouse ACVR1 or binds to mouse ACVRI extracellular domain fused to myc-myc-hexahistag (e.g., SEQ ID NO:
• 340) at 37° C. with a KD of greater than 500 nM, as measured in a surface plasmon resonance assay;
• (k) binds to cells expressing human ACVRI protein or human ACVR1 (R206H) protein;
• (1) inhibits activation of cells expressing human ACVR1(R206H) by human Activin A with a ICso of less than 25 nM, as measured in a cell-based bioassay;
• (m) inhibits activation of cells expressing human ACVRI(R206H) by human BMP7 with a IC50 of less than 20 nM, less than 5 nM, less than 3 nM, or less than 1 nM, or less than as measured in a cell-based bioassay;
• (m) significantly decreases serum hepcidin when administered to mice expressing human ACVR1 in place of mouse allele;
• (n) significantly increases serum iron levels when administered to mice expressing human ACVR1 in place of mouse allele;
• and/or (o) inhibits wild-type ACVR1 signaling when administered to mice expressing human ACVR1 in place of mouse allele;
• and (p) comprises a HCVR comprising an amino acid sequence selected from the group consisting of HCVR sequence listed in Table 1 and a LCVR comprising an amino acid sequence selected from the group consisting of LCVR sequences listed in Table 1.

The method of claim 33, wherein the antibody or antigen-binding fragment comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within a HCVR and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within a LCVR;

• wherein the HCVR comprises:
• (i) an amino acid sequence selected from the group consisting of SEQ ID NOs:
• 2, 22, 42, 58, 76, 96, 116, 128, 148, 166, 186, 203, 223, 241, 255, 273, 289, 300, and 319;
• (ii) an amino acid sequence having at least 90% identity to the amino acid sequence selected from the group consisting of SEQ ID NOs:
• 2, 22, 42, 58, 76, 96, 116, 128, 148, 166, 186, 203, 223, 241, 255, 273, 289, 300, and 319;
• (iii) an amino acid sequence having at least 95% identity to the amino acid sequence selected from the group consisting of SEQ ID NOs:
• 2, 22, 42, 58, 76, 96, 116, 128, 148, 166, 186, 203, 223, 241, 255, 273, 289, 300, and 319;
• or
• (iv) an amino acid sequence selected from the group consisting of SEQ ID NOs:
• 2, 22, 42, 58, 76, 96, 116, 128, 148, 166, 186, 203, 223, 241, 255, 273, 289, 300, and 319, said amino acid sequence having no more than 12 amino acid substitutions, and the LCVR comprises:
• (a) an amino acid sequence selected from the group consisting of SEQ ID NOs:
• 10, 30, 48, 62, 72, 84, 104, 119, 136, 156, 174, 193, 211, 231, 245, 263, 277, 293, 307, and 327;
• (b) an amino acid sequence having at least 90% identity to the amino acid sequence selected from the group consisting of SEQ ID NOs:
• 10, 30, 48, 62, 72, 84, 104, 119, 136, 156, 174, 193, 211, 231, 245, 263, 277, 293, 307, and 327;
• (c) an amino acid sequence having at least 95% identity to the amino acid sequence selected from the group consisting of SEQ ID NOs:
• 10, 30, 48, 62, 72, 84, 104, 119, 136, 156, 174, 193, 211, 231, 245, 263, 277, 293, 307, and 327;
• or
• (d) an amino acid sequence selected from the group consisting of SEQ ID NOs:
• 10, 30, 48, 62, 72, 84, 104, 119, 136, 156, 174, 193, 211, 231, 245, 263, 277, 293, 307, and 327, said amino acid sequence having no more than 10 amino acid substitutions.