Neutralizing antibodies against GDF-8 and uses therefor
The disclosure provides novel antibodies against growth and differentiation factor-8 (GDF-8), in particular human antibodies, and antibody fragments, including those that inhibit GDF-8 activity in vitro and/or in vivo. The disclosure also provides methods for diagnosing, preventing, or treating degenerative disorders of muscle or bone, or disorders of insulin metabolism.
1. An isolated antibody or fragment thereof that specifically binds GDF-8, comprising:
an antibody variable heavy (VH) domain having a first, second and third CDR respectively defined by the amino acid sequences of SEQ ID NO:43 (CDR1), SEQ ID NO:44 (CDR2) and SEQ ID NO:45 (CDR3); and
an antibody variable light (VL) domain having a first, second and third CDR respectively defined by the amino acid sequences of SEQ ID NO:46 (CDR1), SEQ ID NO:47 (CDR2) and SEQ ID NO:48 (CDR3).
2. An isolated antibody or fragment thereof that specifically binds GDF-8, comprising a VH domain and a VL domain,
wherein said VH domain comprises SEQ ID NO:4; and
wherein said VL domain comprises SEQ ID NO:6.
3. An isolated antibody that specifically binds GDF-8, consisting of:
two heavy chains, each consisting essentially of the VH domain of the amino acid sequence of SEQ ID NO:4 and the heavy chain constant domain of the amino acid sequence of SEQ ID NO:53; and
two light chains, each consisting essentially of the VL domain of the amino acid sequence of SEQ ID NO:6 and the light chain constant domain of the amino acid sequence of SEQ ID NO:51.
4. The antibody or fragment of claim 1 , wherein the antibody or fragment is selected from the group consisting of an Fab fragment, an F(ab') 2 fragment, a chimeric antibody, an Fv fragment, a scFV antibody, and the amino acid sequence of SEQ ID NO:2.
5. The antibody or fragment of claim 1 , further comprising an antibody heavy chain constant domain from a human immunoglobulin subtype selected from the group consisting IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgE, and IgM.
6. The antibody or fragment of claim 5 , wherein said heavy chain constant domain is modified to alter a constant domain effector function.
7. The antibody or fragment of claim 6 , wherein said constant domain effector function is Fc receptor binding.
8. The antibody or fragment of claim 1 , further comprising a human antibody light chain constant domain selected from the group consisting of a kappa light chain constant domain and a lambda light chain constant domain.
9. The antibody of claim 3 , wherein the amino acid sequence of SEQ ID NO:53 is modified at residue 117 or 120 to alter an Fc region effector function.
10. The antibody or fragment of claim 1 , wherein said antibody or fragment is fully humanized.
11. The antibody or fragment of claim 1 , wherein said antibody or fragment is neutralizing.
12. A pharmaceutical composition comprising the antibody or fragment of claim 1 and a pharmaceutically acceptable carrier.