Compositions and methods for growth factor modulation
Provided herein are antibodies that bind growth factor prodomain complexes, for example, growth factor prodomain complexes that include GDF-8 growth factor and GDF-8 prodomain. Also included are antibodies that bind growth factor prodomain complexes that have been altered by proteolytic processing.
1. An isolated monoclonal antibody, or a fragment thereof, that binds a growth factor prodomain complex (GPC),
wherein said GPC comprises a GDF-8 growth factor and a GDF-8 prodomain (SEQ ID NO: 70),
wherein the antibody or fragment thereof binds the GDF-8 prodomain of said GPC,
wherein the antibody or fragment thereof but does not bind a mature GDF-8 growth factor, a mature GDF-11 growth factor, a GDF-11 prodomain or a complex comprising a GDF-11 prodomain and a GDF-11 growth factor,
wherein said antibody, or fragment thereof, prevents proteolytic cleavage between residues Arg 75 and Asp 76 of GDF-8 prodomain, and
wherein said antibody, or fragment thereof, inhibits the release of said mature GDF-8 growth factor from the GPC.
2. The antibody of claim 1 , wherein said antibody recognizes an epitope within the GDF-8 arm region of the GDF-8 prodomain set forth in SEQ ID NO: 77.
3. The antibody of claim 1 , wherein said prodomain has not been cleaved at the BMP/tolloid cleavage site between residues Arg 75 and Asp 76 of the GDF-8 prodomain (SEQ ID NO: 70).
4. The antibody of claim 1 , wherein said antibody prevents the proteolytic cleavage by at least one metalloproteinase.
5. The antibody of claim 4 , wherein said metalloproteinase is mammalian tolloid-like 2 (mTLL2).
6. The antibody of claim 1 , wherein said GDF-8 prodomain has not been cleaved at a furin cleavage site.
7. The antibody of claim 1 , wherein said GDF-8 prodomain has been cleaved at a furin cleavage site.
8. The antibody of claim 7 , wherein said furin cleavage site is Arg-Ser-Arg-Arg set forth in SEQ ID NO: 76.
9. The antibody of claim 1 , wherein said antibody is an IgG antibody.
10. The antibody of claim 9 , wherein said IgG antibody is a human or humanized antibody.