Methods of treating complement-associated disorders with anti-C5a antibodies
The present disclosure relates to, inter alia, antibodies, or antigen-binding fragments thereof, that bind to C5a and to use of the antibodies in methods for treating or preventing complement-associated disorders such as, but not limited to, atypical hemolytic uremic syndrome, age-related macular degeneration, rheumatoid arthritis, sepsis, severe burn, antiphospholipid syndrome, asthma, lupus nephritis, Goodpasture's syndrome, and chronic obstructive pulmonary disease.
1. A method for treating a complement-associated disorder, the method comprising administering to a human in need thereof, an isolated antibody, or antigen-binding fragment thereof, that binds C5a, wherein the antibody, or antigen-binding fragment thereof, comprises complementarity determining regions (CDRs) of a heavy chain variable region comprising the amino acid sequence depicted in SEQ ID NO: 45 and CDRs of a light chain variable region comprising the amino acid sequence depicted in SEQ ID NO: 42.
2. A method for treating a complement-associated disorder, the method comprising administering to a human in need thereof, an isolated antibody, or antigen-binding fragment thereof, that binds human C5a, wherein the antibody, or antigen-binding fragment thereof, comprises a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:20; a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:21; a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:22; a heavy chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:28; a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:46; and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:47.
3. A method for treating a complement-associated disorder, the method comprising administering to a human in need thereof, an isolated antibody, or antigen-binding fragment thereof, that binds human C5a, wherein the antibody, or antigen-binding fragment thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region comprises the amino acid sequence depicted in SEQ ID NO: 45 and the light chain variable region comprises the amino acid sequence depicted in SEQ ID NO: 42.
4. A method for treating a complement-associated disorder, the method comprising administering to a human in need thereof, an isolated antibody, or antigen-binding fragment thereof, that binds human C5a, wherein the isolated antibody, or antigen-binding fragment thereof, that binds human C5a, comprises heavy and light chains, wherein the heavy chain comprises the amino acid sequence depicted in SEQ ID NO: 49 and the light chain comprises the amino acid sequence depicted in SEQ ID NO: 40.
5. A method for treating graft-versus-host disease (GVHD), the method comprising administering to a human in need thereof, an isolated antibody, or antigen-binding fragment thereof, that binds C5a, wherein the antibody, or antigen-binding fragment thereof, comprises complementarity determining regions (CDRs) of a heavy chain variable region comprising the amino acid sequence depicted in SEQ ID NO: 45 and CDRs of a light chain variable region comprising the amino acid sequence depicted in SEQ ID NO: 42.
6. A method for treating graft-versus-host disease (GVHD), the method comprising administering to a human in need thereof, an isolated antibody, or antigen-binding fragment thereof, that binds human C5a, wherein the antibody, or antigen-binding fragment thereof, comprises a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:20; a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:21; a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:22; a heavy chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:28; a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:46; and a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:47.
7. A method for treating graft-versus-host disease (GVHD), the method comprising administering to a human in need thereof, an isolated antibody, or antigen-binding fragment thereof, that binds human C5a, wherein the antibody, or antigen-binding fragment thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region comprises the amino acid sequence depicted in SEQ ID NO: 45 and the light chain variable region comprises the amino acid sequence depicted in SEQ ID NO: 42.
8. A method for treating graft-versus-host disease (GVHD), the method comprising administering to a human in need thereof, an isolated antibody, or antigen-binding fragment thereof, that binds human C5a, wherein the isolated antibody, or antigen-binding fragment thereof, that binds human C5a, comprises heavy and light chains, wherein the heavy chain comprises the amino acid sequence depicted in SEQ ID NO: 49 and the light chain comprises the amino acid sequence depicted in SEQ ID NO: 40.
9. The method of any one of claims 1 - 8 , wherein the isolated antibody, or antigen-binding fragment thereof, binds to human C5a with a K D that is less than 8.0×10 −11 M.
10. The method of any one of claims 1 - 8 , wherein the isolated antibody, or antigen-binding fragment thereof, inhibits by at least 90% human C5a-dependent human neutrophil activation at a molar ratio of 1:1 (antigen-binding site: C5a).
11. The method of any one of claims 1 - 8 , wherein the isolated antibody, or antigen-binding fragment thereof, inhibits the interaction between C5a and a C5a receptor.
12. The method of any one of claims 1 - 8 , wherein the isolated antibody, or antigen-binding fragment thereof, binds to a free C5a polypeptide, wherein the free C5a is a human polypeptide (hC5a) having the amino acid sequence depicted in SEQ ID NO: 1, and wherein the antibody, or antigen-binding fragment thereof, binds to the free hC5a polypeptide in vitro with a K D that is less than 1.25×10 −9 M in the presence of a molar excess of uncleaved, native human C5.
13. The method of any one of claims 1 - 8 , wherein the isolated antibody, or antigen-binding fragment thereof, is a humanized antibody.
14. The method of any one of claims 1 - 4 , wherein the complement-associated disorder is graft-versus-host disease (GVHD).