IL-6 binding molecules
The present invention provides binding molecules (e.g., antibodies or antigen binding fragments thereof) that specifically bind to and inhibit the biological activity of IL-6 (e.g., human, mouse and non-human primate IL-6). In a preferred embodiment, the antibodies or antigen binding fragments of the invention bind to IL-6 and inhibit its binding to an IL-6 receptor. Such antibodies or antigen binding fragments are particularly useful for treating IL-6-associated diseases or disorders (e.g., inflammatory disease and cancer).
1. A method of neutralizing IL-6 activity in a subject in need thereof, comprising administering to a subject an effective amount of an antibody or antigen binding fragment thereof that specifically binds to IL-6, comprising:
a VH domain comprising the HCDR3, HCDR2, and HCDR1 amino acid sequences of the VH amino acid sequence set forth as SEQ ID NO: 152, and
a VL domain comprising the LCDR3, LCDR2, and LCDR1 amino acid sequences of the VL amino acid sequence set forth as SEQ ID NO: 416.
2. The method of claim 1 , wherein the subject has an inflammatory disease, cancer, cancer-related anorexia, oral mucositis, or cachexia.
3. The method of claim 1 , wherein the subject has an inflammatory disease selected from the group consisting of rheumatoid arthritis (RA), spondylosing arthropathy, systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), psoriasis, and Castleman's disease.
4. The method of claim 1 , wherein the subject has a cancer selected from the group consisting of prostate cancer, diffuse large cell lymphoma, multiple myeloma, and renal cell cancer.
5. The method of claim 1 , wherein:
the VH domain comprises the HCDR3 amino acid sequence set forth as SEQ ID NO: 497; the HCDR2 amino acid sequence set forth as SEQ ID NO: 501; and the HCDR1 amino acid sequence set forth as SEQ ID NO: 508, and
the VL domain comprises the LCDR3 amino acid sequence set forth as SEQ ID NO: 513; the LCDR2 amino acid sequence set forth as SEQ ID NO: 525; and the LCDR1 amino acid sequence set forth as SEQ ID NO: 536.
6. The method of claim 1 , wherein the antibody or antigen binding fragment thereof further comprises a human Fc domain comprising a H433K/N434F double mutation, according to the EU numbering system.
7. The method of claim 1 , wherein the VH domain comprises the amino acid sequence set forth as SEQ ID NO: 152.
8. The method of claim 1 , wherein the antibody or antigen binding fragment thereof further comprises a human Fc domain comprising a H433K/N434F double mutation, according to the EU numbering system.
9. The method of claim 1 , wherein the VH domain comprises the amino acid sequence set forth as SEQ ID NO: 152, wherein the glutamine at position 1 of SEQ ID NO: 152 has been changed to glutamic acid.
10. The method of claim 9 , wherein the antibody or antigen binding fragment thereof further comprises a human Fc domain comprising a H433K/N434F double mutation, according to the EU numbering system.
11. The method of claim 1 , wherein the VL domain comprises the amino acid sequence set forth as SEQ ID NO: 416.
12. The method of claim 11 , wherein the antibody or antigen binding fragment thereof further comprises a human Fc domain comprising a H433K/N434F double mutation, according to the EU numbering system.
13. The method of claim 1 , wherein the VH domain comprises the amino acid sequence set forth as SEQ ID NO: 152, and the VL domain comprises the amino acid sequence set forth as SEQ ID NO: 416.
14. The method of claim 13 , wherein the antibody or antigen binding fragment thereof further comprises a human Fc domain comprising a H433K/N434F double mutation, according to the EU numbering system.
15. The method of claim 12 , the VH domain comprises the amino acid sequence set forth as SEQ ID NO: 152, wherein the glutamine at position 1 of SEQ ID NO: 152 has been changed to glutamic acid, and the VL domain comprises the amino acid sequence set forth as SEQ ID NO: 416.
16. The method of claim 15 , wherein the antibody or antigen binding fragment further comprises a human Fc domain comprising a H433K/N434F double mutation, according to the EU numbering system.
17. The method of claim 1 , wherein the IL-6 activity is promotion of cell proliferation.
18. The method of claim 1 , wherein the IL-6 activity is IL-6 binding to an IL-6 receptor.