Antagonistic CD40 monoclonal antibodies and uses in treating immune responses
The disclosure provides for antibodies that bind CD40, including a humanized antibody. The antibodies bind CD40 and do not exhibit CD40 agonist activity. The antibodies may comprise a modified IgG1 Fc domain, and exhibit minimal activation of immature dendritic cells. Compositions comprising antibodies, methods of use for treatment of diseases involving CD40 activity, and use in the preparation of a medicament for treatment of a disease involving CD40 activity are provided.
1. An isolated antibody, or antigen binding portion thereof, that specifically binds to human CD40, wherein said antibody comprises a first polypeptide portion comprising a heavy chain variable region, and a second polypeptide portion comprising a light chain variable region, wherein:
said heavy chain variable region comprises a CDR1 comprising SEQ ID NO: 1, a CDR2 comprising SEQ ID NO: 2, and a CDR3 comprising SEQ ID NO: 3; and
said light chain variable region comprises a CDR1 comprising SEQ ID NO: 7, a CDR2 comprising SEQ ID NO: 8, and a CDR3 comprising SEQ ID NO: 9.
2. The isolated antibody or antigen binding portion thereof of claim 1 , wherein said antibody or antigen binding portion thereof antagonizes a CD40 activity.
3. The isolated antibody or antigen binding portion thereof of claim 1 , wherein:
said heavy chain variable region comprises a CDR1 consisting of SEQ ID NO: 1, a CDR2 consisting of SEQ ID NO: 2, and a CDR3 consisting of SEQ ID NO: 3; and
said light chain variable region comprises a CDR1 consisting of SEQ ID NO: 7, a CDR2 consisting of SEQ ID NO: 8, and a CDR3 consisting of SEQ ID NO: 9.
4. The isolated antibody or antigen binding portion thereof of claim 1 , wherein said heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 4, and said light chain variable region comprises the amino acid sequence of SEQ ID NO: 10.
5. The isolated antibody or antigen binding portion thereof of claim 1 , wherein said first polypeptide portion comprises a human heavy chain constant region; and said second polypeptide portion comprises a human light chain constant region.
6. The isolated antibody or antigen binding portion thereof of claim 5 , wherein said human heavy chain constant region is a human IgG1 Fc domain comprising a mutation at Kabat position 238 that reduces binding to Fc-gamma-receptors (FcγRs), wherein proline 238 (P238) is substituted with an amino acid selected from the group consisting of: lysine, serine, alanine, arginine, and tryptophan, and wherein the antibody or antigen binding portion thereof has reduced FcγR binding.
7. The isolated antibody or antigen binding portion thereof of claim 6 , wherein the substituted amino acid is lysine.
8. The isolated antibody or antigen binding portion thereof of claim 7 , wherein the Fc domain comprises an amino acid sequence selected from: SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, or SEQ ID NO: 29.
9. The isolated antibody or antigen binding portion thereof of claim 6 , wherein:
said heavy chain variable region comprises a CDR1 consisting of SEQ ID NO: 1, a CDR2 consisting of SEQ ID NO: 2, and a CDR3 consisting of SEQ ID NO: 3; and
said light chain variable region comprises a CDR1 consisting of SEQ ID NO: 7, a CDR2 consisting of SEQ ID NO: 8, and a CDR3 consisting of SEQ ID NO: 9.
10. The isolated antibody or antigen binding portion thereof of claim 9 , wherein the human IgG1 Fc domain comprises the amino acid sequence of SEQ ID NO: 22 or SEQ ID NO: 23.
11. The isolated antibody or antigen binding portion thereof of claim 1 , wherein
the first polypeptide portion comprises or consists of an amino acid sequence selected from the group consisting of: SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 30, and SEQ ID NO: 31;
and
the second polypeptide portion comprises or consists of the amino acid sequence of SEQ ID NO: 11.
12. The isolated antibody or antigen binding portion thereof of claim 1 , wherein
the first polypeptide portion comprises or consists of the amino acid sequence of SEQ ID NO: 5;
and
the second polypeptide portion comprises or consists of the amino acid sequence of SEQ ID NO: 11.
13. The isolated antibody or antigen binding portion thereof of claim 1 , wherein the isolated antibody or antigen binding portion thereof is humanized.
14. The antibody or antigen binding portion thereof of any of claim 1 , wherein the antigen binding portion thereof is an scFv-Fc.
15. The antibody or antigen binding portion thereof of claim 1 , wherein the antibody or antigen-binding portion thereof is linked to a therapeutic agent.
16. The antibody or antigen binding portion thereof of claim 1 , wherein the antibody or antigen-binding portion thereof is linked to a second functional moiety having a different binding specificity than said antibody or antigen binding portion thereof.
17. The antibody or antigen binding portion thereof of claim 1 , further comprising an additional moiety.
18. The isolated antibody or antigen binding portion thereof of claim 1 , wherein said heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 4, and said light chain variable region comprises the amino acid sequence of SEQ ID NO: 16.
19. A pharmaceutical composition comprising: a) the antibody, or antigen binding portion thereof, of claim 1 ; and b) a pharmaceutically acceptable carrier.
20. A method of treating or preventing an immune response in a subject comprising administering to the subject the antibody, or the antigen binding portion thereof, of claim 1 .
21. A method of treating or preventing an autoimmune or inflammatory disease in a subject, comprising administering to the subject the antibody, or the antigen binding portion thereof, of claim 1 .
22. The method of claim 21 , wherein the antibody, or the antigen binding portion thereof, is administered with an immunosuppressive, immunomodulatory, and/or anti-inflammatory agent.
23. The method of claim 22 , wherein said immunosuppressive, immunomodulatory, and/or anti-inflammatory agent is CTLA4 mutant molecule L104EA29Y-Ig (belatacept).
24. The method of claim 21 , wherein the subject has a disease selected from the group consisting of: Addison's disease, allergies, anaphylaxis, ankylosing spondylitis, asthma, atherosclerosis, atopic allergy, autoimmune diseases of the ear, autoimmune diseases of the eye, autoimmune hepatitis, autoimmune parotitis, bronchial asthma, coronary heart disease, Crohn's disease, diabetes, epididymitis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia, idiopathic thrombocytopenic purpura, inflammatory bowel disease, an immune response to recombinant drug products, lupus nephritis, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, pemphigus, psoriasis, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthropathies, thyroiditis, transplant rejection, vasculitis, and ulcerative colitis.
25. The method of claim 21 , wherein the subject has Sjogren's syndrome.