Methods of treatment or prevention of immune responses and inflammatory diseases with antagonistic CD40 monoclonal antibodies
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. A method of treating or preventing at least one of an immune response, an autoimmune disease, or an inflammatory disease in a subject comprising administering to the subject a pharmaceutical composition comprising:
(a) an antibody, or antigen-binding portion thereof, that specifically binds to human CD40; and
(b) a pharmaceutically acceptable carrier,
wherein the antibody or antigen-binding portion thereof comprises a first polypeptide portion comprising a heavy chain variable region and a human heavy chain constant region, and a second polypeptide portion comprising a light chain variable region and a human light chain constant 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 method of claim 1 , wherein said antibody or antigen-binding portion thereof thereof antagonizes a CD40 activity.
3. The method 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.
4. The method of claim 1 , wherein said human heavy chain constant region is a human IgG1 Fc domain comprising either
(1) a mutation at Kabat position 238 that reduces binding to Fc-gamma-receptors (FcγRs), wherein proline 238 (P238) is mutated to one of the residues 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; or
(2) an alanine substituted at Kabat position 297.
5. The method of claim 1 , 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 mutated to one of the residues 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.
6. The method of claim 1 , wherein said human heavy chain constant region is a human IgG1 Fc domain comprising a lysine mutation at Kabat position 238 that reduces binding to Fc-gamma-receptors (FcγRs).
7. The method of claim 6 , 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.
8. The method of claim 6 , wherein the Fc domain comprises the amino acid sequence of SEQ ID NO: 22 or SEQ ID NO: 23.
9. The method 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 method of claim 9 , 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.
11. The method of claim 9 , wherein the Fc domain comprises the amino acid sequence of SEQ ID NO: 22 or SEQ ID NO: 23.
12. The method of claim 1 , wherein:
the first polypeptide portion comprises 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 the amino acid sequence of SEQ ID NO: 11.
13. The method of claim 1 , wherein
the first polypeptide portion comprises the amino acid sequence of SEQ ID NO: 5; and
the second polypeptide portion comprises the amino acid sequence of SEQ ID NO: 11.
14. The method of claim 1 , wherein the antigen-binding portion is an scFv-Fc.
15. The method 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; or
the antibody or antigen-binding portion thereof is linked to a therapeutic agent.
16. The method of claim 1 , further comprising administering an immunosuppressive, immunomodulatory, and/or anti-inflammatory agent.
17. The method of claim 16 , wherein said immunosuppressive, immunomodulatory, and/or anti-inflammatory agent is a CTLA4 mutant molecule.
18. The method of claim 17 , wherein said CTLA4 mutant molecule is L104EA29Y-Ig (belatacept).
19. The method of claim 1 , 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 thrombocytopenia 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, Sjögren's syndrome, spondyloarthropathies, thyroiditis, transplant rejection, vasculitis, and ulcerative colitis.
20. The method of claim 1 , wherein the subject has Sjögren's syndrome.