Identification and engineering of antibodies with variant FC regions and methods of using same
The present invention relates to molecules, particularly polypeptides, more particularly immunoglobulins (e.g., antibodies), comprising a variant Fc region, wherein said variant Fc region comprises at least one amino acid modification relative to a wild-type Fc region, which variant Fc region binds FcγRIIIA and/or FcγRIIA with a greater affinity, relative to a comparable molecule comprising the wild-type Fc region. The molecules of the invention are particularly useful in preventing, treating, or ameliorating one or more symptoms associated with a disease, disorder, or infection. The molecules of the invention are particularly useful for the treatment or prevention of a disease or disorder where an enhanced efficacy of effector cell function (e.g., ADCC) mediated by FcγR is desired, e.g., cancer, infectious disease, and in enhancing the therapeutic efficacy of therapeutic antibodies the effect of which is mediated by ADCC.
1. A method of dampening FcγRIIIA receptor activity in a subject, said method comprising administering to said subject an antibody or an antigen-binding fragment thereof, said antibody or said fragment thereof comprising a variant IgG1 Fc region, wherein said variant IgG1 Fc region comprises at least one amino acid substitution relative to a wild-type IgG1 Fc region, wherein said at least one amino acid substitution is:
(1) a substitution at position 247 with leucine; or
(2) a substitution at position 268 with aspartic acid and at position 318 with aspartic acid;
and wherein said variant IgG1 Fc region binds FcγRIIB with an increased affinity relative to the affinity of said wild-type IgG1 Fc region.
2. The method of claim 1 , wherein said variant IgG1 Fc region additionally exhibits increased affinity for FcγRIIIA relative to the affinity of said wild-type IgG1 Fc region for FcγRIIIA, wherein the magnitude of said increased affinity for FcγRIIB is greater than the magnitude of said increased affinity for FcγRIIIA.
3. The method of claim 1 , wherein said antibody or fragment thereof has a variable domain that binds to complement, alpha4beta7, beta2-integrin, CBL, CD2, CD3, CD4, CD11, CD14, CD18, CD23, CD25, CD40L, CD64, CD80, CD147, E-selectin, Fact VII, gpIIbIIIa, ICAM-3, IgE, IL-4, IL-5, IL-8, TNF alpha, or VLA-4.
4. The method of claim 3 , wherein said subject has an autoimmune disorder selected from the group consisting of: ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Rieter's Syndrome, psoriasis, and lupus erythematosus.
5. The method of claim 4 , further comprising administering to said subject a therapeutically effective amount one or more anti-inflammatory agents.
6. The method of claim 4 , further comprising administering to said subject a therapeutically effective amount of one or more immunomodulatory agents.
7. The method of claim 6 , wherein at least one immunomodulatory agent is a small organic molecule.
8. The method of claim 7 , wherein the small organic molecule is methotrexate, leflunomide, cyclophosphamide, cyclosporin A, FK506, mycophenolate mofetil, rapamycin, mizoribine, deoxyspergualin, brequinar, malonitrolamide, steroid, or corticosteroid.
9. The method of claim 5 , wherein said one or more anti-inflammatory agents is a non-steroidal anti-inflammatory drug.
10. The method of claim 9 , wherein the non-steroidal anti-inflammatory drug is aspirin, ibuprofen, diclofenae, nabumetone, naproxen, or ketoproten.