Anti-CD154 antibodies having impaired FcR binding and/or complement binding properties and related therapies
Improved anti-CD154 antibodies are provided herein which have ablated FcR binding and/or complement binding/activation. The use of these antibodies for inducing tolerance and treating immune diseases including autoimmunity, inflammation and allergic disorders is disclosed herein.
1. A method of inducing immunosuppression without eliciting thrombotic events in a patient in need thereof comprising administering to a patient an effective amount of a human or humanized antibody of the human IgG1 isotype that specifically binds human CD154 wherein said antibody contains light chain CDR1, CDR2 and CDR3 polypeptides respectively comprising the polypeptide sequences of SEQ ID NO's: 17, 18 and 19, and heavy chain CDR1, CDR2 and CDR3 polypeptides respectively comprising the polypeptide sequences of SEQ ID NO's: 24, 25 and 26, wherein the Fc region of the IgG1 antibody contains an E269R mutation which impairs FcR binding and a mutation which impairs C 1q binding activity which is selected from the group consisting of K322A, P331G, and P331G/K322A and further comprises another mutation which impairs binding to an Fc receptor which mutation is K326V.
2. A method of treating autoimmunity, allergy, transplant, GVHD, or inflammation in a patient in need thereof by administering an effective amount of a human or humanized antibody of the human IgG1 isotype that specifically binds human CD154 wherein said antibody contains light chain CDR1, CDR2 and CDR3 polypeptides respectively comprising the polypeptide sequences of SEQ ID NO's: 17, 18 and 19, and heavy chain CDR1, CDR2 and CDR3 polypeptides respectively comprising the polypeptide sequences of SEQ ID NO's: 24, 25 and 26, wherein the Fc region of the IgG1 antibody contains an E269R mutation which impairs FcR binding and a mutation which impairs C 1q binding activity which is selected from the group consisting of K322A, P331G, and P331G/K322A and further comprises another mutation which impairs binding to an Fc receptor which mutation is K326V.
3. The method of claim 1 which further includes administration of an antigen.
4. The method of claim 2 which further includes administration of an antigen.
5. The method of claim 1 , wherein the patient comprises an autoimmune disease or allergy condition selected from rheumatoid arthritis, Myasthenia gravis, systemic lupus erythematosus, Graves' disease, idiopathic thrombocytopenia purpura, hemolytic anemia, diabetes mellitus, psoriasis, Addison's disease, multiple sclerosis, lupus, inflammatory bowel disorder, asthma and drug-induced asthma.
6. The method of claim 2 , wherein the patient has a condition selected from rheumatoid arthritis, Myasthenia gravis, systemic lupus erythematosus, Graves' disease, idiopathic thrombocytopenia purpura, hemolytic anemia, diabetes mellitus, psoriasis, Addison's disease, multiple sclerosis, lupus, inflammatory bowel disorder, asthma and drug-induced asthma.
7. The method of claim 1 , wherein the mutation which impairs C 1q binding activity is a K322A mutation.
8. The method of claim 1 , wherein the mutation which impairs C 1q binding activity is a P331G mutation.
9. The method of claim 1 , wherein the mutation which impairs C 1q binding activity is a P331G/K322A mutation.
10. The method of claim 2 , wherein the mutation which impairs C 1q binding activity is a K322A mutation.
11. The method of claim 2 , wherein the mutation which impairs C 1q binding activity is a P331G mutation.
12. The method of claim 2 , wherein the mutation which impairs C1q binding activity is a P331G/K322A mutation.