Methods for the treatment of autoimmune disorders using immunosuppressive monoclonal antibodies with reduced toxicity
The present invention provides methods of treating, preventing, slowing the progression of, or ameliorating the symptoms of T cell mediated immunological diseases, particularly autoimmune diseases (e.g., autoimmune diabetes (i.e. type 1 diabetes or insulin-dependent diabetes mellitus (IDDM)) and multiple sclerosis) through the use of anti-human CD3 antibodies. The antibodies of the invention of the invention are preferably used in low dose dosing regimens, chronic dosing regimens or regimens that involve redosing after a certain period of time. The methods of the invention provide for administration of antibodies that specifically bind the epsilon subunit within the human CD3 complex. Such antibodies modulate the T cell receptor/alloantigen interaction and, thus, regulate the T cell mediated cytotoxicity associated with autoimmune disorders. Additionally, the methods of the invention provide for use of anti-human CD3 antibodies modified such that they exhibit reduced or eliminated effector function and T cell activation as compared to non-modified anti-human CD3 antibodies.
1. A method of treating, slowing the progression of, or ameliorating one or more symptoms of an autoimmune disorder in a patient diagnosed with said disorder, said method comprising administering to said patient a course of treatment with a therapeutically effective amount of an anti-human CD3 antibody wherein said antibody is humanized OKT3γ1 (ala-ala),
wherein less than 9000 μg/m 2 is administered parenterally in total during said course of treatment;
wherein said treatment comprises a dosage regimen comprising doses of increasing amounts of said antibody on at least the initial 4 days of said course of treatment;
wherein said autoimmune disorder is rheumatoid arthritis; and
wherein said patient is in early stages of the autoimmune disorder,
during which, autoreactive cytotoxic T-lymphocytes are detected in synovial tissues but clinical symptoms of rheumatoid arthritis have not yet developed.
2. The method of claim 1 , wherein the antibody is ChAglyCD3 or visilizumab.
3. The method of claim 1 , wherein the dose on day 1 is approximately 51 μg/m 2 , the dose on day 2 is approximately 103 μg/m 2 , the dose on day 3 is approximately 207 μg/m 2 , the dose on day 4 is approximately 413 μg/m 2 , and the dose on subsequent days is approximately 826 μg/m 2 .
4. The method of claim 1 wherein each dose of said antibody is administered intravenously in one infusion over a period of at least 18 hours.
5. The method of claim 4 in which said administration results in serum levels of free anti-human CD3 antibody that do not exceed 200 ng/ml.
6. The method of claim 1 , in which said administration does not result in EBV-induced lymphoproliferative diseases or lymphocyte counts less than 1000 lymphocytes/μl serum.
7. The method of claim 1 , further comprising redosing said patient with an additional round of said course of treatment.
8. The method of claim 7 , wherein said patient had been administered a 6 to 20 day course of treatment with said anti-human CD3 antibodies prior to said additional round.