Methods for the Treatment of Autoimmune Disorders Using Immunosuppressive Monoclonal Antibodies with Reduced Toxicity

Abstract

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 the anti-human CD3 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 type 1 diabetes; and   wherein said patient is in early stages of the autoimmune disorder before about 80% of β-cells have been destroyed.   
     
     
         2 - 11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the antibody is ChAglyCD3 or visilizumab. 
     
     
         13 - 18 . (canceled) 
     
     
         19 . 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 . 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 1 , wherein the dose on day 1 is approximately 17 μg/m 2 , the dose on day 2 is approximately 34.3 μg/m 2 , the dose on day 3 is approximately 69 μg/m 2 , the dose on day 4 is approximately 137 μg/m 2 , and the dose on subsequent days is approximately 275 μg/m 2 . 
     
     
         22 - 24 . (canceled) 
     
     
         25 . The method of  claim 1  wherein each dose of said antibody is administered in one infusion over a period of at least 18 hours. 
     
     
         26 . The method of  claim 25  in which said administration results in serum levels of free antihuman CD3 antibody that do not exceed 200 ng/ml. 
     
     
         27 - 32 . (canceled) 
     
     
         33 . The method of  claim 1  wherein said patient is redosed if the average daily dose of insulin has increased by 50% or more, if autoantibodies against one or more islet cell antigens are detected, if islet cell antigen specific T cells are detected, if β-cell mass decreases by 50% or more, or if the incidence of hypoglycemic or ketoacidosis episodes increases by 1 or more incidents per day in said patient, at least 2 years after initial administration of said course of treatment. 
     
     
         34 - 37 . (canceled) 
     
     
         38 . The method of  claim 1 , wherein said treatment results in an increase in the average daily dose of insulin of no more than 0.2 U/kg/day six months after said treatment; in a HA1c of less than 7.5% one year after said treatment; or a C-peptide response to MMTT twelve months after said treatment that is at least 90% of the C-peptide response to MTT in said patient before said treatment. 
     
     
         39 - 45 . (canceled) 
     
     
         46 . 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. 
     
     
         47 - 50 . (canceled) 
     
     
         51 . The method of  claim 55 , 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. 
     
     
         52 - 54 . (canceled) 
     
     
         55 . The method of  claim 1 , further comprising redosing said patient with an additional round of said course of treatment. 
     
     
         56 . A method for treating, or slowing the progression of, an autoimmune disorder in a patient diagnosed with said disorder, or for preventing or delaying the onset of an autoimmune disorder in a patient predisposed thereto but not diagnosed with said disorder, said method comprising:
 administering to said patient a dosage regime with a prophylactically or therapeutically effective amount of an anti-human CD3 antibody, said dosage regimen comprising administration of a total daily prophylactically or therapeutically effective amount of 35 μg/kg or less of said antibody;   wherein said antibody is administered at doses that escalate over at least the initial 4 days of said dosage regimen until the total daily prophylactically or therapeutically effective amount of said antibody is achieved;   wherein the anti-human CD3 antibody is humanized OKT3γ1 ala-ala;   wherein said autoimmune disorder is selected from the group consisting of rheumatoid arthritis, psoriasis, and type 1 diabetes; and   wherein said patient is in early stages of the autoimmune disorder, during which, when the autoimmune disorder is rheumatoid arthritis, autoreactive cytotoxic T-lymphocytes are detected in synovial tissues but clinical symptoms of rheumatoid arthritis have not yet developed and, when the autoimmune disorder is type 1 diabetes, less than about 80% of β-cells have been destroyed.   
     
     
         57 . The method of  claim 56 , wherein said antibody is administered at doses that escalate over the first half of the dosage regimen until the total daily prophylactically or therapeutically effective amount of said antibody is achieved. 
     
     
         58 . The method of  claim 56 , wherein said antibody is administered at doses that escalate by a factor of 2 until the total daily prophylactically or therapeutically effective amount of said antibody is achieved. 
     
     
         59 . The method of  claim 56 , wherein the total daily prophylactically or therapeutically effective amount is 30 μg/kg or less, 25 μg/kg or less, 20 μg/kg or less, 15 μg/kg or less, or 10 μg/kg or less, of said antibody. 
     
     
         60 . The method of  claim 56 , wherein said dosage regimen is 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. 
     
     
         61 . The method of  claim 56 , wherein on at least the first day of said dosage regimen, said antibody is administered in portions at intervals of 6 hours, 8 hours, or 12 hours. 
     
     
         62 . The method of  claim 56 , wherein said anti-human CD3 antibody is administered by a route selected from the group consisting of intravenous, intramuscular, subcutaneous, or oral administration. 
     
     
         63 . The method of  claim 62 , wherein said anti-human CD3 antibody is administered by an intravenous route over a period of at least 30 minutes for each administration. 
     
     
         64 . The method of  claim 56 , wherein said anti-human CD3 antibody is administered in combination with an immunosuppressant. 
     
     
         65 . The method of  claim 56 , wherein said autoimmune disease is Type 1 diabetes and wherein said anti-human CD3 antibody is administered in combination with administration of insulin, exenatide, or pramlinitide. 
     
     
         66 . The method of  claim 56 , wherein said autoimmune disease is Type 1 diabetes and, prior to said dosage regime, the HA1c of said patient is less than 7.5% or the C-peptide response of said patient to a mixed-meal tolerance test (MMTT) results in a mean area under the curve of at least 100 pmol/ml. 
     
     
         67 . The method of  claim 56 , wherein said autoimmune disorder is Type 1 diabetes and said patient is a child. 
     
     
         68 . The method of  claim 67 , wherein said child is between 7 and 20 years of age.