Ctla4 fusion proteins for the treatment of diabetes

Abstract

A method of treating, preventing, or delaying the progression of Type 1 diabetes mellitus autoimmunity by administering an effective amount of a cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) molecule is provided herewith. The CTLA4 molecule may be a fusion protein of a CTLA4 extracellular region and an immunoglobulin, such as abatacept.

1 . A method of treating diabetes mellitus in a subject comprising administering an effective amount of a fusion protein composition comprising a T-cell co-stimulation antagonist and a portion of an immunoglobulin molecule. 
     
     
         2 . The method of  claim 1  wherein the T-cell co-stimulation antagonist comprises the extracellular domain of CTLA4, an effective fragment of the extracellular domain or immunologically active variant of the extracellular domain. 
     
     
         3 . The method of  claim 1  wherein the T-cell co-stimulation antagonist binds a B7 antigen expressed on B cells and/or on antigen presenting cells (APCs). 
     
     
         4 . The method of  claim 1  wherein the composition comprises Abatacept. 
     
     
         5 . The method of  claim 1  wherein the composition is administered as a pharmaceutically acceptable salt. 
     
     
         6 . The method of  claim 1  wherein the composition further comprises an oil-based carrier. 
     
     
         7 . The method of  claim 6 , wherein said oil-based carrier is a water-in-oil emulsion. 
     
     
         8 . The method of  claim 6 , wherein said oil-based carrier is an oil-in-water emulsion. 
     
     
         9 . The method of  claim 6 , wherein said oil-based carrier is IFA. 
     
     
         10 . The method of  claim 6 , wherein said oil-based carrier is Montanide ISA. 
     
     
         11 . The method of  claim 1 , wherein the composition is administered by intravenous infusion. 
     
     
         12 . The method of  claim 11 , wherein the composition is administered by intravenous infusion in about 50 to 200 ml of physiological saline. 
     
     
         13 . The method of  claim 11 , wherein the composition is administered at a dose ranging from about 5 mg/kg to about 50 mg/kg 
     
     
         14 . The method of  claim 11 , wherein the intravenous infusion of the composition is repeated over time. 
     
     
         15 . The method of  claim 11 , wherein the intravenous infusion of the composition is repeated at least once following a time interval ranging from about one week to about two months. 
     
     
         16 . The method of  claim 11 , wherein the composition is administered at a dose ranging from about 250 to 2000 mg. 
     
     
         17 . The method of  claim 16 , wherein the composition is administered at a dose of 500 mg. 
     
     
         18 . The method of  claim 16 , wherein the composition is administered at a dose of 750 mg. 
     
     
         19 . The method of  claim 16 , wherein the composition is administered at a dose of 1000 mg. 
     
     
         20 . The method of  claim 1 , wherein the method further comprises determining levels of C-peptide in blood samples taken from the subject over time as an indicator of effectiveness of the treatment in inhibiting activation of auto-aggressive T-cells. 
     
     
         21 . The method of  claim 20 , wherein the effectiveness of the composition in inhibiting activation of auto-aggressive T-cells is indicated by maintenance of C-peptide production or a delay in reduction of C-peptide production as compared to a standard. 
     
     
         22 . The method of  claim 20 , wherein the effectiveness of the composition in inhibiting activation of auto-aggressive T-cells is indicated by improved HbA1c or reduction in the use of insulin by said subject as compared to a standard. 
     
     
         23 . The method of  claim 20 , wherein the reduction of C-peptide production in said subject is delayed for at least six months. 
     
     
         24 . The method of  claim 20 , wherein the reduction of C-peptide production in said subject is delayed for at least nine months. 
     
     
         25 . The method of  claim 1 , wherein the subject is white. 
     
     
         26 . The method of  claim 1 , wherein said treating diabetes mellitus in a subject comprising preventing the onset of diabetes in a subject at risk for diabetes mellitus. 
     
     
         27 . The method of  claim 1 , wherein said treating diabetes mellitus in a subject comprising delaying the onset of diabetes by at least six months in a subject at risk for diabetes mellitus.