Methods for treating immune disorders associated with graft transplantation with soluble CTLA4 mutant molecules

Abstract

The present invention provides use of soluble CTLA4 mutant molecules which bind with greater avidity to the CD80 and/or CD86 antigen than wild type CTLA4 or non-mutated CTLA4Ig in the treatment of immune disorders associated with graft transplantation.

1 . A method for treating an immune disorder associated with graft transplantation in subjects that have received an alternate immunosuppressive therapy post transplantation comprising administering to a subject an effective dose of a CTLA4 mutant molecule comprising an extracellular domain of CTLA4 as shown in SEQ ID NO:8 beginning with alanine at position 26 or methionine at position 27 and ending with aspartic acid at position 150, or a portion thereof, wherein in the extracellular domain or portion thereof an alanine at position 55 is substituted with a tyrosine, and a leucine at position 130 is substituted with a glutamic acid and wherein the administration regimen comprises a conversion from the alternate immunosuppressive therapy to the CTLA4 mutant molecule, wherein the alternate immunosuppressive therapy is decreased over an appropriate period of time and the CTLA4 mutant molecule is administered more frequently than monthly. 
     
     
         2 . A method for treating an immune disorder associated with graft transplantation in subjects that have received an alternate immunosuppressive therapy post transplantation comprising administering to a subject an effective dose of a CTLA4 mutant molecule comprising:
 (a) an amino acid sequence beginning with methionine at position 27 and ending with aspartic acid at position 150 of SEQ ID NO:4, or   (b) an amino acid sequence beginning with alanine at position 26 and ending with aspartic acid at position 150 of SEQ ID NO:4 and   wherein the administration regimen comprises a conversion from the alternate immunosuppressive therapy to the CTLA4 mutant molecule, wherein the alternate immunosuppressive therapy is decreased over an appropriate period of time and the CTLA4 mutant molecule is administered more frequently than monthly.   
     
     
         3 . The method according to  claim 1  or  2  wherein the CTLA4 mutant molecule is administered every two weeks during the conversion period of the alternate immunosuppressive therapy. 
     
     
         4 . The method according to  claims 1  or  2  wherein the administration regimen further comprises a maintenance phase regimen wherein the maintenance phase regimen begins after the alternative immunosuppressive therapy has been totally removed and wherein administration of CTLA4 mutant molecule is not more frequent than monthly. 
     
     
         5 . The method according to  claim 3  wherein the effective dose of CTLA4 mutant molecule during the conversion is about 5 mg/kg weight of the subject. 
     
     
         6 . The method according to  claim 4  wherein the effective dose of CTLA4 mutant molecule during the maintenance phase is about 5 mg/kg weight of the subject. 
     
     
         7 . The method according to  claim 1  or  2  wherein the immune disorders associated with graft transplantation comprises solid organ, tissue and/or cell transplant rejection. 
     
     
         8 . The method according to  claim 7  wherein the immune disorders associated with graft transplantation comprises kidney or liver transplant rejection. 
     
     
         9 . The method according to  claim 1  or  2  wherein the CTLA4 mutant molecules further comprise an amino acid sequence which alters the solubility, affinity and/or valency of the soluble CTLA4 mutant molecule. 
     
     
         10 . The method according to  claim 9 , wherein the amino acid sequence which alters the solubility, affinity and/or valency comprises an immunoglobulin moiety. 
     
     
         11 . The method according to  claim 10 , wherein the immunoglobulin moiety is an immunoglobulin constant region or portion thereof. 
     
     
         12 . The method according to  claim 11 , wherein the immunoglobulin constant region or portion thereof is mutated to reduce effector function. 
     
     
         13 . The method according to  claim 11  wherein the immunoglobulin constant region or portion thereof comprises a hinge, CH2 and CH3 regions of a human or monkey immunoglobulin molecule. 
     
     
         14 . The method according to  claim 12  wherein the immunoglobulin constant region or portion thereof comprises a hinge, CH2 and CH3 regions of a human or monkey immunoglobulin molecule. 
     
     
         15 . The method according to  claim 10 , wherein the immunoglobulin comprises an amino acid sequence which begins with glutamic acid at position +152 and ends with lysine at position +383, as shown in SEQ ID NO:4. 
     
     
         16 . The method according to  claims 1  or  2  further comprising a junction amino acid residue and an immunoglobulin, where the junction amino acid residue is located between the amino acid sequence which ends with aspartic acid at position +150 and the immunoglobulin. 
     
     
         17 . The method according to  claim 1  or  2  wherein said CTLA4 mutant molecule is co-administered with at least one of the agents selected from the group consisting of basiliximab, daclizumab, anti-thymocyte globulin, calcineurin inhibitors, cyclosporine, tacrolimus, mycophenolate mofetil, mycophenolic acid, rapamycin, azathioprine, muromonab, rituximab, sirolmus, everolimus, FTY720, FK778, Jak-3, centican, corticosteroids, betamethasone, budesonide, cortisol, cortisone, dexamethasone, hydrocritisone, methylprednisolone, prednisolone, prednisone and triamcinolone. 
     
     
         18 . A method according to  claim 1  or  2  wherein development and/or progression of an outcome selected from the group consisting of CAN, hyperlipidemia, hypertension, diabetes, hirsuitism, alopecia, gingival hyperplasia, tremor, neurotoxicity and bone loss is reduced. 
     
     
         19 . The method according to  claim 1  or  2  further comprising a target trough serum concentration of the CTLA4 mutant molecule between about 3 μg/ml and about 30 μg/ml. 
     
     
         20 . A method for treating an immune disorder associated with graft transplantation in subjects that have received an alternate immunosuppressive therapy post transplantation comprising administering to a subject an effective dose of a CTLA4 mutant molecule comprising:
 (a) an amino acid sequence beginning with methionine at position 27 and ending with lysine at position +357 or glycine at position +356 of  FIG. 7 , or   (b) an amino acid sequence beginning with alanine at position 26 and ending with lysine at position +357 or glycine at position +356 of  FIG. 7  and wherein the administration regimen comprises a conversion from the alternate immunosuppressive therapy to the CTLA4 mutant molecule, wherein the alternate immunosuppressive therapy is decreased over an appropriate period of time and the CTLA4 mutant molecule is administered more frequently than monthly.   
     
     
         21 . The method according to  claim 1 ,  2  or  20  wherein the CTLA4 mutant molecule is co-administered concomitantly or sequentially with agents comprising basiliximab and MMF. 
     
     
         22 . The method according to  claim 1 ,  2  or  20  wherein the CTLA4 mutant molecule is co-administered concomitantly or sequentially with agents comprising daclizumab and siroliums. 
     
     
         23 . The method according to  claim 1 ,  2  or  20  wherein renal function of the transplanted subject is improved. 
     
     
         24 . The method according to claim  28  wherein renal function is measured by glomerular filtration rate (GFR).