Methods for enhancing immunosuppressive therapy by multiple administration of alpha beta tcr-binding polypeptide

Abstract

The present disclosure is related to improved methods for use of a humanized binding polypeptide specific for the alpha beta T cell receptor (αβ-TCR). In particular, this disclosure relates to improved methods of use of a humanized anti-αβ-TCR antibody, which is derived from the murine monoclonal antibody BMA031, in immunosuppressive therapy. Novel methods using humanized monoclonal antibodies and/or humanized monoclonal antibody fragments (e.g., anti-αβTCR antibodies and/or fragments thereof) are also provided. Novel methods using repetitive administration of humanized monoclonal antibodies and/or humanized monoclonal antibody fragments (e.g., anti-αβTCR antibodies and/or fragments thereof) to reduce αβ T cells in the subject relative to γδ T cells in the subject are provided.

1 . A method of preferentially reducing αβ T cells relative to γδ T cells in a subject, comprising administering to the subject a humanized anti-αβTCR binding polypeptide in two or more doses. 
     
     
         2 - 5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein three or more doses are administered. 
     
     
         7 . The method of  claim 1 , wherein the αβ T cells that are preferentially reduced are CD4+ human αβ T cells. 
     
     
         8 . A method of increasing the proportion of γδ cells within a CD3+ T cell population in a subject, comprising administering to the subject a humanized anti-αβTCR binding polypeptide in two or more doses. 
     
     
         9 . The method of  claim 1 , wherein the subject has a T cell-mediated disorder. 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 9 , wherein the T cell-mediated disorder is selected from the group consisting of an autoimmune disorder, a xenotransplant-related disorder, an allotransplant-related disorder, a xenopregnancy-related disorder, pre-eclampsia, and Rh disease. 
     
     
         12 . A method of sparing pathogen inactive cells while suppressing a T cell-mediated response in a subject, comprising the steps of administering to the subject a humanized anti-αβTCR binding polypeptide in two or more doses. 
     
     
         13 . The method of  claim 12 , wherein the pathogen inactive cells are selected from the group consisting of CD3+ effector cells, γδ T cells, iNK T cells, and NK cells. 
     
     
         14 - 17 . (canceled) 
     
     
         18 . A method of treating a T cell-mediated disorder in a subject, comprising administering to the subject a humanized anti-αβTCR binding polypeptide in two or more doses. 
     
     
         19 . The method of  claim 18 , wherein the T cell-mediated disorder is selected from the group consisting of an autoimmune disorder, a xenotransplant-related disorder, an allotransplant-related disorder, a xenopregnancy-related disorder, pre-eclampsia, and Rh disease. 
     
     
         20 . The method of  claim 1 , wherein the humanized anti-αβTCR binding polypeptide is a humanized monoclonal antibody or fragment thereof, wherein the humanized monoclonal antibody is selected from the group consisting of GL1BM VH28, HEBE1 H66, and HEBE1 H71. 
     
     
         21 . (canceled) 
     
     
         22 . The method of  claim 20 , wherein the humanized monoclonal antibody or fragment thereof comprises a heavy chain variable region comprising the amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 13, and 15, and a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO: 14. 
     
     
         23 - 34 . (canceled) 
     
     
         35 . The method of  claim 20 , wherein the antibody fragment is selected from the group consisting of Fab, Fab′, F(ab′)2, and F(v) fragments, or the individual light or heavy chain variable regions or any portion thereof. 
     
     
         36 - 46 . (canceled) 
     
     
         47 . The method of  claim 8 , wherein the subject has a T cell-mediated disorder. 
     
     
         48 . The method of  claim 47 , wherein the T cell-mediated disorder is selected from the group consisting of an autoimmune disorder, a xenotransplant-related disorder, an allotransplant-related disorder, a xenopregnancy-related disorder, pre-eclampsia, and Rh disease. 
     
     
         49 . The method of  claim 8 , wherein the humanized anti-αβTCR binding polypeptide is a humanized monoclonal antibody or fragment thereof, wherein the humanized monoclonal antibody is selected from the group consisting of GL1BM VH28, HEBE1 H66, and HEBE1 H71. 
     
     
         50 . The method of  claim 8 , wherein the humanized monoclonal antibody or fragment thereof comprises a heavy chain variable region selected from the group consisting of an amino acid sequence set forth in SEQ ID NO: 7, SEQ ID NO: 12, and SEQ ID NO: 13, and a light chain variable region sequence comprising an amino acid sequence as set forth in SEQ ID NO: 14. 
     
     
         51 . The method of  claim 12 , wherein the humanized anti-αβTCR binding polypeptide is a humanized monoclonal antibody or fragment thereof, wherein the humanized monoclonal antibody is selected from the group consisting of GL1BM VH28, HEBE1 H66, and HEBE1 H71. 
     
     
         52 . The method of  claim 12 , wherein the humanized monoclonal antibody or fragment thereof comprises a heavy chain variable region selected from the group consisting of an amino acid sequence set forth in SEQ ID NO: 7, SEQ ID NO: 12, and SEQ ID NO: 13, and a light chain variable region sequence comprising an amino acid sequence as set forth in SEQ ID NO: 14. 
     
     
         53 . The method of  claim 18 , wherein the humanized anti-αβTCR binding polypeptide is a humanized monoclonal antibody or fragment thereof, wherein the humanized monoclonal antibody is selected from the group consisting of GL1BM VH28, HEBE1 H66, and HEBE1 H71. 
     
     
         54 . The method of  claim 18 , wherein the humanized monoclonal antibody or fragment thereof comprises a heavy chain variable region selected from the group consisting of an amino acid sequence set forth in SEQ ID NO: 7, SEQ ID NO: 12, and SEQ ID NO: 13, and a light chain variable region sequence comprising an amino acid sequence as set forth in SEQ ID NO: 14.