Human polypeptides causing or leading to the killing of cells including lymphoid tumor cells

Abstract

The present invention relates to polypeptide compositions which bind to cell surface epitopes and, in multivalent forms, cause or lead to the killing of cells including lymphoid tumor cells, and in the case of monovalent forms, cause immunosuppression or otherwise inhibit activation of lymphocytes. The invention further relates to nucleic acids encoding the polypeptides, methods for the production of the polypeptides, methods for killing cells, methods for immunosuppressing a patient, pharmaceutical, diagnostic and multivalent compositions and kits comprising the polypeptides and uses of the polypeptides.

1 - 116 . (canceled) 
     
     
         117 . A polynucleotide encoding a polypeptide, said polypeptide comprising an antibody-based antigen-binding domain of human composition with binding specificity for a HLA-DR antigen expressed on the surface of a human cell, wherein treating cells expressing said antigen with a multivalent polypeptide having two or more of said antigen-binding domains causes or leads to killing of said cells, wherein said antigen-binding domain includes a combination of a VH domain and a VL domain, wherein said combination is found in one of the clones selected from the group consisting of MS-GPC-1 (SEQ ID NOs. 37 and 38, respectively), MS-GPC-6 (SEQ ID NOs. 39 and 40, respectively), MS-GPC-8 (SEQ ID NOs. 41 and 42, respectively), MS-GPC-10 (SEQ ID NOs. 43 and 44, respectively), MS-GPC-8-1 (SEQ ID NOs. 41 and 28, respectively), MS-GPC-8-6 (SEQ ID NOs. 41 and 46, respectively), MS-GPC-8-9 (SEQ ID NOs. 41 and 31, respectively), MS-GPC-8-10 (SEQ ID NOs. 41 and 48, respectively), MS-GPC-8-17 (SEQ ID NOs. 41 and 50, respectively), MS-GPC-8-18 (SEQ ID NOs. 41 and 32, respectively), MS-GPC-8-27 (SEQ ID NOs. 41 and 52, respectively), MS-GPC-8-6-2 (SEQ ID NOs. 41 and 45, respectively), MS-GPC-8-6-19 (SEQ ID NOs. 41 and 47, respectively), MS-GPC-8-6-27 (SEQ ID NOs. 41 and 49, respectively), MS-GPC-8-6-45 (SEQ ID NOs. 41 and 51, respectively), MS-GPC-8-6-13 (SEQ ID NOs. 41 and 54, respectively), MS-GPC-8-6-47 (SEQ ID NOs. 41 and 53, respectively), MS-GPC-8-10-57 (SEQ ID NOs. 41 and 56, respectively), MS-GPC-8-27-7 (SEQ ID NOs. 41 and 55, respectively), MS-GPC-8-27-10 (SEQ ID NOs. 41 and 57, respectively) and MS-GPC-8-27-41 (SEQ ID NOs. 41 and 58, respectively). 
     
     
         118 . A polynucleotide encoding a polypeptide, said polypeptide comprising an antibody-based antigen-binding domain of human composition with binding specificity for a HLA-DR antigen expressed on the surface of a human cell, wherein treating cells expressing said antigen with a multivalent polypeptide having two or more of said antigen-binding domains causes or leads to killing of said cells, wherein said antigen-binding domain includes a combination of HuCAL VH2 and HuCAL Vλ1, wherein the VH CDR3, VL CDR1 and VL CDR3 is found in one of the clones selected from the group consisting of MS-GPC-1 (SEQ ID NOs. 37 and 38, respectively), MS-GPC-6 (SEQ ID NOs. 39 and 40, respectively), MS-GPC-8 (SEQ ID NOs. 41 and 42, respectively), MS-GPC-10 (SEQ ID NOs. 43 and 44, respectively), MS-GPC-8-1 (SEQ ID NOs. 41 and 28, respectively), MS-GPC-8-6 (SEQ ID NOs. 41 and 46, respectively), MS-GPC-8-9 (SEQ ID NOs. 41 and 31, respectively), MS-GPC-8-10 (SEQ ID NOs. 41 and 48, respectively), MS-GPC-8-17 (SEQ ID NOs. 41 and 50, respectively), MS-GPC-8-18 (SEQ ID NOs. 41 and 32, respectively), MS-GPC-8-27 (SEQ ID NOs. 41 and 52, respectively), MS-GPC-8-6-2 (SEQ ID NOs. 41 and 45, respectively), MS-GPC-8-6-19 (SEQ ID NOs. 41 and 47, respectively), MS-GPC-8-6-27 (SEQ ID NOs. 41 and 49, respectively), MS-GPC-8-6-45 (SEQ ID NOs. 41 and 51, respectively), MS-GPC-8-6-13 (SEQ ID NOs. 41 and 54, respectively), MS-GPC-8-6-47 (SEQ ID NOs. 41 and 53, respectively), MS-GPC-8-10-57 (SEQ ID NOs. 41 and 56, respectively), MS-GPC-8-27-7 (SEQ ID NOs. 41 and 55, respectively), MS-GPC-8-27-10 (SEQ ID NOs. 41 and 57, respectively) and MS-GPC-8-27-41 (SEQ ID NOs. 41 and 58, respectively). 
     
     
         119 . A polynucleotide encoding a polypeptide, said polypeptide comprising an antibody-based antigen-binding domain of human composition with binding specificity for a HLA-DR antigen expressed on the surface of a human cell, wherein treating cells expressing said antigen with a multivalent polypeptide having two or more of said antigen-binding domains causes or leads to killing of said cells, wherein said antigen-binding domain includes a combination of HuCAL VH2 and HuCAL Vλ1, wherein the VH CDR3 sequence is taken from the consensus CDR3 sequence 
       
         
           
                 
                 
                 
               
                     
                   XXXXRGXFDX 
                   (SEQ ID NO: 1) 
                 
             
                
               
            
           
         
       
       wherein each X independently represents any amino acid residue; and/or 
       wherein the VL CDR3 sequence is taken from the consensus CDR3 sequence 
       
         
           
                 
                 
                 
               
                     
                   QSYDXXXX 
                   (SEQ ID NO: 2) 
                 
             
                
               
            
           
         
       
       wherein each X independently represents any amino acid residue. 
     
     
         120 . The polynucleotide of  claim 119 , wherein the VH CDR3 sequence of said antigen-binding domain of said polypeptide is SPRYRGAFDY (SEQ ID NO: 3) and/or the VL CDR3 sequence of said antigen-binding domain is QSYDLIRH (SEQ ID NO: 4) or QSYDMNVH (SEQ ID NO: 5). 
     
     
         121 . A polynucleotide encoding a polypeptide, said polypeptide comprising an antibody-based antigen-binding domain of human composition with binding specificity for a HLA-DR antigen expressed on the surface of a human cell, wherein treating cells expressing said antigen with a multivalent polypeptide having two or more of said antigen-binding domains causes or leads to killing of said cells, wherein said antigen-binding domain includes a combination of
 HuCAL VH2 and HuCAL Vλ1, wherein the Vλ1 CDR1 sequence is represented in the general formula   
       
         
           
                 
                 
                 
               
                     
                   SGSXXNIGXNYVX 
                   (SEQ ID NO: 6) 
                 
             
                
               
            
           
         
       
       wherein each X independently represents any amino acid residue. 
     
     
         122 . The polynucleotide of  claim 121 , wherein the CDR1 sequence of said polypeptide is 
       
         
           
                 
                 
                 
               
                     
                   SGSESNIGNNYVQ 
                   (SEQ ID NO: 7). 
                 
             
                
               
            
           
         
       
     
     
         123 . The polynucleotide of any of  claims 117 - 119  or  121 , wherein the multivalent polypeptide encoded by said polynucleotide kills activated lymphoid cells. 
     
     
         124 . The polynucleotide of  claim 123 , wherein said activated lymphoid cells are lymphoid tumor cells representing a disease selected from the group consisting of B cell non-Hodgkin lymphoma, B cell lymphoma, B cell acute lymphoid leukemia, Burkitt lymphoma, Hodgkin lymphoma, hairy cell leukemia, acute myeloid leukemia, T cell lymphoma, T cell non-Hodgkin lymphoma, chronic myeloid leukemia, chronic lymphoid leukemia, and multiple myeloma. 
     
     
         125 . The polynucleotide of any of  claims 117 - 119  or  121 , wherein said cells are non-lymphoid cells that express HLA-DR molecules. 
     
     
         126 . The polynucleotide of any of  claims 117 - 119  or  121 , wherein said antigen-binding domain of said polypeptide binds to the β-chain of HLA-DR. 
     
     
         127 . The polynucleotide of  claim 126 , wherein said antigen-binding domain of said polypeptide binds to the first domain of the β-chain of HLA-DR. 
     
     
         128 . The polynucleotide of  claim 119 , wherein said antigen-binding domain of said polypeptide further comprises a VL CDR1 sequence represented in the general formula 
       
         
           
                 
                 
                 
               
                     
                   SGSXXNIGXNYVX 
                   (SEQ ID NO: 6) 
                 
             
                
               
            
           
         
       
       wherein each X independently represents any amino acid residue. 
     
     
         129 . The polynucleotide of  claim 128 , wherein the VL CDR1 sequence of said polypeptide is 
       
         
           
                 
                 
                 
               
                     
                   SGSESNIGNNYVQ 
                   (SEQ ID NO: 7). 
                 
             
                
               
            
           
         
       
     
     
         130 . A vector comprising the polynucleotide of  claims 117 - 119 , or  121 , and a transcriptional regulatory sequence operably linked thereto. 
     
     
         131 . A host cell harbouring the polynucleotide of  claims 117 - 119 , or  121 .