Bispecific t cell activating antigen binding molecules

Abstract

The present invention generally relates to novel bispecific antigen binding molecules for T cell activation and re-direction to specific target cells. In addition, the present invention relates to polynucleotides encoding such bispecific antigen binding molecules, and vectors and host cells comprising such polynucleotides. The invention further relates to methods for producing the bispecific antigen binding molecules of the invention, and to methods of using these bispecific antigen binding molecules in the treatment of disease.

1 . A T cell activating bispecific antigen binding molecule comprising
 (i) a first antigen binding moiety which is a Fab molecule capable of specific binding to CD3, comprising at least one heavy chain complementarity determining region (CDR) selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 and at least one light chain CDR selected from the group of SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10;   (ii) a second antigen binding moiety which is a Fab molecule capable of specific binding to a target cell antigen.   
     
     
         2 . The T cell activating bispecific antigen binding molecule of  claim 1 , wherein the first antigen binding moiety comprises a heavy chain variable region comprising an amino acid sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to an amino acid sequence selected from the group of: SEQ ID NO: 3, SEQ ID NO: 32 and SEQ ID NO: 33 and a light chain variable region comprising an amino acid sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence selected from the group of: SEQ ID NO: 7 and SEQ ID NO: 31. 
     
     
         3 . The T cell activating bispecific antigen binding molecule of  claim 1 , wherein the first antigen binding moiety comprises a heavy chain variable region comprising an amino acid sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising an amino acid sequence that is at least about 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 7. 
     
     
         4 - 9 . (canceled) 
     
     
         10 . The T cell activating bispecific antigen binding molecule of  claim 1 , wherein the first antigen binding moiety is a crossover Fab molecule wherein either the variable or the constant regions of the Fab light chain and the Fab heavy chain are exchanged. 
     
     
         11 . The T cell activating bispecific antigen binding molecule of  claim 10 , wherein the first antigen binding moiety is a crossover Fab molecule wherein the constant regions of the Fab light chain and the Fab heavy chain are exchanged. 
     
     
         12 . The T cell activating bispecific antigen binding molecule of  claim 1 , wherein the second antigen binding moiety is a conventional Fab molecule. 
     
     
         13 . The T cell activating bispecific antigen binding molecule of  claim 1 , comprising not more than one antigen binding moiety capable of specific binding to CD3. 
     
     
         14 . The T cell activating bispecific antigen binding molecule of  claim 1 , comprising a third antigen binding moiety which is a Fab molecule capable of specific binding to a target cell antigen. 
     
     
         15 . (canceled) 
     
     
         16 . The T cell activating bispecific antigen binding molecule of  claim 14 , wherein the third antigen binding moiety is identical to the second antigen binding moiety. 
     
     
         17 - 18 . (canceled) 
     
     
         19 . The T cell activating bispecific antigen binding molecule of  claim 1 , wherein the first and the second antigen binding moiety are fused to each other, optionally via a peptide linker. 
     
     
         20 - 22 . (canceled) 
     
     
         23 . The T cell activating bispecific antigen binding molecule of  claim 1 , additionally comprising
 (iii) an Fc domain composed of a first and a second subunit capable of stable association.   
     
     
         24 - 26 . (canceled) 
     
     
         27 . The T cell activating bispecific antigen binding molecule of  claim 23 , wherein a third antigen binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first or second subunit of the Fc domain. 
     
     
         28 - 35 . (canceled) 
     
     
         36 . The T cell activating bispecific antigen binding molecule of  claim 23 , wherein the Fc domain is an IgG, specifically an IgG 1  or IgG 4 , Fc domain. 
     
     
         37 . (canceled) 
     
     
         38 . The T cell activating bispecific antigen binding molecule of  claim 23 , wherein the Fc domain comprises a modification promoting the association of the first and the second subunit of the Fc domain. 
     
     
         39 - 45 . (canceled) 
     
     
         46 . An isolated polynucleotide encoding the T cell activating bispecific antigen binding molecule of  claim 1  or a fragment thereof. 
     
     
         47 - 49 . (canceled) 
     
     
         50 . A vector, particularly an expression vector, comprising the polynucleotide of  claim 46 . 
     
     
         51 . A host cell comprising the vector of  claim 50 . 
     
     
         52 . A method of producing the T cell activating bispecific antigen binding molecule capable of specific binding to CD3 and a target cell antigen, comprising the steps of a) culturing the host cell of  claim 51  under conditions suitable for the expression of the T cell activating bispecific antigen binding molecule and b) recovering the T cell activating bispecific antigen binding molecule. 
     
     
         53 . A T cell activating bispecific antigen binding molecule produced by the method of  claim 52 . 
     
     
         54 . A pharmaceutical composition comprising the T cell activating bispecific antigen binding molecule of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         55 - 79 . (canceled)