Binding agents binding to pd-l1 and cd137 and use thereof

Abstract

The present invention relates to novel binding agents and their use in medicine. In particular, the invention relates to binding agents such as bispecific antibodies binding human PD-L1 and binding human CD137. The invention furthermore relates to uses of the antibodies of the invention and to methods, nucleic acid constructs and host cells for producing antibodies of the invention.

1 - 88 . (canceled) 
     
     
         89 . A multispecific antibody comprising a first antigen-binding region binding to human CD137 and a second antigen-binding region binding to human PD-L1, wherein the second antigen-binding region inhibits the binding of human PD-L1 to human PD-1. 
     
     
         90 . The multispecific antibody of  claim 89 , wherein in the first antigen-binding region comprises a first heavy chain constant region (CH) wherein at least one of the amino acids in a position corresponding to a position selected from the group consisting of T366, L368, K370, D399, F405, Y407, and K409 in a human IgG1 heavy chain according to EU numbering has been substituted, and the second antigen-binding region comprised a second heavy chain constant region (CH) wherein at least one of the amino acids in a position corresponding to a position selected from the group consisting of T366, L368, K370, D399, F405, Y407, and K409 in a human IgG1 heavy chain according to EU numbering has been substituted, and wherein said first and said second heavy chains are not substituted in the same positions. 
     
     
         91 . The multispecific antibody of  claim 90 , wherein (i) the amino acid in the position corresponding to F405 in a human IgG1 heavy chain according to EU numbering is L in said first heavy chain constant region (CH), and the amino acid in the position corresponding to K409 in a human IgG1 heavy chain according to EU numbering is R in said second heavy chain constant region (CH), or (ii) the amino acid in the position corresponding to K409 in a human IgG1 heavy chain according to EU numbering is R in said first heavy chain, and the amino acid in the position corresponding to F405 in a human IgG1 heavy chain according to EU numbering is L in said second heavy chain. 
     
     
         92 . The multispecific antibody of  claim 90 , wherein in at least one of said first and second heavy chain constant region (CH) one or more amino acids in the positions corresponding to positions L234, L235, D265, N297, and P331 in a human IgG1 heavy chain according to EU numbering, are not L, L, D, N, and P, respectively. 
     
     
         93 . The multispecific antibody of  claim 92 , wherein the positions corresponding to positions L234 and L235 in a human IgG1 heavy chain according to EU numbering are F and E, respectively, in said first and second heavy chains. 
     
     
         94 . The multispecific antibody of  claim 92 , wherein the positions corresponding to positions L234, L235, and D265 in a human IgG1 heavy chain according to EU numbering are F, E, and A, respectively, in said first and second heavy chain constant regions. 
     
     
         95 . The multispecific antibody of  claim 92 , wherein the positions corresponding to positions L234, L235, and D265 in a human IgG1 heavy chain according to EU numbering of both the first and second heavy chain constant regions are F, E, and A, respectively, and wherein (i) the position corresponding to F405 in a human IgG1 heavy chain according to EU numbering of the first heavy chain constant regio is L, and the position corresponding to K409 in a human IgG1 heavy chain according to EU numbering of the second heavy chain constant region is R, or (ii) the position corresponding to K409 in a human IgG1 heavy chain according to EU numbering of the first heavy chain is R, and the position corresponding to F405 in a human IgG1 heavy chain according to EU numbering of the second heavy chain is L. 
     
     
         96 . The multispecific antibody of  claim 92 , wherein the positions corresponding to positions L234 and L235 in a human IgG1 heavy chain according to EU numbering of both the first and second heavy chain constant regions are F and E, respectively, and wherein (i) the position corresponding to F405 in a human IgG1 heavy chain according to EU numbering of the first heavy chain constant region is L, and the position corresponding to K409 in a human IgG1 heavy chain according to EU numbering of the second heavy chain is R, or (ii) the position corresponding to K409 in a human IgG1 heavy chain according to EU numbering of the first heavy chain constant region is R, and the position corresponding to F405 in a human IgG1 heavy chain according to EU numbering of the second heavy chain is L. 
     
     
         97 . The multispecific antibody of  claim 90 , wherein the first CH comprises the amino acid sequence as set forth in SEQ ID NO: 24, and the second CH comprises the amino acid sequence as set forth in SEQ ID NO: 25. 
     
     
         98 . The multispecific antibody of  claim 90 , wherein the first CH comprises the amino acid sequence as set forth in SEQ ID NO: 25, and the second CH comprises the amino acid sequence as set forth in SEQ ID NO: 24. 
     
     
         99 . The multispecific antibody of  claim 89 , wherein the first antigen-binding region comprises a first heavy chain variable region (VH) and a first light chain variable region (VL), wherein the first VH comprises a first HCDR1 sequence, a first HCDR2 sequence, and a first HCDR3 sequence, wherein the first HCDR1 sequence comprises an amino acid sequence as set forth in SEQ ID NO: 9, wherein the first HCDR2 sequence comprises an amino acid sequence as set forth in SEQ ID NO: 10, and wherein the first HCDR3 sequence comprises an amino acid sequence as set forth in SEQ ID NO:11, and wherein the first VL comprises a first LCDR1 sequence, a first LCDR2 sequence, and a first LCDR3 sequence, wherein the first LCDR1 sequence comprises an amino acid sequence as set forth in SEQ ID NO: 13, wherein the first LCDR2 sequence comprises the amino acid sequence GAS, and wherein the first LCDR3 sequence comprises an amino acid sequence as set forth in SEQ ID NO:14; 
     
     
         100 . The multispecific antibody of  claim 89 , wherein the first antigen-binding region comprises a heavy chain variable region (VH) comprising a HCDR1, HCDR2, and HCDR3 sequence, as set forth in: SEQ ID NO: 50, 51 and 52, respectively, and a light chain variable region (VL) comprising a LCDR1, LCDR2, and LCDR3 sequence, as set forth in: SEQ ID NO: 54, SAS and 55, respectively. 
     
     
         101 . The multispecific antibody of  claim 89 , wherein the second antigen-binding region comprises a second heavy chain variable region (VH) and a second light chain variable region (VL), wherein the second VH comprises a second HCDR1 sequence, a second HCDR2 sequence, and a second HCDR3 sequence, wherein the second HCDR1 sequence comprises an amino acid sequence as set forth in SEQ ID NO: 18, wherein the second HCDR2 sequence comprises an amino acid sequence as set forth in SEQ ID NO: 19, and wherein the second HCDR3 sequence comprises an amino acid sequence as set forth in SEQ ID NO:20, and wherein the second VL comprises a second LCDR1 sequence, a second LCDR2 sequence, and a second LCDR3 sequence, wherein the second LCDR1 sequence comprises an amino acid sequence as set forth in SEQ ID NO: 22, wherein the second LCDR2 sequence comprises the amino acid sequence DDN, and wherein the second LCDR3 sequence comprises an amino acid sequence as set forth in SEQ ID NO:23. 
     
     
         102 . The multispecific antibody of  claim 89 , wherein said first antigen-binding region binding to human CD137 comprises a VH sequence as set forth in SEQ ID NO: 15 and a VL sequence as set forth in SEQ ID NO: 16. 
     
     
         103 . The multispecific antibody of  claim 89 , wherein said first antigen-binding region binding to human CD137 comprises a VH sequence as set forth in SEQ ID NO: 49 and a VL sequence as set forth in SEQ ID NO: 53. 
     
     
         104 . The multispecific antibody of  claim 89 , wherein the second antigen-binding region comprises a heavy chain variable region (VH) comprising the sequence as set forth in: SEQ ID NO:17 and a light chain variable region (VL) comprising the sequence as set forth in: SEQ ID NO:21.