Bispecific checkpoint inhibitor antibodies

Abstract

The present invention is directed to heterodimeric anti-LAG-3×anti-CTLA-4. Also provided are nucleic acid compositions that encode the antibodies, expression vector compositions that include the nucleic acids, and host cells that include the expression vector compositions.

What is claimed: 
     
         1 . A heterodimeric antibody comprising:
 a) a first heavy chain comprising:
 i) a first variant Fc domain; and 
 ii) a single chain Fv region (scFv) that binds a first antigen, wherein said scFv region comprises a first variable heavy domain, a first variable light domain and a charged scFv linker, wherein said charged scFv linker covalently attaches said first variable heavy domain and said variable light domain; and 
   b) a second heavy chain comprising a VH-CH1-hinge-CH2-CH3 monomer, wherein VH is a second variable heavy domain and CH2-CH3 is a second variant Fc domain; and   c) a light chain comprising a second variable light domain and a light constant domain;   wherein said second variant Fc domain comprises amino acid substitutions N208D/Q295E/N384D/Q418E/N241D, wherein said first and second variant Fc domains each comprise amino acid substitutions E233P/L234V/L235A/G236del/S267K; wherein said first variant Fc domain comprises amino acid substitutions S364K/E357Q and second variant Fc domain comprises amino acid substitutions L368D/K370S, wherein said first variable heavy domain and first variable light domain are selected from the sets comprising SEQ ID NO:11376 and SEQ ID NO: 11377, SEQ ID NO:22970 and SEQ ID NO:22971, SEQ ID NO:11394 and SEQ ID NO:11395, SEQ ID NO:11367 and SEQ ID NO:11368 and SEQ ID NO:11412 and SEQ ID NO:11413, wherein numbering is according to the EU index as in Kabat.   
     
     
         2 . A heterodimeric antibody according to  claim 1  wherein the CH1-hinge-CH2-CH3 component of the second heavy chain has SEQ ID NO:37725, said first variant Fc domain has SEQ ID NO:37726 and said constant light domain has SEQ ID NO:37727. 
     
     
         3 . A heterodimeric antibody according to  claim 1 , wherein said second variable heavy domain and said second variable light domain form an antigen binding domain that binds a human checkpoint receptor from the group human CTLA-4, human LAG-3, human TIM-3 and human TIGIT. 
     
     
         4 . A heterodimeric antibody according to  claim 1  wherein said first variable heavy domain has SEQ ID NO:11394 and first variable light domain has SEQ ID NO:11395. 
     
     
         5 . A heterodimeric antibody according to  claim 1  wherein said first heavy chain has SEQ ID NO:23581, said second heavy chain has SEQ ID NO: 23576 and said light chain has SEQ ID NO:23591. 
     
     
         6 . A nucleic acid composition comprising:
 a) a first nucleic acid encoding said first heavy chain of  claim 1 ;   b) a second nucleic acid encoding said second heavy chain of  claim 1 ; and   c) a third nucleic acid encoding said light chain of  claim 1 .   
     
     
         7 . An expression vector composition comprising:
 a) a first expression vector comprising said first nucleic acid of  claim 6 ;   b) a second expression vector comprising said second nucleic acid of  claim 6 ; and   c) a third expression vector comprising said third nucleic acid of  claim 6 .   
     
     
         8 . A host cell comprising said expression vector composition of  claim 7 . 
     
     
         9 . A method of making a heterodimeric antibody according to  claim 1  comprising culturing said host cell of  claim 8  under conditions wherein said antibody is expressed, and recovering said antibody. 
     
     
         10 . A heterodimeric antibody comprising:
 a) a first heavy chain comprising:
 i) a first variant Fc domain; and 
 ii) a single chain Fv region (scFv) that binds a first antigen, wherein said scFv region comprises a first variable heavy domain, a first variable light domain and a charged scFv linker, wherein said charged scFv linker covalently attaches said first variable heavy domain and said variable light domain; and 
   b) a second heavy chain comprising a VH-CH1-hinge-CH2-CH3 monomer, wherein VH is a second variable heavy domain and CH2-CH3 is a second variant Fc domain; and   c) a light chain comprising a second variable light domain and a light constant domain;   wherein said second variant Fc domain comprises amino acid substitutions N208D/Q295E/N384D/Q418E/N241D, wherein said first and second variant Fc domains each comprise amino acid substitutions E233P/L234V/L235A/G236del/S267K; wherein said first variant Fc domain comprises amino acid substitutions S364K/E357Q and second variant Fc domain comprises amino acid substitutions L368D/K370S, wherein said first variable heavy domain and first variable light domain are selected from the sets comprising SEQ ID NO:6149 and SEQ ID NO:6154, SEQ ID NO:6119 and SEQ ID NO:6124, SEQ ID NO:6159 and SEQ ID NO:6164, SEQ ID NO:5709 and SEQ ID NO:5714 and SEQ ID NO:5549 and SEQ ID NO:5554, wherein numbering is according to the EU index as in Kabat.   
     
     
         12 . A heterodimeric antibody according to  claim 10  wherein the CH1-hinge-CH2-CH3 component of the second heavy chain has SEQ ID NO:37725, said first variant Fc domain has SEQ ID NO:37726 and said constant light domain has SEQ ID NO:37727. 
     
     
         13 . A heterodimeric antibody according to  claim 10 , wherein said second variable heavy domain and said second variable light domain form an antigen binding domain that binds a human checkpoint receptor from the group human PD-1, human LAG-3, human TIM-3 and human TIGIT. 
     
     
         14 . A heterodimeric antibody according to  claim 12  wherein said first variable heavy domain has SEQ ID NO:6149 and first variable light domain has SEQ ID NO:6154. 
     
     
         15 . A heterodimeric antibody according to  claim 10  wherein said first heavy chain has SEQ ID NO:35612, said second heavy chain has SEQ ID NO:35607 and said light chain has SEQ ID NO:35622. 
     
     
         16 . A nucleic acid composition comprising:
 a) a first nucleic acid encoding said first heavy chain of  claim 10 ;   b) a second nucleic acid encoding said second heavy chain of  claim 10 ; and   c) a third nucleic acid encoding said light chain of  claim 10 .   
     
     
         17 . An expression vector composition comprising:
 a) a first expression vector comprising said first nucleic acid of  claim 16 ;   b) a second expression vector comprising said second nucleic acid of  claim 16 ; and   c) a third expression vector comprising said third nucleic acid of  claim 16 .   
     
     
         18 . A host cell comprising said expression vector composition of  claim 17 . 
     
     
         19 . A method of making a heterodimeric antibody according to  claim 10  comprising culturing said host cell of  claim 8  under conditions wherein said antibody is expressed, and recovering said antibody.