Bispecific immunomodulatory antibodies that bind costimulatory and checkpoint receptors

Abstract

The present invention is directed to bispecific, heterodimeric immunomodulatory antibodies.

1 .- 25 . (canceled) 
     
     
         26 . A method for activating T cells for the treatment of cancer, the method comprising administering to a subject a bispecific antibody that binds human ICOS and binds a human checkpoint receptor, wherein the binding to ICOS results in agonism of ICOS and said binding to said checkpoint receptor results in inhibition of said checkpoint receptor. 
     
     
         27 . The method according to  claim 26 , wherein said checkpoint receptor is selected from the group consisting of PD-1, PD-L1, CTLA-4, LAG-3, and TIM-3. 
     
     
         28 . The method according to  claim 26 , wherein the bispecific antibody comprises:
 a) a first heavy chain comprising:
 i) a first variant Fc domain; and 
 ii) a first antigen binding domain that is a single chain Fv region (scFv), wherein said scFv region comprises a first variable heavy chain, a variable light chain and an scFv linker, wherein said scFv linker covalently attaches said first variable heavy chain and said variable light chain; and 
   b) a second heavy chain comprising a VH-CH1-hinge-CH2-CH3 monomer, wherein VH is a second variable heavy chain and CH2-CH3 is a second variant Fc domain; and   c) a light chain;   wherein said variable heavy domain and said variable light domain form a second antigen binding domain, and   
       wherein one of said first and second antigen binding domains binds human ICOS and the other binds to said checkpoint receptor. 
     
     
         29 . The method according to  claim 27 , wherein said bispecific antibody binds ICOS and PD-1. 
     
     
         30 . The method according to  claim 27 , wherein said bispecific antibody binds ICOS and PD-L1. 
     
     
         31 . The method according to  claim 27 , wherein said bispecific antibody binds ICOS and CTLA-4. 
     
     
         32 . The method according to  claim 27 , wherein said bispecific antibody binds ICOS and LAG-3. 
     
     
         33 . The method according to  claim 27 , wherein said bispecific antibody binds ICOS and TIM-3. 
     
     
         34 . The method according to  claim 27 , wherein said bispecific antibody binds ICOS and BTLA. 
     
     
         35 . The method according to  claim 27 , wherein said bispecific antibody binds ICOS and TIGIT. 
     
     
         36 . A heterodimeric antibody comprising:
 a) a first heavy chain comprising a first Fc domain, an optional domain linker and a first antigen binding domain comprising an scFv that binds a first antigen;   b) a second heavy chain comprising a heavy chain comprising a heavy chain constant domain comprising a second Fc domain, a hinge domain, a CH1 domain and a variable heavy domain; and   c) a light chain comprising a variable light domain and a light chain constant domain;   
       wherein said variable heavy domain and said variable light domain form a second antigen binding domain that binds a second antigen, wherein one of said first and second antigen binding domains binds human ICOS resulting in agonism of said ICOS and the other binds human checkpoint receptor and results in inhibition of said checkpoint receptor, and 
       wherein said antigen binding domain that binds ICOS comprises a variable heavy domain comprising a vhCDR1, vhCDR2, and vhCDR3 and a variable light domain comprising a vlCDR1, vlCDR2, and vlCDR3 selected from the following:
 i) a vhCDR1 having SEQ ID NO: 26364, a vhCDR2 having SEQ ID NO: 26365, a vhCDR3 having SEQ ID NO: 26366, a vlCDR1 having SEQ ID NO: 26379, a vlCDR2 having SEQ ID NO: 26380, and a vlCDR3 having SEQ ID NO: 26381, and 
 ii) a vhCDR1 having SEQ ID NO: 26644, a vhCDR2 having SEQ ID NO: 26645, a vhCDR3 having SEQ ID NO: 26646, a vlCDR1 having SEQ ID NO: 26659, a vlCDR2 having SEQ ID NO: 26660, and a vlCDR3 having SEQ ID NO: 26661. 
 
     
     
         37 . A heterodimeric antibody according to  claim 36 , 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; and   wherein said first variant Fc domain comprises amino acid substitutions S364K/E357Q and second variant Fc domain comprises amino acid substitutions L368D/K370S,   
     
     
         38 . A heterodimeric antibody according to  claim 36 , wherein said first and second variant Fc domains comprises a set of heterodimerization variants selected from the group consisting of L368D/K370S:S364K/E357Q; L368D/K370S:S364K; L368E/K370S:S364K; T411E/K360E/Q362E:D401K; and T366S/L368A/Y407V:T366W. 
     
     
         39 . A heterodimeric antibody according to  claim 36 , wherein said checkpoint receptor is selected from the group consisting of PD-1, PD-L1, CTLA-4, LAG-3, TIM-3, BTLA, and TIGIT. 
     
     
         40 . A heterodimeric antibody according to  claim 36 , wherein said first and second variant Fc domains each comprise M428L/N434S. 
     
     
         41 . A heterodimeric antibody according to  claim 36 , wherein said antigen binding domain that binds ICOS is formed from a variable light domain and a variable heavy domain selected from the following:
 i) variable light domain having SEQ ID NO:26378 and a variable heavy domain having SEQ ID NO:26363, and   ii) variable light domain having SEQ ID NO:26658 and a variable heavy domain having SEQ ID NO:26643.   
     
     
         42 . A nucleic acid composition comprising:
 a) a first nucleic acid encoding a first heavy chain of a heterodimeric antibody according to  claim 36 ;   b) a second nucleic acid encoding a second heavy chain of the heterodimeric antibody; and   c) a third nucleic acid encoding a light chain of the heterodimeric antibody.   
     
     
         43 . An expression vector composition comprising:
 a) a first expression vector comprising said first nucleic acid of  claim 42 ;   b) a second expression vector comprising said second nucleic acid of  claim 42 ; and   c) a third expression vector comprising said third nucleic acid of  claim 42 .   
     
     
         44 . A host cell comprising the expression vector composition of  claim 43 . 
     
     
         45 . A method of making a heterodimeric antibody comprising culturing a host cell of  claim 44  under conditions wherein said heterodimeric antibody is expressed, and recovering said antibody.