Bispecific immunomodulatory antibodies that bind costimulatory and checkpoint receptors

Abstract

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

1 . A bispecific antibody that monovalently binds a human costimulatory receptor and monovalently binds a human checkpoint receptor for use in activating T cells for the treatment of cancer. 
     
     
         2 . A bispecific antibody according to  claim 1  wherein said costimulatory receptor is selected from the group consisting of ICOS, GITR, OX40 and 4-1BB. 
     
     
         3 . A bispecific antibody according to  claim 1  or  2  wherein said checkpoint receptor is selected from the group consisting of PD-1, PD-L1, CTLA-4, LAG-3 and TIM-3. 
     
     
         4 . A bispecific antibody according to  claim 1 ,  2  or  3  wherein said costimulatory receptor is human ICOS. 
     
     
         5 . A bispecific antibody according to  claim 4  wherein said antibody binds ICOS and PD-1. 
     
     
         6 . A bispecific antibody according to  claim 4  wherein said antibody binds ICOS and PD-L1. 
     
     
         7 . A bispecific antibody according to  claim 4  wherein said antibody binds ICOS and CTLA-4. 
     
     
         8 . A bispecific antibody according to  claim 4  wherein said antibody binds ICOS and LAG-3. 
     
     
         9 . A bispecific antibody according to  claim 4  wherein said antibody binds ICOS and TIM-3. 
     
     
         10 . A bispecific antibody according to any previous claim wherein said antibody has the format of  FIG. 2A . 
     
     
         11 . A bispecific antibody according to any previous claim wherein said antibody has the format of  FIG. 2E . 
     
     
         12 . A bispecific antibody according to any previous claim wherein said antibody has the format of  FIG. 2F . 
     
     
         13 . A bispecific antibody according to any previous claim wherein said antibody has the format of  FIG. 2G . 
     
     
         14 . A bispecific antibody according to  claim 5  wherein said antibody comprises:
 a) a first sequence having SEQ ID NO:26642; 
 b) a second sequence having SEQ ID NO:26657; and 
 c) a third sequence having SEQ ID NO:26647. 
 
     
     
         15 . 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 and the other binds human PD-1. 
     
     
         16 . 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 chain, a variable light chain and a charged scFv linker, wherein said charged 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 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, wherein one of said first and second antigen binding domains binds human ICOS and the other binds human PD-1, and wherein numbering is according to the EU index as in Kabat.   
     
     
         17 . A heterodimeric antibody according to any previous claim wherein said first and second variant Fc domains each comprise M428L/N434S. 
     
     
         18 . 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 chain, a variable light chain and a charged scFv linker, wherein said charged 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 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, and wherein one of said first and second antigen binding domains binds human ICOS and the other binds human PD-1, and wherein numbering is according to the EU index as in Kabat.   
     
     
         19 . A nucleic acid composition comprising:
 a) a first nucleic acid encoding a first heavy chain according to any of  claims 1  to  18 ;   b) a second nucleic acid encoding a second heavy chain according to any of  claims 1  to  18 , respectively; and   c) a third nucleic acid encoding a light chain according to any of  claims 1  to  18 , respectively.   
     
     
         20 . An expression vector composition comprising:
 a) a first expression vector comprising said first nucleic acid of  claim 19 ;   b) a second expression vector comprising said second nucleic acid of  claim 19 ; and   c) a third expression vector comprising said third nucleic acid of  claim 19 .   
     
     
         21 . A host cell comprising the expression vector composition of  claim 20 . 
     
     
         22 . A method of making a heterodimeric antibody comprising culturing a host cell of  claim 21  under conditions wherein said heterodimeric antibody is expressed, and recovering said antibody. 
     
     
         23 . A method of activating cytotoxic T cells (CTLs) in a patient comprising administering a heterodimeric antibody according to any of  claims 1  to  18  to said patient. 
     
     
         24 . A method of increasing IFNγ levels in a patient comprising administering a heterodimeric antibody according to any of  claims 1  to  18  to said patient. 
     
     
         25 . A method of increasing IL-2 levels in a patient comprising administering a heterodimeric antibody according to any of  claims 1  to  18  to said patient.