Anti-cd28 x anti-psma antibodies

Abstract

Provided herein are novel anti-CD28×anti-PSMA antibodies and methods of using such antibodies for the treatment of PSMA-associated cancers. Subject anti-CD28×anti-PSMA antibodies are capable of agonistically binding to CD28 costimulatory molecules on T cells and PSMA on tumor cells. Thus, such antibodies selectively enhance anti-tumor activity at tumor sites while minimizing peripheral toxicity. The subject antibodies provided herein are particularly useful in combination with other anti-cancer therapies (e.g., anti-CD3×anti-PSMA antibodies) for the treatment of prostate cancers.

1 - 159 . (canceled) 
     
     
         160 . A heterodimeric antibody comprising:
 a) a first monomer having an amino acid sequence of SEQ ID NO:342;   b) a second monomer having an amino acid sequence of SEQ ID NO:343; and   c) a light chain having an amino acid sequence of SEQ ID NO:344.   
     
     
         161 . A nucleic acid composition comprising:
 a) a first nucleic acid encoding the first monomer of  claim 160 ;   b) a second nucleic acid encoding the second monomer of  claim 160 ; and   b) a third nucleic acid encoding the light chain of  claim 160 .   
     
     
         162 . An expression vector composition comprising:
 a) a first expression vector comprising the first nucleic acid of  claim 161 ;   b) a second expression vector comprising the second nucleic acid of  claim 161 ; and   c) a third expression vector comprising the light chain of  claim 161 .   
     
     
         163 . A host cell comprising the expression vector composition of  claim 162 . 
     
     
         164 . A method of making the heterodimeric antibody of  claim 160  comprising culturing the host cell of  claim 163  under conditions wherein the heterodimeric antibody is expressed, and recovering the heterodimeric antibody. 
     
     
         165 . A bispecific antibody comprising:
 a first antigen binding domain having:   (i) a VH1 comprising a vhCDR1 having an amino acid sequence of SEQ ID NO:215; a vhCDR2 having an amino acid sequence of SEQ ID NO:216; and a vhCDR3 having an amino acid sequence of SEQ ID NO:217; and (ii) a VL1 comprising a vlCDR1 having an amino acid sequence of SEQ ID NO:219, a vlCDR2 having an amino acid sequence of SEQ ID NO: 220, and a vlCDR3 having an amino acid sequence of SEQ ID NO:221; and   a second antigen binding domain having:   (i) a VH2 comprising a vhCDR1 having an amino acid sequence of SEQ ID NO:397; a vhCDR2 having an amino acid sequence of SEQ ID NO:398; and a vhCDR3 having an amino acid sequence of SEQ ID NO:399; and (ii) a VL2 comprising a vlCDR1 having an amino acid sequence of SEQ ID NO:401, a vlCDR2 having an amino acid sequence of SEQ ID NO:402, and a vlCDR3 having an amino acid sequence of SEQ ID NO:403.   
     
     
         166 . The bispecific antibody of  claim 165 , wherein VH1 has the amino acid sequence of SEQ ID NO:214, VL1 has the amino acid sequence of SEQ ID NO:218, VH2 has the amino acid sequence of SEQ ID NO:396, and VL2 has the amino acid sequence of SEQ ID NO:400. 
     
     
         167 . The bispecific antibody of  claim 165 , wherein the antibody further comprises a first Fc domain and a second Fc domain. 
     
     
         168 . The bispecific antibody of  claim 167 , wherein the first Fc domain and second Fc domain are each variant human IgG Fc domains. 
     
     
         169 . The bispecific antibody of  claim 168 , wherein the first Fc domain and second domain are each variant human IgG1 Fc domains. 
     
     
         170 . The bispecific antibody of  claim 168 , wherein one of the first and second Fe domains comprises heterodimerization variant T366W, and the other of the first and second Fc domains comprises heterodimerization variants T366S/L368A/Y407V, wherein numbering is according to EU numbering. 
     
     
         171 . The bispecific antibody of  claim 170 , wherein the first Fc domain comprises heterodimerization variant T366W, and the second Fc domain comprises heterodimerization variants T366S/L368A/Y407V. 
     
     
         172 . The bispecific antibody of  claim 168 , wherein the first and second Fc domains each comprise one or more ablation variants. 
     
     
         173 . The bispecific antibody of  claim 172 , wherein the one or more ablation variants comprise L234A/L235A/D265S, wherein numbering is according to EU numbering. 
     
     
         174 . The bispecific antibody of  claim 168 , wherein the first or second Fc domain comprises purification variants H435R/Y436F, wherein numbering is according to EU numbering. 
     
     
         175 . The bispecific antibody of  claim 174 , wherein the second Fc domain comprises purification variants H435R/Y436F. 
     
     
         176 . The bispecific antibody of  claim 168 , wherein the first Fc domain comprises amino acid substitutions L234A/L235A/D265S/LT366W, and the second Fc domain comprises amino acid substitutions L234A/L235A/D265S/T366S/L368A/Y407V/H435R/Y436F, wherein numbering is according to EU numbering. 
     
     
         177 . The bispecific antibody of  claim 165 , wherein the first antigen binding domain or second antigen binding domain is an scFv. 
     
     
         178 . The bispecific antibody of  claim 177 , wherein the scFv comprises an scFv linker selected from GKPGSGKPGSGKPGSGKPGS (SEQ ID NO: 443), GGSEGKSSGSGSESKSTGGS (SEQ ID NO: 456), and GGGSGGSGGCPPCGGSGG (SEQ ID NO: 457). 
     
     
         179 . A nucleic acid composition encoding the bispecific antibody of  claim 165 . 
     
     
         180 . An expression vector composition comprising the nucleic acid composition of  claim 179 . 
     
     
         181 . A host cell comprising the expression vector composition of  claim 180 . 
     
     
         182 . A method of making a bispecific antibody of  claim 165  comprising culturing the host cell of  claim 181  under conditions wherein the bispecific antibody is expressed and recovering the bispecific antibody.