Chimeric antigen receptors (car) to selectively target protein complexes

Abstract

Chimeric antigen receptor (CAR) constructs are provided that are able to selectively bind to specific protein complexes, such as HER1/HER3 heterodimer receptors. CAR T-cells comprising these constructs can be used to safely and efficiently target cancer cells expressing specific protein complexes.

1 .- 48 . (canceled) 
     
     
         49 . A pharmaceutical composition comprising an anti-tumor effective amount of a population of human T cells, said cells comprising a chimeric antigen receptor (CAR) that binds to HER1-HER3 heterodimer protein complex, said CAR comprising (i) an immunoglobulin light chain variable domain comprising the CDR sequences: CDR1 (NIATDV, SEQ ID NO. 1); CDR2 (SASF, SEQ ID NO. 2); and CDR3 (SEPEPY, SEQ ID NO. 3); and (ii) and immunoglobulin heavy chain variable domain comprising the CDR sequences: CDR1 (LSGDW, SEQ ID NO. 5); CDR2 (EISAAGGYTD, SEQ ID NO. 6); and CDR3 (ESRVSFEAAMDY, SEQ ID NO. 7). 
     
     
         50 . A chimeric antigen receptor (CAR) polypeptide comprising an antigen binding domain; a hinge domain; a transmembrane domain(s) and one or more intracellular cell signaling domain, wherein the antigen binding domain of said CAR comprises (i) an immunoglobulin light chain variable domain comprising the CDR sequences: CDR1 (NIATDV, SEQ ID NO. 1); CDR2 (SASF, SEQ ID NO. 2); and CDR3 (SEPEPY, SEQ ID NO. 3); and (ii) and immunoglobulin heavy chain variable domain comprising the CDR sequences: CDR1 (LSGDW, SEQ ID NO. 5); CDR2 (EISAAGGYTD, SEQ ID NO. 6); and CDR3 (ESRVSFEAAMDY, SEQ ID NO. 7). 
     
     
         51 . (canceled) 
     
     
         52 . A method of treating a subject comprising administering a pharmaceutical composition of  claim 49 , wherein the subject has a cancer that expresses HER1-HER3 heterodimers. 
     
     
         53 . A method of treating a subject comprising administering a pharmaceutical composition of  claim 49 , wherein the subject has been identified as having a cancer that expresses HER1-HER3 heterodimers. 
     
     
         54 . The CAR of  claim 50 , wherein the antigen binding domain further comprises a linker sequence between the light chain variable domain and heavy chain variable domain. 
     
     
         55 . The CAR polypeptide of  claim 50 , wherein the linker sequence is a Whitlow linker. 
     
     
         56 . The CAR polypeptide of  claim 50 , wherein the hinge domain comprises the hinge, CH2 and CH3 domains of human IgG4. 
     
     
         57 . The CAR polypeptide of  claim 50 , wherein the hinge domain comprises the sequence of SEQ ID NO: 16 or 17. 
     
     
         58 . The CAR polypeptide of  claim 50 , wherein the hinge domain comprises CD8a extracellular sequence. 
     
     
         59 . The CAR polypeptide of  claim 50 , wherein the hinge domain comprises the sequence of SEQ ID NO: 18. 
     
     
         60 . The CAR polypeptide of  claim 50 , wherein the intracellular cell signaling domain comprises a CD3ζ signaling domain. 
     
     
         61 . The CAR polypeptide of  claim 50 , wherein the intracellular cell signaling domain comprises the sequence of SEQ ID NO: 13. 
     
     
         62 . The CAR polypeptide of  claim 50 , wherein the intracellular cell signaling domain further comprises a signaling domain from CD28 or CD137. 
     
     
         63 . The CAR polypeptide of  claim 50 , wherein the intracellular cell signaling domain comprises the sequence of SEQ ID NO: 14 or 15. 
     
     
         64 . The CAR polypeptide of  claim 50 , wherein the transmembrane domain comprises a transmembrane domain of CD28 or CD137. 
     
     
         65 . An isolated immune effector cell comprising a HER1-HER3 heterodimer specific CAR polypeptide wherein the CAR polypeptide comprises an antigen binding domain; a hinge domain; a transmembrane domain(s) and one or more intracellular cell signaling domain, wherein the antigen binding domain of said CAR comprises (i) an immunoglobulin light chain variable domain comprising the CDR sequences: CDR1 (NIATDV, SEQ ID NO. 1); CDR2 (SASF, SEQ ID NO. 2); and CDR3 (SEPEPY, SEQ ID NO. 3); and (ii) and immunoglobulin heavy chain variable domain comprising the CDR sequences: CDR1 (LSGDW, SEQ ID NO. 5); CDR2 (EISAAGGYTD, SEQ ID NO. 6); and CDR3 (ESRVSFEAAMDY, SEQ ID NO. 7). 
     
     
         66 . The cell of  claim 65 , wherein the cell is a T-cell. 
     
     
         67 . The cell of  claim 66  wherein the T-cells are allogeneic cells. 
     
     
         68 . The cell of  claim 66  wherein the T-cells are autologous cells. 
     
     
         69 . The cell of  claim 66  wherein the T-cells are HLA matched to the subject.