Receptors providing targeted costimulation for adoptive cell therapy

Abstract

The present invention relates to a chimeric costimulatory antigen receptor (CoStAR) useful in adoptive cell therapy (ACT), and cells comprising the CoStAR. The CoStAR can act as a modulator of cellular activity enhancing responses to defined antigens. The present invention also provides CoStAR proteins, nucleic acids encoding the CoStAR and therapeutic uses thereof.

1 . A chimeric costimulatory antigen receptor (CoStAR) which comprises: an extracellular binding domain operatively linked to a transmembrane domain, a CD28 signaling domain and a CD40 signaling domain,
 wherein the at least one extracellular binding domain comprises the amino acid sequence of SEQ ID NO:4,   wherein the CD28 signaling domain comprises the amino acid sequence of SEQ ID NO: 16, and   wherein the CD40 signaling domain comprises the amino acid sequence of SEQ ID NO: 23.   
     
     
         2 - 16 . (canceled) 
     
     
         17 . The CoStAR of  claim 1 , wherein the extracellular binding domain is operatively linked to the transmembrane domain by a linker and/or a spacer. 
     
     
         18 . The CoStAR of  claim 17 , wherein the linker comprises from about 5 to about 20 amino acids. 
     
     
         19 . The CoStAR of  claim 17 , wherein the linker comprises the amino acid sequence AAAGSGGSG (SEQ ID NO:8). 
     
     
         20 . The CoStAR of  claim 17 , wherein the spacer comprises from about 10 to about 250 amino acids. 
     
     
         21 - 22 . (canceled) 
     
     
         23 . The CoStAR of  claim 17 , wherein the spacer comprises one or more immunoglobulin domains or an immunoglobulin constant region. 
     
     
         24 . The CoStAR of  claim 17 , wherein the spacer comprises one or more immunoglobulin domains or an immunoglobulin constant region of SEQ ID NO:13. 
     
     
         25 . The CoStAR of  claim 1 , wherein the CoStAR further comprises the transmembrane domain of CD28 or CD8. 
     
     
         26 . The CoStAR of  claim 1 , wherein the CoStAR further comprises the transmembrane domain sequence of SEQ ID NO:11 or SEQ ID NO:12. 
     
     
         27 - 54 . (canceled) 
     
     
         55 . A protein that comprises:
 a first portion that comprises the amino acid sequence of SEQ ID NO:4 that is linked to;   a second portion that comprises a transmembrane domain that is linked to;   a third portion that comprises the amino acid sequence of SEQ ID NO: 16 that is linked to;   a fourth portion that comprises the amino acid sequence of SEQ ID NO: 23.   
     
     
         56 . The protein of  claim 55 , wherein the transmembrane domain comprises the transmembrane domain sequence of SEQ ID NO: 11 or SEQ ID NO: 12. 
     
     
         57 . The protein of  claim 56 , further comprising a linker that comprises the amino acid sequence of SEQ ID NO: 8. 
     
     
         58 . The protein of  claim 55 , further comprising a signaling domain of SEQ ID NO: 1. 
     
     
         59 . The protein of  claim 55 , wherein the protein is humanized. 
     
     
         60 . The protein of  claim 59 , further comprising a VH segment and a VL segment, which are joined together via a linker comprising the sequence of SEQ ID NO: 62. 
     
     
         61 . The protein of  claim 60 , further comprising a linker, wherein the linker comprises the amino acid sequence of SEQ ID NO: 62. 
     
     
         62 . The CoStAR of  claim 1  wherein the CoStAR is humanized. 
     
     
         63 . The CoStAR of  claim 62 , further comprising a VH segment and a VL segment, which are joined together via a linker comprising the sequence of SEQ ID NO: 62. 
     
     
         64 . The CoStAR of  claim 63 , further comprising a linker, wherein the linker comprises the amino acid sequence of SEQ ID NO: 62. 
     
     
         65 . A protein that comprises:
 a first portion that comprises the amino acid sequence of SEQ ID NO:4;   a second portion that comprises the amino acid sequence of SEQ ID NO: 11;   a third portion that comprises the amino acid sequence of SEQ ID NO: 16;   a fourth portion that comprises the amino acid sequence of SEQ ID NO: 23; and   a fifth portion that comprises SEQ ID NO: 8,   wherein the first portion is linked to the second portion by the fifth portion,   wherein the third portion is linked to the second portion, and   wherein the fourth portion is linked to the third portion.   
     
     
         66 . A cell comprising:
 a nucleic acid sequence that encodes a fusion protein, the fusion protein comprising:   a first portion that comprises the amino acid sequence of SEQ ID NO:4;   a second portion that comprises the amino acid sequence of SEQ ID NO: 11;   a third portion that comprises the amino acid sequence of SEQ ID NO: 16;   a fourth portion that comprises the amino acid sequence of SEQ ID NO: 23; and   a fifth portion that comprises SEQ ID NO: 8,   wherein the first portion is linked to the second portion by the fifth portion,   wherein the third portion is linked to the second portion, and   wherein the fourth portion is linked to the third portion.   
     
     
         67 . The cell of  claim 66 , wherein the cell is configured to express the fusion protein on a surface of the cell. 
     
     
         68 . The cell of  claim 67 , wherein the cell comprises an alpha-beta T cell, gamma-delta T cell, T regulatory cell, TIL, NKT cell or NK cell. 
     
     
         69 . The cell of  claim 68 , wherein the cell comprises a TIL. 
     
     
         70 . The cell of  claim 69 , wherein the cell co-expresses a CAR or a TCR.