Methods and compositions for chimeric antigen receptor targeting cancer cells
AssigneesThe University of North Carolina at Chapel Hill, The General Hospital Corporation
InventorsGianpietro Dotti, Soldano Ferrone, Hongwei Du, Xinhui Wang, Cristina Ferrone
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Abstract
The present invention provides a chimeric antigen receptor (CAR) that recognizes B7-H3 (CD276), as well as methods of use in the treatment of diseases and disorders.
Claims22
A method of stimulating a T cell-mediated immune response to a B7-H3 expressing target cell population or tissue in a subject, comprising administering to the subject an effective amount of a cell comprising a CAR comprising:
- a) a signal peptide;
- b) a light chain variable region comprising the amino acid sequence:
- (SEQ ID NO:
- 6)
- DIVMTQSHKFMSTSIGARVSITCKASQDVRTAVAWYQQKPGQSPKLLIYS
- ASYRYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQHYGTPPWTFG
- GGTKLEIK;
- c) a linker peptide;
- d) a heavy chain variable region comprising the amino acid sequence:
- (SEQ ID NO:
- 7)
- EVQLVESGGGLVKPGGSLKLSCEASRFTFSSYAMSWVRQTPEKRLEWVAA
- ISGGGRYTYYPDSMKGRFTISRDNAKNFLYLQMSSLRSEDTAMYYCARHY
- DGYLDYWGQGTTLTVSS;
- e) a CD8α hinge polypeptide;
- f) a CD8α transmembrane domain;
- g) a 4-1BB or CD28 costimulatory domain;
- and
- h) a CD3ζ signaling domain;
- thereby stimulating a T cell-mediated immune response to the B7-H3 expressing target cell population or tissue in the subject.
A method of treating a subject having a disease or disorder associated with elevated expression of B7-H3 (CD276) by a cell of the subject, comprising administering to the subject an effective amount of a cell comprising a chimeric antigen receptor (CAR) comprising:
- a) a signal peptide;
- b) a light chain variable region comprising the amino acid sequence:
- (SEQ ID NO:
- 6)
- DIVMTQSHKFMSTSIGARVSITCKASQDVRTAVAWYQQKPGQSPKLLIYS
- ASYRYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQHYGTPPWTFG
- GGTKLEIK;
- c) a linker peptide;
- d) a heavy chain variable region comprising the amino acid sequence:
- (SEQ ID NO:
- 7)
- EVQLVESGGGLVKPGGSLKLSCEASRFTFSSYAMSWVRQTPEKRLEWVAA
- ISGGGRYTYYPDSMKGRFTISRDNAKNFLYLQMSSLRSEDTAMYYCARHY
- DGYLDYWGQGTTLTVSS;
- e) a CD8α hinge polypeptide;
- f) a CD8α transmembrane domain;
- g) a 4-1BB or CD28 costimulatory domain;
- and
- h) a CD3ζ signaling domain;
- thereby treating the subject having the disease or disorder associated with elevated expression of B7-H3 by the cell of the subject.
A method of targeting a cancer cell and/or a cancer initiating cell (CIC) having a B7-H3 (CD276) antigen, comprising contacting the cancer cell and/or the CIC with a cell comprising a CAR comprising:
- a) a signal peptide;
- b) a light chain variable region comprising the amino acid sequence:
- (SEQ ID NO:
- 6)
- DIVMTQSHKFMSTSIGARVSITCKASQDVRTAVAWYQQKPGQSPKLLIYS
- ASYRYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQHYGTPPWTFG
- GGTKLEIK;
- c) a linker peptide;
- d) a heavy chain variable region comprising the amino acid sequence:
- (SEQ ID NO:
- 7)
- EVQLVESGGGLVKPGGSLKLSCEASRFTFSSYAMSWVRQTPEKRLEWVAA
- ISGGGRYTYYPDSMKGRFTISRDNAKNFLYLQMSSLRSEDTAMYYCARHY
- DGYLDYWGQGTTLTVSS;
- e) a CD8α hinge polypeptide;
- f) a CD8α transmembrane domain;
- g) a 4-1BB or CD28 costimulatory domain;
- and
- h) a CD3ζ signaling domain.
A method of detecting cancer cells and/or cancer initiating cells (CICs) having a B7-H3 (CD276) antigen in a cell population, comprising:
- a) contacting the cell population with a CAR comprising:
- a) a signal peptide;
- b) a light chain variable region comprising the amino acid sequence:
- (SEQ ID NO:
- 6)
- DIVMTQSHKFMSTSIGARVSITCKASQDVRTAVAWYQQKPGQSPKLLIYS
- ASYRYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQHYGTPPWTFG
- GGTKLEIK;
- c) a linker peptide;
- d) a heavy chain variable region comprising the amino acid sequence:
- (SEQ ID NO:
- 7)
- EVQLVESGGGLVKPGGSLKLSCEASRFTFSSYAMSWVRQTPEKRLEWVAA
- ISGGGRYTYYPDSMKGRFTISRDNAKNFLYLQMSSLRSEDTAMYYCARHY
- DGYLDYWGQGTTLTVSS;
- e) a CD8α hinge polypeptide;
- f) a CD8α transmembrane domain;
- g) a 4-1BB or CD28 costimulatory domain;
- and
- h) a CD3ζ signaling domain;
- under conditions whereby a binding complex can form;
- and
- b) detecting formation of the binding complex, thereby detecting cancer cells and/or cancer initiating cells (CICs) having a B7-H3 (CD276) antigen in the cell population.
Dependencies are inferred from the claim text.