Compositions and methods for treating cancer
Disclosed are compositions and methods for targeted treatment of cancer. The present disclosure provides chimeric antigen receptors and cells expressing such chimeric antigen receptors. In certain embodiments, engineered cells expressing the chimeric antigen receptors are specific for a low density cancer antigen or peptide in groove antigen.
1. A method of treating a tumor in a subject, the method comprising conjointly administering to the subject a first CAR polypeptide and a second CAR polypeptide, wherein the first CAR polypeptide comprises:
a) at least one intracytoplasmic/costimulatory region comprising a cluster of differentiation 28 zeta (CD28/ζ) domain,
b) at least one intracytoplasmic signaling region comprising a cluster of differentiation 3 zeta (CD3/ζ) domain, and
c) an antigen binding domain comprising:
(i) a light chain comprising SEQ ID NO:17 and a heavy chain comprising SEQ ID NO: 21;
(ii) a light chain comprising SEQ ID NO:18 and a heavy chain comprising SEQ ID NO: 22;
(iii) a light chain comprising SEQ ID NO:19 and a heavy chain comprising SEQ ID NO: 23;
(iv) a light chain comprising SEQ ID NO:31 and a heavy chain comprising SEQ ID NO: 32;
or
(v) a light chain comprising SEQ ID NO:37 and a heavy chain comprising SEQ ID NO: 38, and the second CAR polypeptide comprises:
a) a 4-1BB domain in the costimulatory region of the CAR polypeptide,
b) at least one intracytoplasmic signaling region comprising a cluster of differentiation 3 zeta (CD3/ζ) domain, and
c) an extracellular antigen binding domain comprising:
(i) a light chain comprising SEQ ID NO:17 and a heavy chain comprising SEQ ID NO: 21;
(ii) a light chain comprising SEQ ID NO:18 and a heavy chain comprising SEQ ID NO: 22;
(iii) a light chain comprising SEQ ID NO:19 and a heavy chain comprising SEQ ID NO: 23;
(iv) a light chain comprising SEQ ID NO:31 and a heavy chain comprising SEQ ID NO: 32;
or
(v) a light chain comprising SEQ ID NO:37 and a heavy chain comprising SEQ ID NO: 38.
2. The method of claim 1 , wherein the second CAR polypeptide comprises a cluster of differentiation 8 alpha (CD8/α) peptide in a hinge/transmembrane region.
3. The method of claim 1 , wherein the cluster of differentiation 28 zeta (CD28/ζ) domain comprises an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 1 to 3.
4. The method of claim 1 , wherein the first CAR polypeptide further comprises a hinge/spacer region that comprises at least one cluster of differentiation 28 zeta (CD28/ζ) domain.
5. The method of claim 1 , wherein the first CAR polypeptide further comprises a transmembrane region that comprises at least one cluster of differentiation 28 zeta (CD28/ζ) domain.
6. The method of claim 1 , wherein the intracytoplasmic/costimulatory region of the first CAR polypeptide further comprises a 4-1BB domain.
7. The method of claim 1 , wherein the first CAR polypeptide is expressed by an immune cell, and the immune cell is administered to the subject.
8. The method of claim 7 , wherein the immune cell is a cytotoxic T lymphocyte (CTL), or a Natural Killer (NK) cell.
9. The method of claim 1 , wherein the second CAR polypeptide is expressed in an immune cell, and the immune cell is administered to the subject.
10. The method of claim 9 , wherein the immune cell is a is a cytotoxic T lymphocyte (CTL), or a Natural Killer (NK) cell.
11. The method of claim 1 , wherein the antigen binding domain of the first CAR polypeptide and the antigen binding domain of the second CAR polypeptide each comprise a light chain comprising SEQ ID NO: 17 and a heavy chain comprising SEQ ID NO: 21.
12. The method of claim 1 , wherein the antigen binding domain of the first CAR polypeptide and the antigen binding domain of the second CAR polypeptide each comprise a light chain comprising SEQ ID NO: 18 and a heavy chain comprising SEQ ID NO: 22.
13. The method of claim 1 , wherein the antigen binding domain of the first CAR polypeptide and the antigen binding domain of the second CAR polypeptide each comprise a light chain comprising SEQ ID NO: 19 and a heavy chain comprising SEQ ID NO: 23.
14. The method of claim 1 , wherein the antigen binding domain of the first CAR polypeptide and the antigen binding domain of the second CAR polypeptide each comprise a light chain comprising SEQ ID NO: 31 and a heavy chain comprising SEQ ID NO: 32.
15. The method of claim 1 , wherein the antigen binding domain of the first CAR polypeptide and the antigen binding domain of the second CAR polypeptide each comprise a light chain comprising SEQ ID NO: 37 and a heavy chain comprising SEQ ID NO: 38.