Anti-mesothelin chimeric antigen receptors
The invention provides a chimeric antigen receptor (CAR) (a) an antigen binding domain of HN1 or SS, a transmembrane domain, and an intracellular T cell signaling domain, or (b) an antigen binding domain of SS1, a transmembrane domain, an intracellular T cell signaling domain, and a granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor 2 leader. Nucleic acids, recombinant expression vectors, host cells, populations of cells, antibodies, or antigen binding portions thereof, and pharmaceutical compositions relating to the CARs are disclosed. Methods of detecting the presence of cancer in a mammal and methods of treating or preventing cancer in a mammal are also disclosed.
1. A chimeric antigen receptor (CAR) comprising:
(a) an antigen binding domain of HN1 or SS, a transmembrane domain, and an intracellular T cell signaling domain, or
(b) an antigen binding domain of SS1, a transmembrane domain, an intracellular T cell signaling domain, and a granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor 2 leader.
2. The CAR according to claim 1 , wherein the antigen binding domain comprises a light chain variable region comprising any one of SEQ ID NOs: 1-3.
3. The CAR according to claim 1 , wherein the antigen binding domain comprises a heavy chain variable region comprising any one of SEQ ID NOs: 4-6.
4. The CAR according to claim 1 , wherein the antigen binding domain comprises a linker comprising SEQ ID NO: 7 or 8.
5. The CAR according to claim 1 , wherein the antigen binding domain comprises a leader sequence comprising SEQ ID NO: 9.
6. The CAR according to claim 1 , wherein the antigen binding domain comprises any one of SEQ ID NOs: 10-12.
7. The CAR according to claim 1 , wherein the transmembrane domain comprises i) CD8 and/or ii) CD28.
8. The CAR according to claim 1 , wherein the transmembrane domain comprises a CD8 amino acid sequence comprising SEQ ID NO: 13 and/or a CD28 amino acid sequence comprising SEQ ID NO: 14.
9. The CAR according to claim 1 , wherein the intracellular T cell signaling domain comprises i) CD28, ii) CD137, and/or iii) CD3 zeta.
10. The CAR according to claim 1 , wherein the intracellular T cell signaling domain comprises a CD28 amino acid sequence comprising SEQ ID NO: 15.
11. The CAR according to claim 1 , wherein the intracellular T cell signaling domain comprises a CD137 amino acid sequence comprising SEQ ID NO: 16.
12. The CAR according to claim 1 , wherein the intracellular T cell signaling domain comprises a CD3 zeta amino acid sequence comprising SEQ ID NO: 17.
13. The CAR according to claim 1 , comprising any one of SEQ ID NOs: 18-23.
14. A nucleic acid comprising a nucleotide sequence encoding the CAR according to claim 1 .
15. The nucleic acid according to claim 14 , wherein the nucleotide sequence is codon-optimized.
16. The nucleic acid according to claim 14 , comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 24-26.
17. The nucleic acid according to claim 14 , comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 27-32.
18. A recombinant expression vector comprising the nucleic acid according to claim 14 .
19. The recombinant expression vector according to claim 18 , wherein the recombinant expression vector is a gammaretroviral vector.
20. An isolated host cell comprising the recombinant expression vector of claim 18 .
21. A population of cells comprising at least one host cell of claim 20 .
22. An antibody, or antigen binding portion thereof, which specifically binds to a CAR according to claim 1 .
23. A pharmaceutical composition comprising the CAR of claim 1 and a pharmaceutically acceptable carrier.
24. A method of detecting the presence of cancer, comprising:
(a) contacting a sample comprising one or more cells with the CAR of claim 1 , thereby forming a complex, and
(b) detecting the complex, wherein detection of the complex is indicative of the presence of cancer.
25. The method of claim 24 , wherein the cancer is ovarian cancer, pancreatic cancer, lung cancer, esophageal cancer, gastric cancer, synovial sarcoma, or mesothelioma.
26. A method of treating or preventing cancer in a mammal, the method comprising administering the CAR of claim 1 to the mammal in an amount effective to treat or prevent cancer in the mammal.
27. The method of claim 26 , wherein the cancer is ovarian cancer, pancreatic cancer, lung cancer, esophageal cancer, gastric cancer, synovial sarcoma, or mesothelioma.