Thymic stromal lymphopoietin receptor-specific chimeric antigen receptors and methods using same
The invention provides a chimeric antigen receptor (CAR) comprising an antigen binding domain specific for TSLPR, a transmembrane domain, and an intracellular T cell signaling domain. 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 a proliferative disorder, e.g., cancer, in a mammal and methods of treating or preventing a proliferative disorder, e.g., cancer, in a mammal are also disclosed.
1. A chimeric antigen receptor (CAR) comprising an antigen binding domain specific for TSLPR, a transmembrane domain, and an intracellular T cell signaling domain, wherein the antigen binding domain comprises (a) the light chain variable region CDR sequences of (i) SEQ ID NOS: 20, 24, and 27 or (ii) SEQ ID NOS: 21, 24, and 28, and (b) the heavy chain variable region CDR sequences of (i) SEQ ID NOS: 7, 10, and 13 or (ii) SEQ ID NOS: 8, 10, and 14.
2. A chimeric antigen receptor (CAR) comprising an antigen binding domain specific for TSLPR, a transmembrane domain, and an intracellular T cell signaling domain wherein the antigen binding domain comprises a light chain variable region and a heavy chain variable region, wherein (1) the light chain variable region has CDR sequences of SEQ ID NOS: 20, 24, and 27, the light chain further comprising the sequences of SEQ ID NOS: 18, 22, 25, and 29 or (2) the light chain variable region has CDR sequences of SEQ ID NOS: 21, 24, and 28, the light chain further comprising the sequences of SEQ ID NOS: 19, 23, 26, and 29.
3. A chimeric antigen receptor (CAR) comprising an antigen binding domain specific for TSLPR, a transmembrane domain, and an intracellular T cell signaling domain, wherein the antigen binding domain comprises a light chain variable region and a heavy chain variable region, wherein (1) the heavy chain variable region has CDR sequences of SEQ ID NOS: 7, 10, and 13, the heavy chain further comprising the sequences of SEQ ID NOS: 6, 9, 11, and 15 or (2) the heavy chain variable region has CDR sequences of SEQ ID NOS: 8, 10, and 14, the heavy chain further comprising the sequences of SEQ ID NOS: 6, 9, 12, and 16.
4. The CAR according to claim 1 , wherein the antigen binding domain comprises the linker sequence of SEQ ID NO: 17.
5. The CAR according to claim 1 , wherein the antigen binding domain comprises SEQ ID NO: 1.
6. The CAR according to claim 1 , wherein the transmembrane domain comprises CD8 amino acid sequence comprising the CD8α hinge sequence of SEQ ID NO: 35 and the transmembrane domain of sequence SEQ ID NO: 36.
7. The CAR according to claim 1 , wherein the intracellular T cell signaling domain comprises the 4-1BB amino acid sequence of SEQ ID NO: 37.
8. The CAR according to claim 1 , wherein the intracellular T cell signaling domain comprises the CD3 zeta amino acid sequence of SEQ ID NO: 38.
9. The CAR according to claim 1 , wherein the CAR comprises any one of the sequences of SEQ ID NO: 39-46.
10. A pharmaceutical composition comprising the CAR of claim 1 , and a pharmaceutically acceptable carrier.
11. The CAR according to claim 1 , wherein the CAR comprises the sequence of SEQ ID NO: 39.
12. The CAR according to claim 1 , wherein the antigen binding domain comprises the light chain variable region CDR sequences of SEQ ID NOS: 20, 24, and 27 and the heavy chain variable region CDR sequences of SEQ ID NOS: 7, 10, and 13.
13. The CAR according to claim 1 , wherein the antigen binding domain comprises the light chain variable region CDR sequences of SEQ ID NOS: 21, 24, and 28 and the heavy chain variable region CDR sequences of SEQ ID NOS: 8, 10, and 14.
14. The CAR according to claim 2 , wherein the antigen binding domain comprises the linker sequence of SEQ ID NO: 17.
15. The CAR according to claim 2 , wherein the transmembrane domain comprises CD8 amino acid sequence comprising the CD8α hinge sequence of SEQ ID NO: 35 and the transmembrane domain of sequence SEQ ID NO: 36.
16. The CAR according to claim 2 , wherein the intracellular T cell signaling domain comprises the 4-1BB amino acid sequence of SEQ ID NO: 37.
17. The CAR according to claim 2 , wherein the intracellular T cell signaling domain comprises the CD3 zeta amino acid sequence of SEQ ID NO: 38.
18. The CAR according to claim 3 , wherein the antigen binding domain comprises the linker sequence of SEQ ID NO: 17.
19. The CAR according to claim 3 , wherein the transmembrane domain comprises CD8 amino acid sequence comprising the CD8α hinge sequence of SEQ ID NO: 35 and the transmembrane domain of sequence SEQ ID NO: 36.
20. The CAR according to claim 3 , wherein the intracellular T cell signaling domain comprises the 4-1BB amino acid sequence of SEQ ID NO: 37.
21. The CAR according to claim 3 , wherein the intracellular T cell signaling domain comprises the CD3 zeta amino acid sequence of SEQ ID NO: 38.
22. The CAR according to claim 3 , wherein the antigen binding domain comprises (1) the light chain variable region CDR sequences of SEQ ID NOS: 20, 24, and 27, the light chain further comprising the sequences of SEQ ID NOS: 18, 22, 25, and 29, and the heavy chain variable region CDR sequences of SEQ ID NOS: 7, 10, and 13, the heavy chain further comprising the sequences of SEQ ID NOS: 6, 9, 11, and 15 or (2) the light chain variable region CDR sequences of SEQ ID NOS: 21, 24, and 28, the light chain further comprising the sequences of SEQ ID NOS: 19, 23, 26, and 29, and the heavy chain variable region CDR sequences of SEQ ID NOS: 8, 10, and 14, the heavy chain further comprising the sequences of SEQ ID NOS: 6, 9, 12, and 16.