Chimeric antigen receptors (CARs), targeting hematologic malignancies, compositions and methods of use thereof
The present disclosure provides chimeric antigen receptor polypeptides having antigen recognition domains for CD2, CD3, CD4, CD5, CD7, CD8, and CD52 antigens, and polynucleotides encoding for the same. The present disclosure also provides for engineered cells expressing the polynucleotide or polypeptides. In some embodiments, the disclosure provides methods for treating diseases associated with CD2, CD3, CD4, CD5, CD7, CD8, and CD52 antigens.
1. An in vitro method of reducing the number of CD4 positive T cell leukemia cells or CD4 positive T cell lymphoma cells, the method comprising the steps of:
(i) contacting a plurality of cells comprising CD4 positive T cell leukemia cells or CD4 positive T cell lymphoma cells with an effective amount of engineered cells comprising a polynucleotide that encodes for a chimeric antigen receptor (CAR) polypeptide comprising: a signal peptide, a CD4 antigen recognition domain, a hinge region, a transmembrane domain, at least one co-stimulatory domain, and a signaling domain; said polynucleotide comprises the nucleotide of SEQ ID NO:4 or SEQ ID NO:5, wherein the CD4 antigen recognition domain specifically recognizes CD4 in a target cell population; and
(ii) optionally, assaying for CD4 positive T cell leukemia cells or CD4 positive lymphoma cells;
wherein the engineered cells comprise at least one of CD8 T-cells, Natural Killer cells, and Natural Killer T cells (NKT cells); and wherein the number of CD4 positive T cell leukemia cells or CD4 positive T cell lymphoma cells are reduced by at least 5% as compared to the number of CD4 positive T cell leukemia cells or CD4 positive T cell lymphoma cells prior to the contacting of step (i).
2. The method of reducing the number of CD4 positive T cell leukemia cells or CD4 positive T cell lymphoma cells according to claim 1 , wherein said engineered cells are Natural Killer cells or Natural Killer T cells (NKT cells).
3. A method of treating a CD4 associated cell proliferative disease in a human patient in need thereof, the method comprising the steps of:
(i) obtaining T cells from said human patient;
(ii) transforming said T cells with a polynucleotide encoding a CD4CAR polypeptide comprising a signal peptide, a CD4 antigen recognition domain that specifically recognizes CD4 in a target cell population, a hinge region, a transmembrane domain, at least one co-stimulatory domain, and a signaling domain; to provide engineered cells that express a chimeric antigen receptor (CAR);
(iii) administering to said human patient in need thereof a therapeutically effective amount of the engineered cells of step (ii);
(iv) reducing the tumor burden of CD4 associated cell proliferative disease cells; and
(v) optionally, assaying for CD4 positive cells associated with the cell proliferative disease;
wherein the human patient in need thereof comprises a human patient who is suffering from a CD4 associated cell proliferative disease; and wherein the engineered cells comprise at least one of CD8 T-cells, and Natural Killer T cells (NKT cells); and said polynucleotide comprises the nucleotide of SEQ ID NO:4 or SEQ ID NO:5.
4. The method of treating a CD4 associated cell proliferative disease in a human patient in need thereof according to claim 3 , wherein the CD4 associated cell proliferative disease is selected from the group consisting of CD4 positive leukemia and CD4 positive lymphoma.
5. The method of treating a CD4 associated cell proliferative disease according to claim 4 , wherein said CD4 associated cell proliferative disease is CD4 positive acute myeloid leukemia.
6. The method of treating a CD4 associated cell proliferative disease according to claim 5 , wherein said CD4 positive acute myeloid leukemia is acute myeloid leukemia M4 or acute myeloid leukemia M5.
7. The method of treating a CD4 associated cell proliferative disease according to claim 3 wherein said engineered cells are Natural Killer T cells (NKT cells).
8. The method of treating a CD4 associated cell proliferative disease according to claim 3 , wherein the method further comprises administration in conjunction with one or more of chemotherapy, radiation, immunosuppressive agents, and antiviral therapy.
9. A method of treating a CD4 associated cell proliferative disease in a human patient in need thereof, the method comprising the steps of:
administering to said human patient in need thereof a therapeutically effective amount of an engineered Natural Killer cell comprising:
a polynucleotide encoding a CD4CAR polypeptide comprising a signal peptide, a CD4 antigen recognition domain, a hinge region, a transmembrane domain, at least one co-stimulatory domain, and a signaling domain, wherein the CD4 antigen recognition domain specifically recognizes CD4 in a target cell population, and said polynucleotide comprises the nucleotide sequences of SEQ ID NO. 4 or SEQ ID NO. 5;
wherein the patient in need thereof comprises a patient who is suffering from a CD4 associated cell proliferative disease; and wherein the number of CD4 associated cell proliferative disease cells are reduced by at least 5% as compared to the number of CD4 associated cell proliferative disease cells prior to administering said engineered Natural Killer cell.
10. The method of treating a CD4 associated cell proliferative disease in a patient in need thereof according to claim 9 , wherein the CD4 associated cell proliferative disease is selected from the group consisting of CD4 positive leukemia and CD4 positive lymphoma.
11. The method of treating a CD4 associated cell proliferative disease according to claim 9 , wherein said CD4 associated cell proliferative disease is CD4 positive acute myeloid leukemia.
12. The method of treating a CD4 associated cell proliferative disease according to claim 11 , wherein said CD4 positive acute myeloid leukemia is acute myeloid leukemia M4 or acute myeloid leukemia M5.
13. The method of treating a CD4 associated cell proliferative disease according to claim 3 , wherein said CD4 associated cell proliferative disease is selected from the group consisting of: CD4 expressing acute myelomonocytic leukemia, CD4 expressing acute monoblastic leukemia, CD4 expressing monocytic leukemia, and CD4 expressing chronic myelomonocytic leukemia.
14. The method of treating a CD4 associated cell proliferative disease according to claim 9 , wherein said CD4 associated cell proliferative disease is selected from the group consisting of: CD4 expressing acute myelomonocytic leukemia, CD4 expressing acute monoblastic leukemia, CD4 expressing monocytic leukemia, and CD4 expressing chronic myelomonocytic leukemia.
15. The method of treating a CD4 associated cell proliferative disease according to claim 9 , wherein the number of CD4 associated cell proliferative disease cells are reduced by at least 50% as compared to the number of CD4 associated cell proliferative disease cells prior to administering said engineered cell.
16. The method of treating a CD4 associated cell proliferative disease according to claim 9 , wherein the CD4CAR polypeptide comprises at least two co-stimulatory domains.
17. The method of treating a CD4 associated cell proliferative disease according to claim 9 , wherein said polynucleotide comprises SEQ ID NO. 4.
18. The method of treating a CD4 associated cell proliferative disease according to claim 9 , wherein said polynucleotide comprises SEQ ID NO. 5.
19. The method of treating a CD4 associated cell proliferative disease according to claim 9 , wherein said engineered Natural Killer cell is an engineered NK-92 cell.
20. The method of reducing the number of CD4 positive T cell leukemia cells or CD4 positive T cell lymphoma cells according to claim 1 , wherein said engineered cell is a Natural Killer cell.