Compositions and methods for inhibition of lineage specific antigens
Disclosed herein are methods of administering an agent targeting a lineage-specific cell-surface antigen and a population of hematopoietic cells that are deficient in the lineage-specific cell-surface antigen for immunotherapy of hematological malignancies.
1. A method of treating a hematopoietic malignancy, comprising administering to a subject in need thereof:
(i) an effective amount of an agent targeting a lineage-specific cell-surface antigen, wherein the agent comprises an antigen-binding fragment that binds the lineage-specific cell-surface antigen, wherein the lineage-specific cell-surface antigen is CD33 or CD19; and wherein the agent is an immune cell expressing a chimeric receptor that comprises the antigen-binding fragment; and
(ii) a population of hematopoietic cells, wherein the hematopoietic cells are genetically-engineered such that the gene encoding the lineage specific cell-surface antigen that is targeted by the antigen-binding fragment of (i) is engineered to reduce or eliminate the expression of the lineage-specific cell-surface antigen that is targeted by the antigen-binding fragment of (i); and
wherein the immune cell set forth in (i) is different from the population of hematopoietic cells set forth in (ii).
2. The method of claim 1 , wherein the immune cells, the hematopoietic cells, or both, are allogeneic or autologous.
3. The method of claim 1 , wherein the hematopoietic cells are hematopoietic stem cells.
4. The method of claim 1 , wherein the antigen-binding fragment in the chimeric receptor is a single-chain antibody fragment (scFv) that specifically binds the lineage-specific cell-surface antigen.
5. The method of claim 4 , wherein the scFv binds to human CD33 or human CD19.
6. The method of claim 1 , wherein the immune cells are T cells.
7. The method of claim 1 , wherein the chimeric receptor further comprises:
(a) a hinge domain,
(b) a transmembrane domain,
(c) at least one co-stimulatory domain,
(d) a cytoplasmic signaling domain, or
(e) a combination thereof.
8. The method of claim 7 , wherein the chimeric receptor comprises at least one co-stimulatory signaling domain, which is derived from a co-stimulatory receptor selected from the group consisting of 4-1BB, CD28, and ICOS.
9. The method of claim 7 , wherein the at least one co-stimulatory signaling domain comprises a signaling domain of CD28 and a signaling domain of ICOS.
10. The method of claim 8 , wherein the at least one co-stimulatory signaling domain is from CD28 and the chimeric receptor further comprises a second co-stimulatory signaling domain from 4-1BB or ICOS.
11. The method of claim 7 wherein the chimeric receptor comprises a cytoplasmic signaling domain, which is from CD3ζ.
12. The method of claim 7 , wherein the chimeric receptor comprises a hinge domain, which is from CD8α or CD28α.
13. The method of claim 7 , wherein the chimeric receptor comprises a transmembrane domain, which is from CD8, CD28, or ICOS.
14. The method of claim 7 , wherein the chimeric receptor comprises, from N terminus to C terminus, (i) a scFv that binds to the lineage-specific cell-surface antigen, (ii) a hinge domain from CD8α, (iii) a transmembrane domain from CD8 or CD28, (iv) a costimulatory domain from 4-1BB or CD28, or a combination thereof and (v) a cytoplasmic signaling domain from CD3ζ.
15. The method of claim 3 , wherein the hematopoietic stem cells are CD34+/CD33−.
16. The method of claim 15 , wherein the hematopoietic stem cells are from bone marrow cells or peripheral blood mononuclear cells (PBMCs).
17. The method of claim 1 , wherein the hematopoietic cells are prepared by editing the endogenous gene coding for CD33 or CD19 to reduce or eliminate the expression of CD33 or CD19.
18. The method of claim 17 , wherein the endogenous gene is edited by CRISPR-Cas9.
19. The method of claim 1 , wherein the subject has Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, or multiple myeloma.
20. The method of claim 1 , wherein the subject has leukemia, which is acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, or chronic lymphoblastic leukemia.