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 in a subject in need thereof, the method comprising
administering to the subject an effective amount of a population of genetically engineered human hematopoietic cells, wherein the hematopoietic cells are engineered such that they are deficient in the expression of a lineage-specific cell-surface antigen which is expressed by their naturally-occurring hematopoietic cell counterpart, and
wherein the genetically engineered hematopoietic cells are hematopoietic stem cells, hematopoietic progenitor cells, or a combination thereof,
wherein the hematopoietic cells do not comprise a chimeric antigen receptor,
wherein the lineage-specific cell-surface antigen is CD33, and
wherein an endogenous gene encoding the lineage-specific cell-surface antigen is disrupted using genome editing.
2. The method of claim 1 , wherein the genetically engineered human hematopoietic cells are hematopoietic stem cells.
3. The method of claim 1 , wherein the human hematopoietic cells are obtained from bone marrow, blood, umbilical cord, or peripheral blood mononuclear cells (PBMCs) of a human subject.
4. The method of claim 1 , wherein the whole or a portion of the endogenous gene encoding the lineage-specific cell-surface antigen is deleted.
5. The method of claim 1 , wherein the level of the lineage-specific cell-surface antigen is reduced as compared with the level of the lineage-specific cell-surface antigen expressed by its naturally-occurring hematopoietic cell counterpart.
6. The method of claim 1 , wherein the genome editing is a CRISPR system.
7. The method of claim 6 , wherein the CRISPR system comprises a guide nucleic acid that hybridizes to a coding or non-coding sequence of the endogenous gene encoding the lineage-specific cell-surface antigen.
8. The method of claim 6 , wherein the CRISPR system cleaves or produces an insertion, deletion and/or substitution of one or more nucleotides in a coding region or a non-coding region of an endogenous gene encoding the lineage-specific cell-surface antigen.
9. The method of claim 1 , further comprising
administering to the subject an effective amount of an agent that targets the lineage-specific cell-surface antigen that is deficient in the hematopoietic cells, wherein the agent comprises an antigen-binding fragment that binds said lineage-specific cell-surface antigen.
10. The method of claim 9 , wherein the agent is an antibody or antibody fragment selected from the group consisting of a monoclonal antibody, fully human antibody, humanized antibody, chimeric antibody, single-chain antibody, bi-specific antibody, and a F(ab') 2 fragment.
11. The method of claim 9 , wherein the agent is an immune cell expressing a chimeric receptor that comprises said antigen-binding fragment.
12. The method of claim 11 , wherein the immune cell expressing a chimeric receptor is a T cell and wherein the antigen-binding fragment binds CD 33 .
13. The method of claim 9 , wherein the hematopoietic malignancy is selected from the group consisting of Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, and multiple myeloma.