Methods of treatments using antigen-binding proteins targeting CD56
Inventors
Sadelain, Michel • Benjamin, Reuben • Dimitrov, Dimiter S. • Feng, Yang
Assignees
Memorial Sloan Kettering Cancer Center • US Department of Health and Human Services
Publication Number
US-12018077-B2
Publication Date
2024-06-25
Expiration Date
2036-08-01
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Abstract
The presently disclosed subject matter provides for methods and compositions for treating cancer (e.g., multiple myeloma). It relates to anti-CD56 antibodies, chimeric antigen receptors (CARs) that specifically target human CD56, and immunoresponsive cells comprising such CARs. The presently disclosed CD56-specific CARs have enhanced immune-activating properties, including anti-tumor activity.
Core Innovation
The invention provides methods and compositions for treating cancer, particularly multiple myeloma, by utilizing antigen-binding proteins including antibodies or antigen-binding portions, and chimeric antigen receptors (CARs) that specifically target human CD56. It includes immunoresponsive cells comprising such CARs and methods using these cells or antibodies for treatment of cancers.
The invention addresses the problem that multiple myeloma remains incurable despite advances with immunomodulatory drugs and proteosome inhibitors, and there is a need for novel therapeutic strategies that induce potent tumor eradication with minimal toxicity and immunogenicity. CD56 is a frequently expressed antigen in myeloma and a target for CAR immunotherapy, but concerns exist about off-tumor toxicity since CD56 is expressed on other normal cells such as natural killer cells and subsets of T lymphocytes.
Claims Coverage
The claims cover methods of treating neoplasms or tumors associated with CD56 overexpression by administering immunoresponsive cells expressing CARs with defined variable regions. The inventive features include the specific structures of the CAR's antigen-binding domain, the types of neoplasms treated, and the characteristics of the CAR and cells.
Methods of treatment with CD56-targeted CAR immunoresponsive cells
A method comprising administering immunoresponsive cells expressing a CAR with an extracellular antigen-binding domain binding human CD56, a transmembrane domain, and intracellular domain, where the antigen-binding domain comprises specified heavy and light chain CDR sequences as set forth in SEQ ID NOS: 1-6, 9-18, or 59, for reducing tumor burden, increasing survival, or treating neoplasia associated with CD56 overexpression.
Treatment of specific neoplasms expressing CD56
The method includes treatment of neoplasms selected from multiple myeloma, neuroblastoma, glioma, acute myeloid leukemia, colon cancer, pancreatic cancer, thyroid cancer, small cell lung cancer, and NK cell lymphoma, with a particular focus on multiple myeloma.
CAR structural components and expression
The CAR comprises a heavy and light chain variable region with defined CDR sequences, optionally with a linker and a signal peptide, transmembrane domain including CD8, CD28, CD3ζ or others, and an intracellular domain with a CD3ζ polypeptide and optionally co-stimulatory signaling domains such as CD28, 4-1BB, OX40 or ICOS, expressed recombinantly in immunoresponsive cells such as T cells or natural killer cells.
Co-expression of receptors targeting a second antigen
Immunoresponsive cells can further comprise an antigen recognizing receptor binding a second antigen different from CD56, including chimeric co-stimulatory receptors or truncated CARs, targeting antigens such as CD138, CS-1, BCMA, and others.
The claims define inventive methods of treating CD56-expressing neoplasms using immunoresponsive cells engineered with CARs that bind specifically to human CD56 via defined CDR sequences, specify the CAR architecture, cell types, treated cancer types, and optionally co-expression of receptors targeting secondary antigens, providing a detailed molecular framework for immunotherapy targeting CD56.
Stated Advantages
The CD56-specific CARs have enhanced immune-activating properties including anti-tumor activity.
CD56-targeted CAR T cells show antigen-dependent expansion, cytokine secretion, and selective cytotoxicity against high CD56-expressing tumor cells while sparing low CD56-expressing normal cells such as NK and NKT cells.
Administration of CD56-targeted CAR T cells eradicated myeloma tumor cells in vivo and prolonged tumor-free survival in a xenograft model.
CAR therapy prevented development of osteolytic myeloma bone disease in vivo.
Long-term persistence of functional CAR T cells in vivo is achieved with antigen-dependent activation and proliferation.
Affinity and epitope selection can modulate CD56 positive target elimination, enabling discrimination between high antigen density tumor cells and low antigen density normal cells, thus potentially reducing off-tumor toxicity.
Documented Applications
Treatment of cancers, including multiple myeloma, neuroblastoma, glioma, acute myeloid leukemia, colon cancer, pancreatic cancer, thyroid cancer, small cell lung cancer, and NK cell lymphoma.
Use of immunoresponsive cells expressing CD56-targeted CARs for reducing tumor burden, increasing or lengthening survival of subjects having neoplasia associated with overexpression of CD56.
Pharmaceutical compositions and kits comprising immunoresponsive cells or antibodies for treating neoplasia associated with CD56 overexpression.
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