Chimeric antigen receptors targeting b-cell maturation antigen
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-10829769-B2
Publication Date
2020-11-10
Expiration Date
2033-03-15
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Abstract
The invention provides an isolated and purified nucleic acid sequence encoding a chimeric antigen receptor (CAR) directed against B-cell Maturation Antigen (BCMA). The invention also provides host cells, such as T-cells or natural killer (NK) cells, expressing the CAR and methods for destroying multiple myeloma cells.
Core Innovation
The invention provides isolated and purified nucleic acid sequences encoding chimeric antigen receptors (CARs) directed against B-cell Maturation Antigen (BCMA). The CAR comprises an antigen recognition moiety that specifically binds BCMA and a T-cell activation moiety. The invention includes host cells, such as T-cells or natural killer (NK) cells, expressing these CARs and methods for destroying multiple myeloma cells by targeting BCMA.
Multiple myeloma is a malignancy characterized by accumulation of malignant plasma cells and currently has limited effective treatments. Conventional therapies often lead to remissions but most patients relapse and die. There are no FDA-approved monoclonal antibody or autologous T-cell therapies that effectively treat multiple myeloma. Although adoptive T-cell therapies targeting CD19 have shown promise for B-cell malignancies, CD19 is rarely expressed on multiple myeloma cells, creating a need for new approaches.
The invention addresses this need by providing compositions and methods using CARs that target BCMA, a cell surface antigen highly expressed on multiple myeloma cells but with restricted expression on normal tissues. BCMA-directed CARs expressed on T-cells enable specific recognition and destruction of BCMA-expressing multiple myeloma cells in a non-MHC-restricted manner, overcoming limitations of prior therapies.
Claims Coverage
The claims include one independent claim describing a therapeutic method and several dependent claims specifying features of the chimeric antigen receptor (CAR) and administration.
Method for treating multiple myeloma with T cells expressing BCMA-targeted CAR
Administering to a human multiple myeloma patient T cells modified to express a CAR comprising a human signal sequence, an antibody or antigen binding domain that binds BCMA, a human hinge domain, a human transmembrane domain, and at least one human intracellular T cell signaling domain.
Signal sequence variants for CAR
The signal sequence can be a granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor sequence or a CD8α signal sequence.
Antigen binding domain of CAR
The antigen binding domain comprises at least portions of a variable light chain and a variable heavy chain joined by a linker, preferably as an anti-BCMA single chain variable fragment (scFv).
Hinge and transmembrane domains
The hinge domain and transmembrane domain are human and can be obtained from the same polypeptide, such as CD8α or CD28.
Intracellular T cell signaling domains
The CAR includes at least one intracellular T cell signaling domain obtained from a cytoplasmic portion of CD27, CD28, CD3ζ, OX40, or 4-1BB, and can include combinations of two such domains (e.g., CD28 and CD3ζ).
Functional properties of modified T cells
The modified T cells proliferate and degranulate when contacted by BCMA-expressing cells and can be autologous or allogeneic, preferably autologous.
Route and method of administration and modification
The modified T cells are parenterally administered, and modification is performed by exposing T cells to a vector encoding the CAR, preferably a retroviral or lentiviral vector.
The claims cover a method of treating multiple myeloma by administering T cells expressing a BCMA-targeted CAR with defined human signal, hinge, transmembrane, and intracellular signaling domains, with details on domain origin, antigen binding moiety, T-cell functionality, source, and administration.
Stated Advantages
The CARs redirect T-cell specificity to BCMA in a non-MHC-restricted manner, bypassing tumor escape mechanisms.
The CARs enable specific recognition and destruction of BCMA-expressing multiple myeloma cells.
The CARs allow T-cells to produce cytokines, proliferate, and degranulate specifically upon BCMA engagement.
The method provides a novel treatment option addressing the lack of effective therapies for multiple myeloma.
Documented Applications
Treatment of multiple myeloma by adoptive transfer of T cells or NK cells expressing anti-BCMA CARs to specifically destroy BCMA-expressing malignant plasma cells.
Treatment of Hodgkin's lymphoma by targeting BCMA expressed on Hodgkin's lymphoma cells using CAR-expressing T cells or NK cells.
Ex vivo modification of patient-derived T cells followed by re-infusion (adoptive cell transfer) as a therapeutic approach.
Use of CAR-encoding nucleic acid sequences or vectors in pharmaceutical compositions for administration to humans.
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