Chimeric antigen receptors targeting B-cell maturation antigen
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-11773396-B2
Publication Date
2023-10-03
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 an isolated and purified nucleic acid sequence encoding a chimeric antigen receptor (CAR) directed against B-cell Maturation Antigen (BCMA). The CAR comprises an antigen recognition moiety that binds BCMA and a T-cell activation moiety, which together reprogram immune cells such as T-cells or natural killer (NK) cells to specifically target and destroy multiple myeloma cells expressing BCMA.
Multiple myeloma is a malignancy characterized by clonal plasma cell accumulation and remains incurable with current therapies due to relapse. While adoptive transfer of T-cells expressing chimeric antigen receptors has shown promise in other B-cell malignancies targeting CD19, CD19 is rarely expressed on multiple myeloma cells, leaving an unmet need for targeted therapies. BCMA is highly and selectively expressed on plasma cells and multiple myeloma cells, providing a suitable target for CAR-based immunotherapy.
Claims Coverage
The claims present three independent features related to methods of treating multiple myeloma using human T cells expressing specific chimeric antigen receptors (CARs) targeting BCMA.
CAR comprising BCMA-specific antigen recognition moiety with defined heavy chain variable region
A chimeric antigen receptor comprising an antigen recognition moiety that binds human BCMA, where the moiety includes a heavy chain variable region sequence as set forth within SEQ ID NO: 10.
CAR with CD8α hinge and transmembrane domains and 4-1BB plus CD3ζ signaling domains
The CAR comprises a CD8α hinge domain, a CD8α transmembrane domain, a 4-1BB intracellular T cell signaling domain, and a CD3ζ intracellular T cell signaling domain.
Administration of human T cells expressing CARs with specified sequences for multiple myeloma treatment
Methods of treating multiple myeloma by administering to a human patient a pharmaceutical composition comprising human T cells expressing a CAR with a CD8α signal sequence, the BCMA-binding antigen recognition moiety comprising a heavy chain variable region sequence as set forth within SEQ ID NO: 10, and the defined hinge, transmembrane, and intracellular signaling domains as set forth within SEQ ID NO: 10.
The claims cover methods using human T cells engineered with CARs comprising a BCMA-specific heavy chain variable region, CD8α hinge and transmembrane domains, and intracellular signaling domains including 4-1BB and CD3ζ, administered in therapeutically effective amounts to treat multiple myeloma in humans.
Stated Advantages
The CARs provide antigen-specific recognition of BCMA on multiple myeloma cells to facilitate tumor targeting and destruction.
Expression of CARs in T-cells or NK cells bypasses MHC restriction and tumor immune evasion mechanisms.
The CAR constructs enable specific cytokine production, cytotoxic degranulation, and proliferation upon recognition of BCMA-expressing cells, enhancing anti-tumor immune responses.
Adoptive transfer of CAR-expressing T-cells offers potential for durable eradication of multiple myeloma cells with restricted off-target effects due to BCMA’s limited expression pattern.
Documented Applications
Treatment of multiple myeloma by administering human T-cells or NK cells expressing anti-BCMA chimeric antigen receptors to target and destroy BCMA-expressing malignant plasma cells.
Treatment of Hodgkin's lymphoma by targeting BCMA expressed on lymphoma cells using CAR-expressing immune cells.
Adoptive cell transfer therapy involving genetic modification of T-cells or NK cells ex vivo followed by infusion into patients to mediate anti-cancer effects.
Use of pharmaceutical compositions comprising CAR-expressing cells or nucleic acid sequences encoding such CARs for therapeutic or prophylactic intervention in hematological malignancies.
In vivo destruction of established multiple myeloma tumors in murine models using CAR-engineered T-cells.
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