Chimeric antigen receptors targeting B-cell maturation antigen
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-12180484-B2
Publication Date
2024-12-31
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
This invention provides an isolated and purified nucleic acid sequence encoding a chimeric antigen receptor (CAR) that comprises an antigen recognition moiety directed against B-cell Maturation Antigen (BCMA) and a T-cell activation moiety. The CAR is capable of redirecting T-cell specificity and reactivity towards BCMA-expressing cells in a non-MHC-restricted manner by exploiting the antigen-binding properties of monoclonal antibodies.
Multiple myeloma (MM) is a malignancy characterized by an accumulation of clonal plasma cells, and current therapies often cause remissions but result in relapse and death. Existing immune-based therapies, such as allogeneic hematopoietic stem cell transplantation, have high toxicity and limited cure rates. There are no clinically effective, FDA-approved monoclonal antibody or autologous T-cell therapies for MM, and prior CAR approaches targeting CD19 are ineffective for MM because CD19 is rarely expressed on malignant plasma cells.
The present invention addresses the need for compositions and methods to treat multiple myeloma by providing nucleic acid sequences encoding CARs targeting BCMA, a receptor expressed predominantly on plasma cells and highly expressed on multiple myeloma cells. This specificity allows for targeted destruction of multiple myeloma cells using T-cells or natural killer cells expressing the anti-BCMA CARs, offering a novel therapeutic approach with the potential to reduce or eliminate myeloma cells.
Claims Coverage
The independent claim defines a human T cell comprising a nucleic acid encoding a chimeric antigen receptor (CAR) with specific structural domains.
Antigen recognition moiety targeting BCMA
The CAR comprises an antigen recognition moiety that binds human B-Cell Maturation Antigen (BCMA).
Structural domains of CAR
The CAR includes a CD8α hinge domain, a CD8α transmembrane domain, a 4-1BB intracellular T cell signaling domain, and a CD3ζ intracellular T cell signaling domain.
The independent claim covers a human T cell engineered to express a CAR specifically designed with an anti-BCMA antigen recognition moiety and particular hinge, transmembrane, and intracellular signaling domains, combining to provide targeted recognition and activation against BCMA-expressing cells.
Stated Advantages
The CARs provide targeted destruction of BCMA-expressing multiple myeloma cells, enabling effective elimination of malignant plasma cells.
The non-MHC-restricted antigen recognition by CARs bypasses tumor escape mechanisms associated with antigen processing.
The CAR-expressing T-cells exhibit BCMA-specific cytokine production, degranulation, and proliferation, indicating specific and potent immune responses against target cells.
The use of the CAR enables eradication of established multiple myeloma tumors in vivo, demonstrating therapeutic potential.
Documented Applications
Use of the isolated nucleic acid sequence encoding anti-BCMA CARs to genetically modify T-cells or natural killer cells for destruction of multiple myeloma cells ex vivo, in vitro, or in vivo.
Adoptive cell transfer therapy involving administration of CAR-expressing T-cells or NK cells to treat multiple myeloma or Hodgkin's lymphoma in a human subject.
Formulation of pharmaceutical compositions comprising T-cells or NK cells expressing the CAR, alone or combined with other chemotherapeutic agents, for therapeutic or prophylactic treatment of multiple myeloma or Hodgkin's lymphoma.
Use of the CARs and CAR-expressing host cells in diagnostic or therapeutic methods involving detection and destruction of BCMA-expressing cancer cells.
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