Chimeric antigen receptors targeting B-cell maturation antigen
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-10829767-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 an isolated nucleic acid sequence encoding a chimeric antigen receptor (CAR) directed against B-cell Maturation Antigen (BCMA), wherein the CAR comprises an antigen recognition moiety and a T-cell activation moiety. The antigen recognition moiety specifically binds BCMA, a protein expressed predominantly on multiple myeloma cells and some plasma cells, enabling targeted immune responses. The CARs are designed to be expressed on host cells such as T-cells or natural killer (NK) cells to direct them against BCMA-expressing cells.
Multiple myeloma is a malignancy characterized by the accumulation of clonal plasma cells, and current therapies often result in relapse and mortality. Existing treatments like allogeneic hematopoietic stem cell transplantation have high toxicity and limited curative rates. There are no clinically effective, FDA-approved monoclonal antibody or autologous T-cell therapies for multiple myeloma. The invention addresses the need for compositions that enable adoptive transfer of immune cells genetically modified to recognize and destroy multiple myeloma cells through CARs targeting BCMA.
Claims Coverage
The patent contains one independent claim describing a pharmaceutical composition comprising T cells expressing an anti-BCMA chimeric antigen receptor (CAR) with defined structural features. The main inventive features focus on the CAR's components and functional properties.
Pharmaceutical composition comprising T cells expressing an anti-BCMA CAR
The composition comprises T cells that express a CAR directed against BCMA, wherein the CAR includes a human signal sequence, an antigen binding domain targeting BCMA, a human hinge domain, a human transmembrane domain, and at least one human intracellular T cell signaling domain, and the composition contains a therapeutically effective amount of such T cells to treat multiple myeloma.
Antigen binding domain comprising anti-BCMA antibody or fragment
The antigen binding domain consists of an anti-BCMA antibody or an antigen binding fragment thereof, with the CAR having a transmembrane and hinge domain derived from the same protein, and contains at least two intracellular signaling domains, one being derived from the cytoplasmic portion of CD3ζ.
CAR comprising single chain variable fragment (scFv)
The antigen binding domain includes at least a variable light chain and variable heavy chain joined by a linker, preferably in the form of a single chain variable fragment (scFv).
Transmembrane and intracellular signaling domains' origin
The CAR's transmembrane domain and at least one intracellular T cell signaling domain may be obtained either from the same protein or from different proteins, allowing modular design of the CAR structure.
Specific protein domain derivations in CAR
The transmembrane domain is derived from CD8α or CD28. Intracellular T cell signaling domains include cytoplasmic portions of CD27, CD28, CD3ζ, OX40, or 4-1BB. The signal sequence can be granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor or CD8α signal sequences.
Therapeutically effective amount and autologous/allogenic nature
The pharmaceutical composition includes a therapeutically effective amount of at least about 100 million T cells expressing the anti-BCMA CAR, which proliferate and degranulate upon contact with BCMA-expressing cells. The CAR T cells can be autologous or allogenic relative to the patient, with preferred retroviral vector transduction, especially using lentiviral vectors.
The claims collectively cover a pharmaceutical composition of T cells expressing a humanized anti-BCMA CAR characterized by defined antigen binding, hinge, transmembrane, and intracellular signaling domains, with specified domain origins, signal sequences, cell counts, and functional responses, intended for treatment of multiple myeloma.
Stated Advantages
The CARs provide specific targeting and destruction of BCMA-expressing multiple myeloma cells.
The CAR-mediated recognition is non-MHC restricted, allowing recognition independent of antigen processing, thus overcoming tumor escape mechanisms.
The CARs redirect T-cell specificity and reactivity efficiently.
The compositions and methods enable adoptive cell transfer to treat multiple myeloma with potential reduction or elimination of cancer cells.
Documented Applications
Treatment of multiple myeloma by targeting and destroying BCMA-expressing cancer cells using T-cells or NK cells expressing anti-BCMA CARs.
Treatment of Hodgkin's lymphoma due to BCMA expression on Hodgkin's lymphoma cells.
Adoptive cell transfer protocols involving ex vivo modification of T-cells or NK cells to express anti-BCMA CARs followed by administration to human patients.
Use of CAR-expressing T-cells or NK cells in pharmaceutical compositions for therapeutic or prophylactic purposes.
Destruction of established multiple myeloma tumors in vivo in mouse models using T-cells expressing anti-BCMA CARs.
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