Chimeric antigen receptors targeting B-cell maturation antigen
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-11377660-B2
Publication Date
2022-07-05
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) that comprises an antigen recognition moiety directed against B-cell Maturation Antigen (BCMA) and a T-cell activation moiety. This CAR is capable of redirecting T-cell specificity toward BCMA-expressing cells in a non-MHC-restricted manner to treat multiple myeloma and Hodgkin's lymphoma. The invention also includes host cells such as T-cells or natural killer (NK) cells expressing the CAR, vectors encoding the CAR, methods of producing the CAR, and pharmaceutical compositions comprising the CAR-expressing cells or nucleic acids.
Multiple myeloma (MM) is a malignancy characterized by an accumulation of clonal plasma cells for which current therapies often cause remissions but generally lead to relapse and death. Existing treatments such as allogeneic hematopoietic stem cell transplantation have high toxicity and low cure rates. Currently, there are no clinically effective FDA-approved monoclonal antibody or autologous T-cell therapies for MM. Adoptive transfer of T-cells genetically modified to express CARs targeting CD19 has shown promise in certain B-cell malignancies but CD19 is rarely expressed on malignant plasma cells of MM. Therefore, there remains a need for compositions and methods to effectively treat multiple myeloma targeting alternative antigens.
The invention solves this problem by providing CARs targeting BCMA, which is a receptor expressed predominantly on plasma cells and subsets of mature B-cells and is universally present in multiple myeloma cells. The CARs comprise antigen recognition moieties derived from monoclonal antibodies specific for BCMA, linked to T-cell activation domains such as CD28, CD3 zeta, 4-1BB, and OX40. The CARs induce BCMA-specific T-cell activation, degranulation, cytokine production, proliferation, and cytotoxicity against multiple myeloma cells both in vitro and in vivo, including primary patient-derived tumor cells and established tumors in mice.
Claims Coverage
The patent includes three independent claims covering CARs with specific domain compositions, polynucleotides encoding such CARs, lentiviral vectors encoding the CARs, host T-cells expressing the CARs, pharmaceutical compositions comprising the T-cells, and methods of treating multiple myeloma using these compositions.
Chimeric antigen receptor with specific antigen binding and signaling domains
A CAR comprising an antigen binding domain that includes an antigen-binding portion or variable region of a monoclonal antibody binding BCMA; a hinge domain; a transmembrane domain comprising either CD28 or CD8α; a 4-1BB intracellular T cell signaling domain; and a CD3 ζ intracellular T cell signaling domain.
Use of scFv as antigen binding domain
A CAR wherein the antigen binding domain includes a single chain variable fragment (scFv) of a monoclonal antibody that binds BCMA.
Specific compositions of hinge and transmembrane domains
CARs with a hinge domain comprising CD8α or CD28 and transmembrane domains of CD8α or CD28, paired with BCMA-binding antigen domains, including scFv or heavy chain variable regions.
Polynucleotides and vectors encoding the CARs
Nucleic acid sequences that encode the CARs and lentiviral vectors comprising such polynucleotides.
Host cells expressing the CARs
T cells transduced to express the CARs targeting BCMA.
Pharmaceutical compositions and methods of treatment
Pharmaceutical compositions comprising the CAR-expressing T cells and methods of treating subjects with multiple myeloma by administering such compositions.
The claims cover the composition and structure of CARs targeting BCMA with specific domain arrangements, genetic materials encoding these CARs, their expression in T cells, pharmaceutical compositions of the modified cells, and therapeutic methods for treating multiple myeloma using these CARs.
Stated Advantages
The CAR specifically targets BCMA, allowing selective recognition and destruction of multiple myeloma cells while sparing most normal tissues due to restricted BCMA expression.
The CAR enables T-cells to elicit strong and specific immune responses, including cytokine production, degranulation, proliferation, and cytotoxicity against BCMA-expressing malignant plasma cells.
Use of the CAR improves potential treatment outcomes for multiple myeloma patients, including eradication of established tumors in vivo and destruction of primary patient tumor cells.
The invention provides compositions and methods that overcome limitations of current therapies, such as the lack of effective FDA-approved monoclonal antibody or T-cell therapies for multiple myeloma.
Documented Applications
Destruction and treatment of multiple myeloma by adoptive transfer of T-cells or NK cells expressing the anti-BCMA CAR ex vivo or in vivo.
Destruction and treatment of Hodgkin's lymphoma using CARs targeting BCMA, as BCMA expression is detected on Hodgkin's lymphoma cells.
Use of pharmaceutical compositions comprising CAR-expressing T-cells or NK cells to treat subjects with multiple myeloma or Hodgkin's lymphoma.
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