Chimeric antigen receptors targeting B-cell maturation antigen
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-10844387-B2
Publication Date
2020-11-24
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). This CAR comprises an antigen recognition moiety and a T-cell activation moiety, wherein the antigen recognition moiety is specifically targeted against BCMA. The invention further includes host cells, such as T-cells or natural killer (NK) cells, engineered to express the CAR, and methods for destroying multiple myeloma cells using these CAR-expressing cells.
Multiple myeloma (MM) is a malignancy characterized by an accumulation of clonal plasma cells. Current therapies for MM frequently induce remission, but most patients eventually relapse and succumb to the disease. Allogeneic hematopoietic stem cell transplantation, although capable of immune-mediated myeloma cell elimination, has high toxicity and cures only a few patients. Notably, there were no clinically effective, FDA-approved monoclonal antibody or autologous T-cell therapies available for MM prior to this invention.
Adoptive transfer of T-cells genetically modified with chimeric antigen receptors has shown promise in treating cancers by enabling T-cells to recognize malignancy-associated antigens in a non-MHC-restricted manner. However, for B-cell malignancies, prior extensive progress focused on anti-CD19 CARs, which are not effective for multiple myeloma due to rare CD19 expression on malignant plasma cells. Thus, a need remained for compositions and methods to effectively target and treat multiple myeloma. This invention addresses that need by providing CARs targeting BCMA, a receptor expressed on multiple myeloma cells, thereby enabling specific recognition and destruction of such cells.
Claims Coverage
The patent contains multiple independent claims focusing on chimeric antigen receptors (CARs) targeting BCMA. The main inventive features relate to the antigen binding domain specific to BCMA, the transmembrane and intracellular signaling domains, and the combination thereof in CARs.
CAR with BCMA-specific binding moiety
A chimeric antigen receptor comprising a means for binding to B-cell Maturation Antigen (BCMA), which includes either a single chain variable fragment (scFv) or a monoclonal antibody or antigen-binding portion directed against BCMA.
Incorporation of specific complementarity determining regions (CDRs)
The means for binding to BCMA comprises heavy chain complementarity determining regions (CDR1, CDR2, CDR3) and light chain CDRs (CDR1, CDR2, CDR3) of amino acid sequences selected from SEQ ID NO: 4, 5, 6, 8, 9, 10, 11, or 12.
Intracellular T-cell signaling domain configuration
The CAR comprises one or more intracellular T-cell signaling domains isolated from CD28, CD3ζ, FcRγ, CD27, OX40, or 4-1BB proteins, including specific combinations such as a human 4-1BB and CD3ζ domain, human CD28 and CD3ζ domains, or human OX40 and CD3ζ domains.
Transmembrane domain origins
The transmembrane domain in the CAR is isolated from either a CD8α protein or a CD28 protein, serving as a joining means for the antigen recognition moiety and the intracellular signaling domains.
Specific structural CAR embodiments
CAR embodiments include combinations such as a CD8α hinge and transmembrane domain with 4-1BB and CD3ζ intracellular signaling domains, and antigen recognition moieties comprising monoclonal antibodies, scFvs, or their variable regions as specified by referenced SEQ ID NOs.
The independent claims collectively cover CARs that specifically bind BCMA through defined antigen recognition elements, include defined transmembrane and intracellular signaling domains derived from established T-cell proteins, and structurally combine these elements to form functional CARs capable of T-cell activation against BCMA-expressing cells.
Stated Advantages
The CARs provide specific targeting and destruction of BCMA-expressing multiple myeloma cells.
The CARs enable recognition of antigen in a non-MHC-restricted manner, allowing bypass of tumor escape mechanisms related to antigen processing.
T-cells expressing the CARs exhibit antigen-specific cytokine production, degranulation, and proliferation, enhancing anti-cancer immune responses.
Use of human-derived signal, hinge, transmembrane, and intracellular signaling sequences enhances CAR expression and function in human T-cells.
Methods employing the CARs offer potential improved therapeutic efficacy for multiple myeloma and Hodgkin's lymphoma with reduced toxicity compared to existing treatments.
Documented Applications
Methods for destroying multiple myeloma cells by contacting BCMA-expressing myeloma cells with T-cells or natural killer cells expressing the anti-BCMA CAR.
Adoptive cell transfer therapies in which autologous or allogeneic T-cells or NK cells expressing the anti-BCMA CAR are administered to subjects with multiple myeloma or Hodgkin's lymphoma.
Pharmaceutical compositions comprising T-cells or NK cells engineered to express the anti-BCMA CAR for treating multiple myeloma or Hodgkin's lymphoma.
In vivo destruction of established multiple myeloma tumors in animal models using T-cells expressing the anti-BCMA CAR.
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