Chimeric antigen receptors targeting B-cell maturation antigen
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-10829768-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 isolated and purified nucleic acid sequences encoding chimeric antigen receptors (CARs) directed against B-cell Maturation Antigen (BCMA). These CARs comprise an antigen recognition moiety targeting BCMA and a T-cell activation moiety, enabling genetically modified host cells such as T-cells or natural killer (NK) cells to express the CAR and specifically bind to BCMA on cells.
The problem being solved is the lack of clinically effective and FDA-approved therapies specifically targeting multiple myeloma (MM). Existing treatments often cause remissions but nearly all patients relapse and die. Adoptive T-cell therapies targeting other B-cell antigens like CD19 are ineffective for multiple myeloma because CD19 is rarely expressed on malignant plasma cells that characterize MM. Thus, there is a need for compositions and methods that can selectively target and destroy multiple myeloma cells.
Claims Coverage
The claims define a method of treating cancer by administering human T cells engineered to express CARs targeting BCMA with various structural features. The claims include multiple inventive features relating to CAR composition, signaling domains, and dosing.
Method of treating cancer with anti-BCMA CAR T cells
Administering human T cells expressing a chimeric antigen receptor that includes an antigen binding domain targeting BCMA, a transmembrane domain, a 4-1BB signaling domain, and a CD3ζ signaling domain.
Antigen binding domain comprising single chain variable fragment (scFv)
The antigen binding domain of the CAR comprises a single chain variable fragment (scFv) containing specific heavy and light chain complementarity determining regions (CDRs) derived from specified SEQ ID NOs.
Hinge and transmembrane domain configurations
The CAR includes various hinge domains (e.g., human CD8α or human CD28) and transmembrane domains (e.g., human CD8α or human CD28), in multiple combinations with the scFv antigen binding domain for structural and signaling functionality.
Inclusion of signal sequences
The CAR optionally includes a signal sequence such as a granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor signal sequence or a CD8α signal sequence to facilitate expression and function.
Amino acid sequence variants of CAR
CARs comprising amino acid sequences that are more than 80%, 90%, or 95% identical to SEQ ID NO:10 are included in the scope, allowing for variants with similar biological activity.
Dosage range for T-cell administration
The population of human T cells administered ranges from about one million to about 100 billion cells, with preferred ranges specified for therapeutic treatment.
The claims cover a method of cancer treatment using human T cells expressing anti-BCMA CARs with defined antigen binding domains, transmembrane and signaling domains including 4-1BB and CD3ζ, hinge regions, signal sequences, and specified dosing ranges, encompassing specific and variant CAR amino acid sequences.
Stated Advantages
The CARs specifically recognize and destroy BCMA-expressing multiple myeloma cells with high specificity, providing a targeted therapeutic approach.
The CAR design enables expression on T-cells that do not dimerize with endogenous T-cell receptors, circumventing tumor escape mechanisms.
The invention provides an effective method for treating multiple myeloma and Hodgkin's lymphoma, diseases inadequately addressed by existing therapies.
The CARs induce BCMA-specific T-cell proliferation, cytokine production, degranulation, and in vivo eradication of tumors, demonstrating potent anti-cancer activity.
Documented Applications
Treatment of multiple myeloma by adoptive transfer of T-cells or NK cells expressing anti-BCMA CARs, targeting BCMA on malignant plasma cells.
Treatment of Hodgkin's lymphoma, as BCMA expression has been detected on Hodgkin's lymphoma cells.
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