Chimeric antigen receptors targeting B-cell maturation antigen
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-10876123-B2
Publication Date
2020-12-29
Expiration Date
2033-03-15
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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 include an antigen recognition moiety specific for BCMA and a T-cell activation moiety. Host cells, such as T-cells or natural killer (NK) cells, expressing these CARs are provided, along with methods for destroying BCMA-expressing multiple myeloma cells.
Multiple myeloma is a malignancy of plasma cells that currently has limited effective treatments, with patients often relapsing after therapy. Existing therapies such as allogeneic hematopoietic stem cell transplantation have high toxicity and limited cure rates. Adoptive transfer of T-cells genetically engineered to recognize tumor-associated antigens via CARs is a promising new approach, but prior CARs targeting CD19 are not effective against multiple myeloma due to low CD19 expression on malignant plasma cells.
The invention solves this problem by providing CARs with antigen recognition domains specifically targeting BCMA, a protein highly expressed on multiple myeloma cells but with limited expression on normal tissues. The CARs thus enable specific targeting and destruction of multiple myeloma cells by genetically modified T-cells or NK cells. The inventive CARs comprise antibody-derived antigen recognition moieties against BCMA, linked to human signal sequences, hinge and transmembrane domains, and intracellular T-cell signaling domains derived from proteins such as CD3ζ, CD28, 4-1BB, and OX40.
Claims Coverage
The patent includes one independent claim directed to a nucleic acid molecule encoding a chimeric antigen receptor (CAR) with multiple specific features.
Nucleic acid molecule encoding a BCMA-targeted CAR
A nucleic acid molecule encoding a CAR comprising a human signal sequence; an antigen binding domain directed against B-cell maturation antigen (BCMA); a human hinge domain; a human transmembrane domain; and at least one human intracellular T cell signaling domain.
Antigen binding domain specificity and structural features
The antigen binding domain comprises an anti-BCMA antibody or antigen binding fragment thereof, possibly including variable light and heavy chains joined by a linker, such as a single chain variable fragment (scFv). The CAR may include at least two intracellular T-cell signaling domains, one being derived from a cytoplasmic portion of CD3ζ.
Transmembrane and hinge domains origin and combinations
The transmembrane domain and hinge domain are obtained from the same protein, such as CD8α or CD28. The transmembrane domain and intracellular T-cell signaling domains may be obtained from the same or different proteins.
Intracellular T-cell signaling domain composition
The intracellular T-cell signaling domains can include amino acid sequences derived from cytoplasmic portions of proteins such as CD27, CD28, CD3ζ, OX40, or 4-1BB. Combinations include CD3ζ plus CD28, 4-1BB, OX40, or CD27 domains.
Vectors comprising the nucleic acid molecule
Vectors including viral, retroviral, or lentiviral vectors comprising the nucleic acid molecule encoding the CAR, where the CAR includes CD8α-derived transmembrane and hinge domains and intracellular domains from 4-1BB and CD3ζ.
The claims cover nucleic acid molecules encoding CARs directed against BCMA with defined human signal, hinge, transmembrane, and intracellular signaling domains; antigen binding domains specific for BCMA; and vectors encoding such CARs. Key inventive features include the BCMA-targeted antigen recognition moiety, combinations of signaling domains, and vector formulations.
Stated Advantages
Targets and destroys BCMA-expressing multiple myeloma cells specifically.
Provides a CAR structure that avoids dimerization with endogenous T-cell receptors, enhancing specificity.
Harnesses the antigen recognition properties of monoclonal antibodies for MHC-independent targeting.
Enables adoptive cell therapies (e.g., T-cell or NK cell therapies) with potentially fewer off-target effects due to BCMA’s restricted normal tissue expression.
Demonstrated in vivo efficacy in eliminating established multiple myeloma tumors and improving survival in animal models.
Documented Applications
Treatment of multiple myeloma by adoptive transfer of T-cells or NK cells expressing the anti-BCMA CAR.
Destruction of BCMA-expressing multiple myeloma cell lines and primary myeloma cells ex vivo and in vivo.
Treatment of Hodgkin's lymphoma by targeting BCMA expressed on Hodgkin's lymphoma cells.
Interested in licensing this patent?