Chimeric antigen receptors targeting B-cell maturation antigen
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-11359204-B2
Publication Date
2022-06-14
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 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. The CAR is expressed on host cells, such as T-cells or natural killer (NK) cells, to target and destroy multiple myeloma cells. BCMA is highly expressed on multiple myeloma cells and has a restricted expression pattern in normal tissues, making it an attractive target for CAR-based immunotherapy.
The problem being solved addresses the lack of clinically effective, FDA-approved monoclonal antibody or autologous T-cell therapies for multiple myeloma. Current therapies often cause remissions but patients frequently relapse and die. Existing T-cell adoptive transfers targeting B-cell lineage malignancies using anti-CD19 CARs are ineffective for multiple myeloma since malignant plasma cells rarely express CD19. Therefore, there is a need for compositions and methods that specifically target BCMA on multiple myeloma cells to achieve effective treatment.
Claims Coverage
The claims disclose two independent claims directed to populations of T cells expressing chimeric antigen receptors (CARs) and T cells comprising a polynucleotide encoding such CARs, specifically targeting BCMA with defined structural domains. There are 2 independent claims identified, covering the CAR construct itself in cell populations and encoding nucleic acids.
CAR comprising BCMA antigen binding domain
The CAR comprises an antigen binding domain that includes an antigen-binding portion or variable region of a monoclonal antibody binding B-cell Maturation Antigen (BCMA).
Inclusion of hinge and transmembrane domains
The CAR includes a hinge domain and a transmembrane domain comprising either a CD28 or CD8α transmembrane domain.
Incorporation of intracellular signaling domains
The CAR contains intracellular T-cell signaling domains comprising a 4-1BB domain and a CD3ζ domain.
Use of scFv or heavy chain variable regions for antigen binding
The antigen binding domain may specifically comprise a single chain variable fragment (scFv) or the heavy chain variable region of a monoclonal antibody that binds BCMA.
T-cell subsets expressing the CAR
The population of T cells includes CD8+ T cells, CD4+ T cells, or a combination of both.
The claims cover populations of T cells expressing CARs targeting BCMA with specified structures including antigen binding domains derived from monoclonal antibodies, hinge and transmembrane domains from CD28 or CD8α, and intracellular domains from 4-1BB and CD3ζ, along with nucleic acids encoding such CARs, encompassing different variations of antigen binding domains and T-cell subset compositions.
Stated Advantages
The use of CARs directed against BCMA allows targeting and destruction of multiple myeloma cells specifically expressing BCMA.
The CARs redirect T-cell specificity in a non-MHC-restricted manner, thus bypassing tumor escape by antigen processing evasion.
The CARs provide enhanced cytokine production, proliferation, degranulation, and effective cytotoxicity against BCMA-positive cells.
The CARs do not dimerize with endogenous T-cell receptor chains, improving specificity and function.
The compositions enable adoptive cell transfer therapies for multiple myeloma and Hodgkin's lymphoma, diseases lacking effective monoclonal antibody or autologous T-cell treatments.
Documented Applications
Treatment of multiple myeloma by adoptive transfer of T-cells or NK cells engineered to express anti-BCMA CARs for destroying BCMA-expressing multiple myeloma cells.
Treatment of Hodgkin's lymphoma by targeting BCMA-expressing Hodgkin's lymphoma cells with CAR-expressing T-cells or NK cells.
Use of adoptive cell transfer (ACT) therapies involving ex vivo modification of T-cells or NK cells followed by infusion into patients with BCMA-positive cancers.
Interested in licensing this patent?