Chimeric antigen receptors targeting B-cell maturation antigen
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-10815488-B2
Publication Date
2020-10-27
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) that target B-cell Maturation Antigen (BCMA). These CARs comprise an antigen recognition moiety directed against BCMA and a T-cell activation moiety, enabling host cells such as T-cells or natural killer (NK) cells to express the CAR and destroy multiple myeloma cells. The CARs are designed to specifically recognize BCMA, which is expressed on malignant plasma cells of multiple myeloma and subsets of mature B-cells, and include domains such as single chain variable fragments (scFv) derived from anti-BCMA monoclonal antibodies, hinge and transmembrane regions, and intracellular signaling domains to activate the T-cells.
Multiple myeloma is a malignancy characterized by accumulation of clonal plasma cells, with current therapies often causing remissions but with nearly all patients eventually relapsing and dying. Existing treatments like allogeneic hematopoietic stem cell transplantation have high toxicity and low cure rates, and there are no clinically effective, FDA-approved monoclonal antibody or autologous T-cell therapies for multiple myeloma. Although adoptive T-cell therapies with anti-CD19 CARs have shown success in other B-cell malignancies, CD19 is rarely expressed on malignant plasma cells of multiple myeloma. Thus, there is a need for compositions and methods to treat multiple myeloma effectively, which this invention addresses by providing CARs targeting BCMA.
The invention also includes methods of destroying multiple myeloma cells by contacting them with T-cells or NK cells expressing the anti-BCMA CAR, which binds to BCMA on the malignant cells and leads to their destruction. The CARs allow for non-MHC-restricted antigen recognition, thus bypassing tumor escape mechanisms, and induce cytokine production, degranulation, proliferation, and cytotoxicity specifically in response to BCMA-expressing cells, both in vitro and in vivo. The invention further encompasses nucleic acid sequences encoding functional variants and portions of the CAR, vectors for expressing the CAR, and pharmaceutical compositions comprising CAR-expressing cells for therapeutic or prophylactic use.
Claims Coverage
The claims define one independent claim outlining a T cell expressing a chimeric antigen receptor (CAR) with specific domains targeting BCMA.
Antigen binding domain targeting BCMA
The CAR comprises an antigen binding domain specific to B-cell Maturation Antigen (BCMA), constructed from an antibody or antigen binding fragment thereof.
Inclusion of a transmembrane domain
The CAR includes a transmembrane domain, which can be derived from human CD28 or human CD8α proteins to anchor the receptor within the T-cell membrane.
Incorporation of a 4-1BB signaling domain
The CAR comprises a 4-1BB intracellular signaling domain that provides T-cell costimulatory signals to enhance activation, proliferation, and survival.
Inclusion of a CD3ζ signaling domain
The CAR further comprises a CD3ζ signaling domain, essential for initiating T-cell activation upon antigen binding.
Variations in hinge and signal sequences
The CAR can include a hinge domain derived from human CD8α or CD28, and 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.
Use of single chain variable fragment (scFv) antigen binding moiety
The antigen binding domain can be a single chain variable fragment (scFv) comprising complementarity determining regions (CDRs) from specified sequences (SEQ ID NOs: 4, 5, 6, 8, 9, 10, 11, and 12).
Specific domain combinations
The CAR can have combinations of domains such as an scFv antigen binding domain, human CD8α or CD28 hinge domain, and human CD8α or CD28 transmembrane domain in various configurations as specified in claims.
The claims cover a CAR expressed in T-cells targeting BCMA, characterized by an antigen binding domain from antibodies or fragments thereof, transmembrane, 4-1BB costimulatory, and CD3ζ signaling domains, with various possible signal sequences, hinges, and domain arrangements to optimize function.
Stated Advantages
The CARs enable targeting and destruction of BCMA-expressing multiple myeloma cells, offering a new therapeutic modality for a disease with limited effective treatments.
Non-MHC-restricted antigen recognition by CARs bypasses tumor escape mechanisms related to antigen processing.
The CARs induce specific T-cell activation, degranulation, cytokine production, proliferation, and cytotoxicity against BCMA-expressing cells both in vitro and in vivo.
Documented Applications
Treatment or destruction of multiple myeloma cells by adoptively transferred T-cells or NK cells expressing anti-BCMA CARs.
Treatment or destruction of Hodgkin's lymphoma cells which express BCMA.
Interested in licensing this patent?