Chimeric antigen receptors targeting B-cell maturation antigen
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-10837019-B2
Publication Date
2020-11-17
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) that comprise an antigen recognition moiety directed against B-cell Maturation Antigen (BCMA) and a T-cell activation moiety. These CARs are designed to be expressed in host cells, such as T-cells or natural killer (NK) cells, to specifically bind BCMA expressed on multiple myeloma cells and enable immune-mediated destruction of these cancer cells.
The problem addressed by the invention arises from the lack of clinically effective, FDA-approved monoclonal antibody or autologous T-cell therapies to treat multiple myeloma, a malignancy characterized by clonal plasma cell accumulation. Standard therapies often lead to relapse and death, and allogeneic stem cell transplantation, while immune-mediated, has high toxicity and limited cure rates. Moreover, existing adoptive T-cell therapies targeting CD19 are ineffective in multiple myeloma since CD19 expression is rarely found on malignant plasma cells.
Claims Coverage
The patent includes one independent claim focused on a method of treating cancer by administering T-cells containing a specific CAR. The claims define detailed structural features of the CAR and parameters of T-cell administration.
CAR targeting B-cell Maturation Antigen with specific signaling domains
The method uses T-cells comprising a lentiviral vector encoding a CAR that includes an antigen binding domain targeting BCMA, comprising an antibody or antigen binding fragment; a transmembrane domain; a 4-1BB signaling domain; and a CD3ζ signaling domain.
Inclusion of a single chain variable fragment (scFv) as the antigen binding domain
The antigen binding domain comprises a single chain variable fragment (scFv) with heavy and light chain complementarity determining regions from specified amino acid sequences (SEQ ID NOS: 4, 5, 6, 8, 9, 10, 11, and 12).
Hinge and transmembrane domain variations
The CAR may include hinge domains and transmembrane domains derived from human CD8α or human CD28 molecules in various combinations with the antigen binding domain and signaling domains.
Optional signal sequence inclusion
The CAR can further include a signal sequence that may be a granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor signal sequence or a CD8α signal sequence.
Administration parameters
The method comprises administering a pharmaceutical composition with a population of human T-cells expressing the CAR, with dosages ranging from about one million to about 100 billion cells.
The claims cover a method of treating cancer by administering human T-cells expressing a CAR specifically targeting BCMA with defined structural components, signaling domains, and administration dosages, emphasizing the use of scFv antigen binding domains and variations in hinge and transmembrane regions.
Stated Advantages
The CARs provide the ability to redirect T-cell specificity and reactivity toward BCMA-expressing multiple myeloma cells in a non-MHC-restricted manner.
CAR expression in T-cells bypasses major tumor escape mechanisms by recognizing antigen independent of antigen processing.
The CARs do not dimerize with endogenous T-cell receptor alpha and beta chains, potentially reducing unintended interactions.
The invention enables targeting and destruction of BCMA-expressing cancer cells, facilitating infiltration of immune cells to tumor sites and enhancing anti-cancer responses.
Documented Applications
Treatment of multiple myeloma by administering T-cells or natural killer cells expressing BCMA-targeted CARs to destroy BCMA-expressing multiple myeloma cells.
Treatment of Hodgkin's lymphoma by targeting BCMA-expressing Hodgkin's lymphoma cells using CAR-expressing T-cells or NK cells.
Use of adoptive cell transfer methods wherein CAR-expressing immune cells are administered autologously or allogeneically to a patient.
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