Chimeric antigen receptors targeting B-cell maturation antigen
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-10815487-B2
Publication Date
2020-10-27
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 an isolated and purified nucleic acid sequence encoding a chimeric antigen receptor (CAR) which comprises an antigen recognition moiety and a T-cell activation moiety directed against B-cell Maturation Antigen (BCMA). The CAR is designed to redirect T-cell specificity and reactivity toward BCMA-expressing multiple myeloma cells, enabling targeted destruction of these cancer cells through immune-mediated mechanisms. Specific CAR constructs incorporate single chain variable fragments from anti-BCMA monoclonal antibodies, along with human-derived hinge, transmembrane, and intracellular signaling domains such as CD8α, CD28, 4-1BB, and CD3ζ.
The problem addressed is the limited availability of clinically effective therapies for multiple myeloma. Current treatments often elicit remissions but relapse is common and fatal. Existing immune therapies such as allogeneic stem cell transplantation exhibit high toxicity, and there are no FDA-approved monoclonal antibody or autologous T-cell therapies targeting multiple myeloma. Prior CAR-T therapy targeting CD19 has been effective in other B-cell malignancies, but CD19 expression is rare on malignant plasma cells in multiple myeloma. Thus, there is a need for CARs targeting antigens specifically expressed on multiple myeloma, such as BCMA, to enable effective immunotherapy.
Claims Coverage
The patent includes one independent claim focusing on a chimeric antigen receptor incorporating specific domains targeting BCMA, with additional claims defining structural variants and related nucleic acid sequences and vectors, totaling multiple inventive features.
Chimeric antigen receptor targeting BCMA
A chimeric antigen receptor comprising an antigen binding domain targeting B-cell Maturation Antigen (BCMA), where the antigen binding domain includes an antibody or antigen binding fragment thereof.
Inclusion of specific intracellular signaling domains
The CAR comprises a 4-1BB signaling domain and a CD3ζ signaling domain to enhance T-cell activation upon antigen binding.
Use of particular transmembrane domains
The CAR incorporates either a human CD28 or a human CD8α transmembrane domain, defining structural variations for membrane anchoring.
Incorporation of hinge domains
The receptor can include a hinge domain selected from human CD8α or human CD28 hinge regions to provide flexibility and spatial configuration.
Use of signal sequences
The CAR may further comprise a signal sequence, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor signal sequence or a CD8α signal sequence, to direct proper protein processing.
Nucleic acid sequences encoding the CAR
Nucleic acid sequences encoding the CAR with specified structural features, including sequences that are more than 80%, 90%, or 95% identical to a reference amino acid sequence (SEQ ID NO:10).
Vectors encoding the CAR
Vectors comprising the CAR-encoding nucleic acid sequence, where the vector may be a retroviral or lentiviral vector and may include promoters, enhancers, polyadenylation signals, transcription terminators, internal ribosome entry sites (IRES), and selectable marker genes.
The claims comprehensively cover the chimeric antigen receptor targeting BCMA with defined domains for antigen binding, transmembrane anchoring, intracellular signaling, nucleic acid sequences encoding the CAR, and expression vectors designed for therapeutic applications.
Stated Advantages
The invention enables targeting and destruction of BCMA-expressing multiple myeloma cells, addressing an unmet need for effective immunotherapy for multiple myeloma.
CARs mediate antigen-specific immune responses independent of MHC restriction, overcoming tumor escape mechanisms involving antigen processing.
Use of BCMA as a target provides selectivity due to its restricted expression pattern primarily on malignant plasma cells and limited normal tissue expression, potentially reducing off-target effects.
The inclusion of intracellular signaling domains such as 4-1BB and CD3ζ enhances T-cell activation, proliferation, and persistence to improve anti-tumor efficacy.
The CARs can be expressed efficiently on T-cells and natural killer cells and are capable of eliciting cytokine production, specific degranulation, proliferation, and cytotoxicity against BCMA-expressing cells.
Documented Applications
Treatment of multiple myeloma by adoptive transfer of T-cells or natural killer cells expressing the anti-BCMA CAR to destroy BCMA-expressing malignant plasma cells.
Destruction of Hodgkin's lymphoma cells that express BCMA using T-cells or NK cells expressing the inventive CAR.
Use in adoptive cell transfer (ACT) therapies including ex vivo modification and in vivo administration of CAR-expressing immune cells to patients.
Co-administration with chemotherapeutic agents or other therapeutic agents such as IL-2 to enhance therapeutic outcomes.
Use of lentiviral or retroviral vectors encoding the CAR for gene transfer into host cells.
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