Chimeric antigen receptors targeting b-cell maturation antigen
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-11066674-B2
Publication Date
2021-07-20
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) directed against B-cell Maturation Antigen (BCMA). The CAR comprises an antigen recognition moiety and a T-cell activation moiety. The antigen recognition moiety is directed against BCMA, which is highly expressed on multiple myeloma cells and has a restricted expression pattern in normal tissues. The CAR includes antibody or antibody fragments that specifically bind BCMA, such as single chain variable fragments (scFv), and incorporates signaling domains including CD28, CD8α, 4-1BB, CD3ζ, and others for T-cell activation.
The problem being solved arises from multiple myeloma (MM), a malignancy of plasma cells for which current therapies often cause remissions but most patients relapse and die. Existing treatments such as allogeneic hematopoietic stem cell transplantation have high toxicity and limited cure rates, and currently approved monoclonal antibody or autologous T-cell therapies for MM are lacking. Furthermore, previous CAR T-cell therapies targeting CD19 are ineffective against MM because malignant plasma cells rarely express CD19. Therefore, there is a need for compositions and methods that enable effective targeting of MM cells through antigen recognition that is different from CD19.
Claims Coverage
There are multiple independent claims directed to CARs comprising BCMA-binding domains combined with specific transmembrane and intracellular T-cell signaling domains. The claims define the structural components and specific CDR sequences from known amino acid sequences defining the antigen binding moiety.
Chimeric antigen receptor with BCMA-binding moiety and specific signaling domains
A CAR comprising a means for binding BCMA (an antigen-binding portion or variable region of a monoclonal antibody containing specified heavy and light chain CDRs), a CD28 or CD8α transmembrane domain, a 4-1BB intracellular T-cell signaling domain, and a CD3ζ intracellular T-cell signaling domain.
Inclusion of a hinge domain in the CAR
The CAR further comprises a hinge domain positioned between the antigen recognition moiety and the transmembrane domain to facilitate antibody flexibility.
CAR antigen recognition moiety as single chain variable fragment (scFv) or variable heavy chain with specified transmembrane and hinge domains
The means for binding BCMA comprises an scFv that binds BCMA with a hinge domain and the CD28 transmembrane domain, or alternatively comprises a heavy chain variable region of a monoclonal antibody coupled with a CD8α hinge and transmembrane domain.
Polynucleotides, vectors, host cells, and compositions encoding or expressing the CAR
Claims include polynucleotides encoding the CAR, lentiviral vectors comprising such polynucleotides, T-cells expressing the CAR, compositions comprising such T-cells, pharmaceutical compositions, and methods of treating multiple myeloma by administering these compositions.
The independent claims cover CARs that target BCMA using specified antibody variable regions or antigen-binding fragments coupled with transmembrane and intracellular signaling domains, as well as the genetic constructs, host cells, pharmaceutical compositions, and therapeutic methods employing such CARs to treat multiple myeloma.
Stated Advantages
The CARs provide specific targeting and destruction of BCMA-expressing multiple myeloma cells.
The antigen recognition is non-MHC-restricted, allowing recognition independent of antigen processing and reducing tumor escape.
The CARs enable adoptive T-cell therapy approaches effective against multiple myeloma, addressing the need for therapies beyond existing treatments with limited efficacy.
The invention includes CAR designs that promote T-cell activation, proliferation, cytokine production, and cytotoxicity specifically in response to BCMA-positive target cells.
Documented Applications
Treatment of multiple myeloma by adoptive transfer of T-cells or natural killer (NK) cells engineered to express anti-BCMA CARs that specifically bind BCMA on malignant plasma cells.
Destruction of multiple myeloma cells in vitro, in vivo (murine tumor models), and ex vivo, including primary patient-derived multiple myeloma cells.
Treatment of Hodgkin's lymphoma by targeting BCMA-expressing lymphoma cells.
Use of pharmaceutical compositions comprising T-cells or NK cells expressing anti-BCMA CARs for administration to patients with BCMA-expressing malignancies.
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