Chimeric antigen receptors targeting CD-19
Inventors
Assignees
US Department of Health and Human Services
Publication Number
US-11236161-B2
Publication Date
2022-02-01
Expiration Date
2035-06-01
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Abstract
The invention is directed to a chimeric antigen receptor (CAR) directed against CD19, which comprises an amino acid sequence of any one of SEQ ID NO: 1-SEQ ID NO: 13. The invention also provides T-cells expressing the CAR and methods for destroying malignant B-cells.
Core Innovation
B-cell malignancies, including lymphoma and leukemia, arise from disrupted regulation of B-cell differentiation and activation. Existing treatments such as chemotherapy, monoclonal antibodies, and allogeneic stem cell transplantation do not provide cures and suffer from drawbacks like high relapse rates, mortality, and morbidity. Monoclonal antibodies targeting CD19, a molecule expressed on normal and malignant B-cells, have limitations including incomplete efficacy and immunogenicity due to murine sequences.
The invention provides isolated or purified chimeric antigen receptors (CARs) directed against CD19 comprising specific amino acid sequences (SEQ ID NO: 1-13). These CARs include antigen recognition moieties derived from human or murine anti-CD19 antibodies, extracellular spacers, transmembrane domains, and multiple intracellular T-cell signaling domains derived from human molecules such as CD28, CD27, CD3ζ, 4-1BB, and the gamma chain of FcεRI. The CARs may be expressed in T-cells, which are genetically modified to target and destroy malignant CD19-expressing B-cells with reduced toxicity and immunogenicity compared to prior art.
Further, the invention encompasses nucleic acid sequences encoding these CARs, vectors comprising such sequences, isolated T-cells expressing them, and methods of treatment involving administering these T-cells or vectors in vivo or ex vivo. The invention addresses the need for compositions useful in treating B-cell malignancies with improved safety profile by avoiding immunogenic murine sequences and reducing cytokine-related toxicities observed in earlier anti-CD19 CAR therapies.
Claims Coverage
The claims include one independent claim focused on a treatment method for B-cell malignancies and cover various specific embodiments thereof.
Method of treating or preventing B-cell malignancy using T cells or NK cells expressing specific anti-CD19 CARs
A method comprising administration to a subject of one or more T cells or NK cells comprising a vector encoding a CAR directed against CD19; the CAR comprises an amino acid sequence selected from SEQ ID NO: 1 through SEQ ID NO: 13; the B-cell malignancy includes leukemia, lymphoma, or multiple myeloma.
The claims broadly cover a method of treating or preventing B-cell malignancies by administering T cells or NK cells engineered to express specific anti-CD19 chimeric antigen receptors characterized by defined amino acid sequences, with embodiments including specific CAR sequences and different types of B-cell malignancies.
Stated Advantages
Reduced toxicity and immunogenicity in humans compared to prior anti-CD19 CAR therapies containing murine sequences.
Enhanced persistence and survival of T-cells expressing CARs with human-derived extracellular spacer and transmembrane components.
Specific and effective targeting and destruction of malignant CD19-expressing B-cells with evidence of cytokine production, proliferation, degranulation, and tumor reduction.
Documented Applications
Treatment of B-cell malignancies such as leukemia, lymphoma, and multiple myeloma by administering autologous or allogeneic T-cells or NK cells expressing the inventive anti-CD19 CARs.
Ex vivo modification of patient T-cells to express anti-CD19 CARs followed by adoptive transfer to the patient for therapeutic effect.
Use of the CAR-expressing cells for reducing tumor burden in immunocompromised animal models, demonstrating efficacy in vivo.
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