Compositions and methods for treating cancer with anti-mesothelin immunotherapy
Inventors
ORENTAS, Rimas • Schneider, Dina • Dropulic , Boro • Dimitrov, Dimiter S. • Zhu, Zhongyu
Assignees
Lentigen Technology Inc • US Department of Health and Human Services
Publication Number
US-10183993-B2
Publication Date
2019-01-22
Expiration Date
2038-01-09
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Abstract
Chimeric antigen receptors containing mesothelin antigen binding domains are disclosed. Nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions, relating to the chimeric antigen receptors are also disclosed. Methods of treating or preventing cancer in a subject, and methods of making chimeric antigen receptor T cells are also disclosed.
Core Innovation
The present invention discloses chimeric antigen receptors (CARs) containing mesothelin antigen binding domains, as well as nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions related to these CARs. The CARs exhibit high surface expression on transduced T cells, exhibit a high degree of cytolysis, and enable transduced T cell in vivo expansion and persistence. Methods of treating or preventing cancer in a subject using these CARs, and methods of making CAR T cells, are also disclosed.
Cancer, particularly solid tumors, remains a leading cause of death with limited improvement in survival rates despite advances in treatment. Mesothelin, a membrane glycoprotein, is overexpressed in many solid tumors and is associated with worse prognoses. It represents an attractive target for immune-based therapies. Existing anti-mesothelin CARs derived from mouse sequences face limitations such as toxicity and poor efficacy, leading to a need for better CAR designs that overcome these issues.
The invention addresses these needs by providing CAR compositions and therapeutic methods that use fully human mesothelin antigen binding domains, which show improved functional activity, including high surface CAR expression, strong cytokine-induced cytolysis, and enhanced in vivo T cell expansion and persistence. Using fully human antigen binding domains instead of mouse-derived ones avoids induction of anti-CAR immunity and enables better tuning of efficacy and specificity, reducing toxicity.
Claims Coverage
The patent claims cover isolated nucleic acid molecules encoding chimeric antigen receptors (CARs) with specific mesothelin antigen binding domains, methods of making CAR T cells, pharmaceutical compositions containing CAR-expressing T cells, and methods of treating cancer using such CAR T cells.
Chimeric antigen receptor with fully human mesothelin binding domain
An isolated nucleic acid molecule encoding a CAR comprising at least one extracellular antigen binding domain with a mesothelin antigen binding domain encoded by nucleotide sequences SEQ ID NOs: 3, 5 or 7, at least one transmembrane domain, and at least one intracellular signaling domain.
Pharmaceutical compositions and methods of treating cancer with CAR T cells
Pharmaceutical compositions comprising human T cells encoding a CAR with extracellular mesothelin antigen binding domains (SEQ ID NOs: 4, 6, or 8), linker domains, transmembrane domains, and intracellular signaling domains; and methods of treating cancer by administering these T cells to subjects in need.
CAR intracellular signaling and transmembrane domain specifications
The CAR transmembrane domain can be from various proteins including T-cell receptor chains (alpha, beta, zeta), CD8, CD28, CD3 epsilon, and others. Intracellular signaling domains include CD3 zeta and costimulatory domains such as OX40, CD28, 4-1BB (CD137), and combinations thereof. Linker or spacer domains can connect extracellular, transmembrane, and intracellular domains, with preference for domains derived from CD8 or CD28 extracellular regions.
Vectors and host cells for CAR expression
Vectors comprising the nucleic acid molecules encoding CARs can be DNA, RNA, plasmid, cosmid, or viral vectors including lentiviral and retroviral vectors. Host cells, including human T cells such as CD8+ T cells, comprising these vectors are included for CAR expression and therapeutic use.
The claims encompass compositions of nucleic acids encoding CARs with specific fully human mesothelin binding domains, the CAR constructs themselves, expression vectors and host cells, pharmaceutical compositions with CAR-expressing T cells, and methods for producing CAR-T cells and treating various cancers with them, highlighting specific intracellular and transmembrane domains used in such CARs.
Stated Advantages
The CARs exhibit high surface expression on transduced T cells, resulting in improved in vivo T cell expansion and persistence.
They demonstrate a high degree of cytokine-induced cytolysis leading to potent anti-tumor activity.
Using fully human mesothelin antigen binding domains avoids anti-CAR immune responses and consequent elimination of CAR T cells seen with mouse-derived sequences.
The disclosed CARs can be tuned for efficacy versus toxicity by using binders with varying affinities to mesothelin, potentially reducing undesired on-target off-tumor effects.
Documented Applications
Treatment or prevention of cancers overexpressing mesothelin, including but not limited to mesotheliomas, pancreatic adenocarcinomas, ovarian cancers, and lung adenocarcinomas.
Treatment of a variety of cancers including hematological cancers such as chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), lymphoma (mantle cell, non-Hodgkin's, Hodgkin's), multiple myeloma, and solid tumors including breast, ovarian, prostate, colon, melanoma, head and neck, pancreatic, brain tumors, and others.
Diagnosis and monitoring of diseases associated with mesothelin expression using anti-mesothelin antibodies or CAR T cells.
Methods of generating CAR T cells for adoptive immunotherapy of cancer in human subjects.
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