Compositions and methods for treating cancer with anti-mesothelin immunotherapy
Inventors
Orentas, Rimas J. • Schneider, Dina • Dropulic , Boro • Dimitrov, Dimiter S. • Zhu, Zhongyu
Assignees
Lentigen Technology Inc • US Department of Health and Human Services
Publication Number
US-10550179-B2
Publication Date
2020-02-04
Expiration Date
2038-01-09
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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 invention provides chimeric antigen receptors (CARs) containing mesothelin antigen binding domains, along with nucleic acids, recombinant expression vectors, host cells expressing the receptors, antigen binding fragments, and pharmaceutical compositions related to the CARs. These CARs exhibit high surface expression on transduced T cells, a high degree of cytolysis, and enhanced in vivo expansion and persistence of the transduced T cells. Methods of treating or preventing cancer in subjects and methods of making CAR T cells are also disclosed.
The invention addresses the urgent need in cancer immunotherapy for compositions and methods that overcome limitations such as toxicity to bystander cells, lack of efficacy, and the need for localized tumor delivery, especially in the context of targeting mesothelin-positive tumors. By using fully human anti-mesothelin antigen binding domains in CARs rather than mouse-derived domains, the invention provides CAR T cells that show improved persistence and functional activity in vivo without inducing anti-CAR immune responses, thereby enhancing therapeutic outcomes.
Claims Coverage
The patent includes several independent claims relating to isolated nucleic acid molecules encoding CARs, CARs themselves, vectors, modified host cells, methods of making CAR T cells, pharmaceutical compositions, and methods of treating cancer.
Isolated nucleic acid encoding CAR with specific mesothelin-binding domains
An isolated nucleic acid encoding a CAR comprising at least one extracellular antigen binding domain including a mesothelin antigen binding domain, wherein the CAR is encoded by nucleotide sequences SEQ ID NO: 13, 15, or 17.
CARs encoded by specific nucleic acid sequences
CARs encoded by the isolated nucleic acid molecules comprising the amino acid sequences SEQ ID NO: 14, 16, or 18.
Vectors comprising nucleic acids encoding the CARs
Vectors comprising the isolated nucleic acid molecules encoding the CARs, including DNA vectors, RNA vectors, plasmids, cosmids, herpes virus vectors, measles virus vectors, lentivirus vectors, adenoviral vectors, retrovirus vectors, or combinations thereof.
Host cells comprising vectors encoding CARs
Isolated cells, including T cells, comprising the vectors encoding CARs.
Method of making CAR-expressing cells
Methods of making cells by transducing isolated T cells with vectors encoding the CARs.
Pharmaceutical compositions comprising CAR-expressing T cells
Pharmaceutical compositions with anti-tumor effective amounts of human T cells comprising nucleic acid sequences encoding the CARs specified by SEQ ID NO: 13, 15, or 17 for treating cancers in humans.
Methods of treating cancer with CAR-expressing T cells
Methods of treating cancer by administering pharmaceutical compositions containing T cells expressing CARs encoded by SEQ ID NO: 13, 15, or 17 to subjects in need thereof.
Specific cancer types targeted by the CAR methods
Incorporation of hematological cancers such as leukemia (chronic lymphocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia), lymphomas (mantle cell lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma), and multiple myeloma within the scope of treatment.
Specific structure of the CARs
CARs comprising combinations of antigen binding domains, transmembrane domains, and intracellular signaling domains (such as 4-1BB and CD3-zeta), as defined by the nucleotide and amino acid sequences referenced in multiple SEQ ID NOs.
The claims comprehensively cover isolated nucleic acids encoding mesothelin-specific CARs, CARs themselves, vectors and host cells incorporating these CARs, methods of making CAR T cells, pharmaceutical compositions for treatment, and methods for treating various cancers, particularly hematological malignancies, using these CAR T cells.
Stated Advantages
The CARs exhibit high surface expression on transduced T cells, leading to enhanced cytolytic activity against mesothelin-expressing tumors.
CARs with fully human mesothelin antigen binding domains prevent the induction of anti-CAR immune responses, thereby improving persistence and function in vivo.
These CARs obviate the need for localized tumor delivery and enable tuning of efficacy versus toxicity due to the availability of binders with different affinities.
Documented Applications
Treatment and prevention of cancers associated with mesothelin expression, including mesotheliomas, pancreatic adenocarcinomas, ovarian cancers, and lung adenocarcinomas.
Use of CAR T cells comprising the disclosed anti-mesothelin CARs for hematological cancers such as leukemia (chronic lymphocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia), mantle cell lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, and multiple myeloma.
Treatment of various solid tumors including oral and pharynx cancers, digestive system cancers, respiratory system cancers, bone and joint cancers, soft tissue cancers, skin cancers, pediatric tumors, CNS tumors, breast, genital system, urinary system cancers, eye and orbit, endocrine system, brain and nervous system cancers.
Interested in licensing this patent?