Anti-mesothelin chimeric antigen receptors
Inventors
Feldman, Steven A. • Rosenberg, Steven A. • Pastan, Ira H.
Assignees
US Department of Health and Human Services
Publication Number
US-9359447-B2
Publication Date
2016-06-07
Expiration Date
2033-03-05
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Abstract
The invention provides a chimeric antigen receptor (CAR) (a) an antigen binding domain of HN1 or SS, a transmembrane domain, and an intracellular T cell signaling domain, or (b) an antigen binding domain of SS1, a transmembrane domain, an intracellular T cell signaling domain, and a granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor 2 leader. Nucleic acids, recombinant expression vectors, host cells, populations of cells, antibodies, or antigen binding portions thereof, and pharmaceutical compositions relating to the CARs are disclosed. Methods of detecting the presence of cancer in a mammal and methods of treating or preventing cancer in a mammal are also disclosed.
Core Innovation
The invention provides chimeric antigen receptors (CARs) comprising an antigen binding domain of HN1 or SS with a transmembrane domain and an intracellular T cell signaling domain, or an antigen binding domain of SS1 with a transmembrane domain, an intracellular T cell signaling domain, and a granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor 2 leader. These CARs specifically target mesothelin, a protein overexpressed in various cancer cells such as ovarian, pancreatic, lung adenocarcinoma, esophageal, gastric, synovial sarcoma, and mesothelioma.
The background describes cancer as a significant public health concern with poor prognosis despite treatments like chemotherapy. For example, ovarian cancer results in significant mortality annually in the United States. There exists an unmet need for additional effective cancer treatments.
The CARs exploit the antigen-binding properties of monoclonal antibodies to redirect T cell specificity and reactivity toward mesothelin-expressing tumors in a non-MHC-restricted manner, bypassing tumor escape mechanisms due to antigen processing. The CARs employ antigen binding domains from mouse antibodies SS and SS1 or human antibody HN1, preferably as single chain variable fragments (scFv), linked with transmembrane and intracellular signaling domains. Optionally, a GM-CSF receptor leader might be included.
Claims Coverage
The patent includes one independent claim covering a chimeric antigen receptor (CAR) and several dependent claims addressing its components and uses.
Chimeric antigen receptor structure
A CAR comprising either (a) an antigen binding domain of HN1 or SS with a transmembrane domain and an intracellular T cell signaling domain, or (b) an antigen binding domain of SS1 with a transmembrane domain, an intracellular T cell signaling domain, and a GM-CSF receptor 2 leader.
Antigen binding domain composition
The antigen binding domain includes variable light and heavy chain regions comprising SEQ ID NOs: 1-6, optionally linked by linkers SEQ ID NO: 7 or 8, and a leader sequence comprising SEQ ID NO: 9.
Transmembrane domain features
The transmembrane domain comprises CD8 and/or CD28 sequences, including SEQ ID NO: 13 and SEQ ID NO: 14.
Intracellular T cell signaling domain components
The intracellular domain includes CD28 (SEQ ID NO: 15), CD137 (SEQ ID NO: 16), and/or CD3 zeta (SEQ ID NO: 17) sequences.
Nucleic acid encoding the CAR
Nucleic acids encoding the CAR, including codon-optimized sequences (SEQ ID NOs: 24-26 and 27-32), are claimed.
Recombinant expression vectors and host cells
Recombinant expression vectors comprising the nucleic acid, specifically gammaretroviral vectors, and host cells containing these vectors are included.
Antibodies against the CAR and pharmaceutical compositions
Antibodies or antigen binding portions that specifically bind to the CAR and pharmaceutical compositions comprising the CAR and a pharmaceutically acceptable carrier are claimed.
Methods of detecting and treating cancer
Methods of detecting cancer by contacting a sample with the CAR and detecting the complex, and methods of treating or preventing cancer in a mammal by administering the CAR in effective amounts are claimed, particularly for cancers expressing mesothelin such as ovarian, pancreatic, lung, esophageal, gastric, synovial sarcoma, or mesothelioma.
The claims encompass a CAR targeting mesothelin with defined antigen binding, transmembrane, and signaling domains, the nucleic acids and vectors encoding it, host cells expressing the CAR, specific antibodies, compositions for therapeutic use, and methods for detecting and treating mesothelin-expressing cancers.
Stated Advantages
The CARs provide antigen-specific targeting and killing of mesothelin-expressing cancer cells.
They enable non-MHC-restricted recognition, bypassing tumor escape mechanisms related to antigen processing.
CARs expressed in T cells do not dimerize with endogenous T cell receptors, preventing unwanted interactions.
Therapeutic CARs maintain surface expression and functionality after cell expansion.
Documented Applications
Detecting the presence of cancer by contacting cell samples with the CAR and detecting binding complexes indicative of cancer.
Treating or preventing cancers that overexpress mesothelin, including ovarian cancer, pancreatic cancer, lung adenocarcinoma, esophageal cancer, gastric cancer, synovial sarcoma, and mesothelioma.
Using host cells expressing the CAR, such as peripheral blood lymphocytes, administered to patients with mesothelin-positive metastatic or unresectable cancers.
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