Anti-epidermal growth factor receptor variant III chimeric antigen receptors and use of same for the treatment of cancer
Inventors
Morgan, Richard A. • Rosenberg, Steven A.
Assignees
US Department of Health and Human Services
Publication Number
US-11124580-B2
Publication Date
2021-09-21
Expiration Date
2032-03-21
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Abstract
The invention provides chimeric antigen receptors (CARs) comprising an antigen binding domain of human antibody 139, an extracellular hinge domain, a transmembrane domain, and an intracellular domain T cell receptor signaling domain. 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 host and methods of treating or preventing cancer in a host are also disclosed.
Core Innovation
The invention provides chimeric antigen receptors (CARs) comprising an antigen binding domain of human antibody 139, an extracellular hinge domain, a transmembrane domain, and an intracellular T cell receptor signaling domain. It further includes nucleic acids, recombinant expression vectors, host cells, populations of cells, antibodies or antigen binding portions thereof, and pharmaceutical compositions related to these CARs. Methods are also disclosed for detecting the presence of cancer in a host and for treating or preventing cancer.
The background of the invention highlights the need for improved cancer treatments, noting that brain tumors, particularly glioblastoma multiforme (GBM), have poor prognoses despite conventional treatments such as surgery, radiation, and chemotherapy. Current therapies offer limited survival benefits, thus creating an unmet need for additional therapeutic approaches for gliomas and other brain and nervous system cancers.
Claims Coverage
The patent includes 20 claims, with independent claims focusing on isolated mammalian cells expressing specific CARs, host cells containing recombinant expression vectors encoding such CARs, and pharmaceutical compositions comprising these cells. There are three main inventive features defined by these independent claims.
Isolated mammalian cells expressing specific CARs
Isolated mammalian cells expressing a chimeric antigen receptor comprising an amino acid sequence selected from SEQ ID NOs: 10 and 11.
Host cells comprising recombinant expression vectors encoding CARs
Isolated host cells containing recombinant expression vectors encoding chimeric antigen receptors with amino acid sequences SEQ ID NOs: 10 or 11, wherein the vectors include plasmids, viral vectors, bacteriophage vectors, or animal expression vectors. The expression vectors may further comprise a suicide gene such as HSV thymidine kinase, cytosine deaminase, purine nucleoside phosphorylase, or nitroreductase, and can be retroviral, including the MSGV1 vector.
Pharmaceutical compositions comprising mammalian or host cell populations
Pharmaceutical compositions comprising the isolated mammalian cells or populations of such cells, formulated with pharmaceutically acceptable carriers suitable for injection or intravenous administration. Populations can be heterogeneous, clonal, or substantially homogeneous.
The independent claims cover novel CAR-expressing mammalian cells, recombinant host cells with specific expression vectors encoding these CARs, and pharmaceutical compositions containing these cells. The main inventive aspects reside in the specific CAR sequences (SEQ ID NOs: 10-11), their recombinant expression in host cells, and their use in therapeutic compositions.
Stated Advantages
The CARs provide specific recognition and immune response against EGFRvIII-expressing tumor cells, potentially reducing or eliminating tumors characterized by this mutation.
The human origin of antibody 139 reduces the risk of immunogenicity in patients.
Inclusion of co-stimulatory domains such as CD28 and 4-1BB enhance T cell activation, persistence, and survival, augmenting anti-tumor efficacy.
The CARs selectively target tumor cells expressing EGFRvIII, which is not present in normal tissues, thereby reducing off-target effects and avoiding damage to normal cells.
The CAR-engineered T cells demonstrate sustained functionality following expansion, supporting their clinical applicability.
Documented Applications
Treatment or prevention of cancers expressing EGFRvIII, including glioblastoma multiforme and other brain, breast, ovarian, lung, head and neck, medulloblastoma, colorectal, prostate, and bladder carcinomas.
Use of the CARs and engineered cells for in vivo detection of cancer by contacting host-derived samples with the CARs or antibodies and detecting complex formation.
Adoptive cell therapy involving infusion of autologous or allogeneic T cells engineered to express anti-EGFRvIII CARs following lymphodepleting preparative regimens.
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