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-9266960-B2
Publication Date
2016-02-23
Expiration Date
2032-03-21
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Abstract
The disclosure 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 signaling domain. These CARs are engineered to have antigen specificity for epidermal growth factor receptor variant III (EGFRvIII), a mutant form of the epidermal growth factor receptor expressed by tumor cells in various cancers such as glioblastoma. The CAR constructs include variations comprising different signaling domain combinations such as CD28, 4-1BB, and CD3ζ.
The problem addressed is the poor prognosis associated with gliomas, particularly glioblastoma multiforme (GBM), and the unmet need for additional treatments for cancer, especially brain and nervous system cancers. Despite advances in conventional treatments like surgery, radiation, and chemotherapy, survival remains low, necessitating novel therapeutic approaches targeting tumor-specific antigens such as EGFRvIII.
Claims Coverage
The patent contains two independent claims focused on chimeric antigen receptors (CARs) with specific amino acid sequences.
Chimeric antigen receptors with specified amino acid sequences
The invention claims CARs comprising an amino acid sequence selected from SEQ ID NOs: 10 and 11, which include an antigen binding domain from human antibody 139, an extracellular hinge domain, a transmembrane domain, and an intracellular T cell signaling domain tailored for targeting EGFRvIII.
The claims cover CARs specifically configured with defined amino acid sequences that combine human antibody 139 antigen binding specificity with particular hinge, transmembrane, and intracellular signaling domains to provide targeted immunotherapy against EGFRvIII-expressing cancer cells.
Stated Advantages
The inventive CARs specifically target and destroy EGFRvIII-expressing tumor cells while substantially avoiding normal tissues, thereby reducing off-target toxicity.
The CARs exhibit the ability to redirect T-cell specificity and reactivity toward EGFRvIII in a non-MHC-restricted manner, overcoming tumor escape mechanisms.
Inclusion of co-stimulatory signaling domains such as 4-1BB enhances T cell differentiation, long-term survival, and persistence of the CAR-engineered T cells.
Documented Applications
Treatment or prevention of cancer in a host, particularly cancers expressing EGFRvIII such as glioblastoma multiforme.
Methods of detecting the presence of cancer in a host by using the CARs, nucleic acids, recombinant vectors, host cells, or antibodies to identify cancer cells expressing EGFRvIII.
Ex vivo engineering of T cells by transduction with recombinant vectors encoding the CARs for adoptive immunotherapy applications.
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