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-9624306-B2
Publication Date
2017-04-18
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. These CARs have antigen specificity for epidermal growth factor receptor variant III (EGFRvIII), which is a variant of epidermal growth factor receptor expressed on tumor cells of various cancers such as glioblastoma and others, but not on normal tissues. The invention also includes nucleic acids, recombinant expression vectors, host cells, populations of cells, antibodies or antigen binding portions thereof, and pharmaceutical compositions relating to these CARs.
The CARs enable T cells to specifically recognize and mediate an immune response against cells expressing EGFRvIII, thereby targeting and destroying such tumor cells while substantially avoiding normal tissue. The invention further encompasses methods of detecting the presence of cancer in a host and methods of treating or preventing cancer by administering the inventive CARs or related materials to the host.
The background identifies the serious unmet medical need for additional treatments for cancers, particularly gliomas such as glioblastoma multiforme (GBM), where conventional therapies have poor prognosis and limited survival. EGFRvIII is a common mutation in such cancers, making it a suitable tumor-specific target for CAR-T cell therapy, which addresses the problem of lack of efficacy and specificity in existing treatments.
Claims Coverage
The patent contains independent claims directed to nucleic acids encoding chimeric antigen receptors and recombinant expression vectors and host cells comprising these nucleic acids, focusing on the EGFRvIII-targeting CARs with specific amino acid sequences.
Nucleic acid encoding chimeric antigen receptor
A nucleic acid comprising a nucleotide sequence encoding a CAR comprising an amino acid sequence selected from SEQ ID NOs: 10 or 11, which include the antigen binding domain of human antibody 139 and intracellular T cell signaling domains.
Recombinant expression vector comprising CAR nucleic acid
A recombinant expression vector comprising the nucleic acid encoding the CAR as described, allowing for expression of the CAR in host cells.
Isolated host cell comprising recombinant expression vector
An isolated host cell, including a T cell or human T cell, comprising the recombinant expression vector encoding the CAR, enabling expression of the CAR within the cell for targeted immune response.
Population of cells containing host cells with CAR expression
A population of cells comprising at least one host cell containing the recombinant expression vector encoding the CAR, which may be heterogeneous or homogeneous in composition.
The independent claims cover nucleic acids encoding CARs with sequences SEQ ID NOs: 10 or 11, recombinant expression vectors containing these nucleic acids, isolated host cells including T cells expressing the CAR, and populations of such cells. These claims collectively encompass the genetic constructs and cellular compositions that mediate the targeting of EGFRvIII-expressing cancer cells using human antibody 139-based CARs.
Stated Advantages
The invention provides CARs that specifically target EGFRvIII-expressing tumor cells, enabling targeted destruction of cancer cells while avoiding normal tissues due to the tumor-specific expression of EGFRvIII.
CARs enable non-MHC-restricted antigen recognition, allowing T cells to recognize tumor antigen independent of antigen processing, thereby overcoming a major mechanism of tumor escape.
Inclusion of co-stimulatory signaling domains such as CD28 and 4-1BB enhances T cell activation, persistence, and long-term survival, improving antitumor responses.
Human origin of the antibody 139-based CAR reduces immunogenicity in patients, enhancing therapeutic applicability.
Documented Applications
Use of the CARs, nucleic acids, recombinant vectors, host cells, or pharmaceutical compositions for the 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 contacting a sample with the inventive CARs or related materials and detecting complex formation indicative of cancer presence.
Clinical methods involving administering CAR-transduced T cells to glioblastoma patients after lymphodepleting preparative regimen and monitoring for safety, persistence, and clinical response.
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