Anti-KRAS-G12D T cell receptors
Inventors
Tran, Eric • Lu, Yong-Chen • Pasetto, Anna • Robbins, Paul F. • Rosenberg, Steven A. • Zheng, Zhili
Assignees
US Department of Health and Human Services
Publication Number
US-11208456-B2
Publication Date
2021-12-28
Expiration Date
2037-07-31
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Disclosed is an isolated or purified T cell receptor (TCR) having antigenic specificity for mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) presented in the context of an HLA-Cw*0802 molecule. Related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions are also provided. Also disclosed are methods of detecting the presence of cancer in a mammal and methods of treating or preventing cancer in a mammal.
Core Innovation
The invention provides isolated or purified T cell receptors (TCRs) having antigenic specificity for mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) presented in the context of an HLA-Cw*0802 molecule. These TCRs specifically recognize the mutated KRAS with a G12D mutation and can elicit immune responses against cancer cells expressing this mutation when presented by the appropriate HLA molecules.
The background highlights the limited treatment options for various metastatic and unresectable cancers such as pancreatic, colorectal, lung, endometrial, ovarian, and prostate cancers, often resulting in poor prognosis despite advances in surgery, chemotherapy, and radiation therapy. There exists an unmet need for additional treatments for cancer.
The inventive TCRs and related components—including polypeptides, proteins, nucleic acids, recombinant expression vectors, host cells, and pharmaceutical compositions—are provided to detect, treat, or prevent cancers that express the mutated KRAS G12D mutation. The invention also discloses methods of detecting cancer presence in a mammal using these TCRs and methods for treating or preventing cancer by administering these TCRs or cells expressing them.
Claims Coverage
The patent encompasses multiple independent claims directed to isolated or purified TCRs, polypeptides, proteins, host cells, recombinant vectors, and methods related to mutated KRAS G12D recognition and related treatments.
Isolated or purified TCRs comprising specific amino acid sequences
TCRs comprising the amino acid sequences of SEQ ID NOs: 9-14; 17-22; 25-30; or 33-38 that exhibit antigenic specificity for mutated KRAS G12D presented by HLA-Cw*0802.
TCRs comprising combinations of variable and constant regions
TCRs comprising variable regions or CDRs with at least 99% identity to SEQ ID NOs: 15-16, 23-24, 31-32, or 39-40 combined with human or murine constant regions (including substituted and cysteine/hydrophobic amino acid substituted constant regions SEQ ID NOs: 41-49).
Polypeptides and proteins comprising functional portions or full-length TCR chains
Isolated or purified polypeptides and proteins comprising the alpha and beta chains described herein, including functional portions with the CDRs or variable regions that bind mutated KRAS G12D, as well as fusion proteins and single-chain constructs linked by peptide linkers.
Nucleic acid constructs and recombinant expression vectors encoding the TCRs
Nucleic acids encoding the inventive TCRs including codon-optimized sequences (e.g., SEQ ID NOs: 63-70) and recombinant expression vectors, particularly retroviral vectors such as MSGV1, that enable expression in host cells.
Host cells and populations of cells expressing the inventive TCRs
Isolated or purified host cells, preferably T cells, genetically engineered to express the inventive TCRs, and populations thereof, which can be expanded for therapy.
Methods of detecting and treating KRAS G12D-expressing cancers
Methods using the inventive TCRs, polypeptides, proteins, nucleic acids, vectors, or host cells for detecting mutated KRAS G12D-positive cancer in a mammal and treating or preventing such cancers by administering effective amounts of these compositions.
The independent claims comprehensively cover TCRs and related biological molecules with specific KRAS G12D antigenic specificity, engineered host cells and recombinant vectors expressing these TCRs, as well as therapeutic and diagnostic methods involving these materials for KRAS G12D-positive cancers.
Stated Advantages
The inventive TCRs specifically target mutated KRAS expressed by cancer cells while sparing normal cells, thereby minimizing toxicity.
They provide the ability to successfully treat or prevent mutated KRAS-positive cancers that are unresponsive to chemotherapy, surgery, or radiation.
High avidity recognition enables detection and killing of unmanipulated tumor cells without requiring pretreatment with IFN-γ or peptide pulsing.
By recognizing mutated KRAS in the context of the HLA-Cw*0802 allele, which is prevalent in specific populations, the TCRs broaden immunotherapy eligibility to new patient groups.
Documented Applications
Detection of KRAS G12D-expressing cancer in a mammal by contacting a sample of cells with the inventive TCRs or related materials and detecting complex formation.
Treatment or prevention of cancers expressing KRAS G12D mutation, including pancreatic, colorectal, lung, endometrial, ovarian, and prostate cancers, by administering TCRs, polypeptides, proteins, nucleic acids, recombinant vectors, or host cells encoding the inventive TCRs.
Interested in licensing this patent?