T cell receptors recognizing HLA-CW8 restricted mutated KRAS
Inventors
Tran, Eric • Lu, Yong-Chen • Rosenberg, Steven A.
Assignees
US Department of Health and Human Services
Publication Number
US-11667692-B2
Publication Date
2023-06-06
Expiration Date
2036-09-09
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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 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 a human leukocyte antigen (HLA)-Cw8 molecule. This includes related polypeptides, proteins, nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions. The invention also encompasses methods of detecting the presence of cancer in a mammal and methods of treating or preventing cancer in a mammal using these TCRs or related materials.
The inventive TCRs specifically recognize mutated human KRAS, particularly the G12D mutation, when presented by HLA-Cw8 molecules such as HLA-Cw*0802. The TCRs comprise variable regions with defined complementarity determining regions (CDRs) that provide specificity for mutated KRAS peptides of various lengths, exemplified by sequences like GADGVGKSA (SEQ ID NO: 18). The invention includes chimeric TCRs with human variable regions linked to murine constant regions, as well as TCRs with substituted constant regions that enhance properties such as recognition, expression, and anti-tumor activity. Functional variants and polypeptide fragments retaining antigenic specificity are also provided.
The background identifies the problem that many cancers, especially when metastatic and unresectable, have limited treatment options and poor prognosis despite current therapies like surgery, chemotherapy, and radiation therapy. There is an unmet need for additional treatments targeting cancers including pancreatic, colorectal, lung, endometrial, ovarian, and prostate cancers. The invention addresses this by providing TCRs that target mutated KRAS expressed on cancer cells presented by HLA-Cw8, potentially allowing for targeted immunotherapy with reduced toxicity to normal cells.
Claims Coverage
The patent includes one independent claim, which covers a method of treating cancer using host cells expressing a TCR specific for KRAS G12D presented by HLA-Cw8 molecules. The independent claim details the composition of the TCR and its use in cancer treatment.
Use of T cells expressing a specific TCR to treat cancer
Administering host cells comprising a recombinant expression vector encoding a TCR with antigenic specificity for KRAS G12D presented by an HLA-Cw8 molecule to a mammal with cancer expressing HLA-Cw8 and KRAS G12D.
TCR specificity defined by complementarity determining regions
The TCR comprises an alpha chain with CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NOs: 3, 4, and 5, respectively, and a beta chain with CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 6, 7, and 8, respectively.
Recognition of specific mutated KRAS peptide by the TCR
The TCR has antigenic specificity for the mutated KRAS peptide sequence GADGVGKSA (SEQ ID NO: 18) when presented by the HLA-Cw8 molecule.
Preferred HLA restriction element
The HLA-Cw8 molecule presenting KRAS G12D is preferably HLA-Cw*0802.
Inclusion of variable region sequences in the TCR
The TCR comprises the alpha chain variable region of SEQ ID NO: 9, the beta chain variable region of SEQ ID NO: 10, or both.
Further specification of TCR constant regions with possible substitutions
The TCR may include an alpha chain constant region (SEQ ID NO: 11) and beta chain constant region (SEQ ID NO: 12) with specified possible amino acid substitutions at certain positions to enhance function or stability.
Full-length chain sequences with defined substitutions
The TCR may comprise an alpha chain of SEQ ID NO: 13 and a beta chain of SEQ ID NO: 14 with specified amino acid options at key positions.
The claims protect the use of host cells expressing engineered TCRs with defined variable and constant regions that specifically recognize the KRAS G12D mutation presented by HLA-Cw8, particularly HLA-Cw*0802, for the treatment of cancers expressing these molecules.
Stated Advantages
The inventive TCRs specifically target mutated KRAS expressed by cancer cells while minimizing recognition of normal, noncancerous cells, thereby reducing toxicity.
They provide the ability to treat or prevent mutated KRAS-positive cancers that do not respond to chemotherapy, surgery, or radiation therapy.
The TCRs demonstrate high avidity recognition, enabling detection and targeting of unmanipulated tumor cells without need for prior treatment or modification.
The use of HLA-Cw*0802-restricted TCRs increases the number of cancer patients eligible for immunotherapy, including those who may not be eligible using TCRs restricted by other MHC molecules.
Documented Applications
Treatment or prevention of cancers expressing mutated KRAS G12D in the context of HLA-Cw8, including pancreatic, colorectal, lung (e.g., lung adenocarcinoma), endometrial, ovarian (e.g., epithelial ovarian cancer), and prostate cancers.
Detection of cancer in a mammal by contacting a sample of cells with the inventive TCRs or related materials and detecting complex formation indicative of cancer presence.
Adoptive cell transfer methods employing host cells genetically engineered to express the inventive TCRs for therapeutic purposes.
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