HLA class II-restricted t cell receptors against mutated RAS
Inventors
Cafri, Gal • Robbins, Paul F. • Rosenberg, Steven A.
Assignees
US Department of Health and Human Services
Publication Number
US-12304940-B2
Publication Date
2025-05-20
Expiration Date
2038-09-19
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Abstract
Disclosed is an isolated or purified T cell receptor (TCR), wherein the TCR has antigenic specificity for mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) presented by a human leukocyte antigen (HLA) Class II 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) that have antigenic specificity for mutated human RAS amino acid sequences, specifically mutated KRAS, HRAS, or NRAS, when these sequences are presented by human leukocyte antigen (HLA) Class II molecules. The TCRs recognize mutated RAS peptides, such as those with G12V or G12C mutations, bound to HLA Class II molecules, particularly HLA-DR and more specifically HLA-DRB1*07:01 or HLA-DRB1*11:01 alleles.
The background addresses the clinical challenge that many cancers, including pancreatic, colorectal, lung, endometrial, ovarian, and prostate cancers, often have limited treatment options, especially when metastatic or unresectable, leading to poor prognosis. There exists an unmet need for additional treatments for such cancers.
The invention further relates to nucleic acids encoding these TCRs, recombinant expression vectors, host cells expressing the TCRs, pharmaceutical compositions, and methods for detecting cancer by using these TCRs. The TCRs specifically recognize mutated RAS peptides presented by HLA Class II molecules, enabling targeted immune responses against cancer cells expressing mutated RAS, while minimizing effects on normal cells not expressing such mutations.
Claims Coverage
The patent claims cover one independent claim that defines a T-cell receptor with specific antigenic specificity, and dependent claims elaborating on molecular characteristics and configurations related to this TCR.
T-cell receptor with specificity for mutated human RAS presented by HLA Class II molecule
An isolated or purified TCR having antigenic specificity for a mutated human RAS amino acid sequence comprising mutated KRAS, HRAS, or NRAS, presented by an HLA Class II molecule, and comprising specific complementarity determining regions (CDRs) with amino acid sequences SEQ ID NOs: 7-12 in the α and β chains.
Recognition of mutated RAS by TCR through HLA-DR and HLA-DRB1 alleles
The TCR is specific for mutated RAS peptides presented by an HLA-DR molecule, particularly HLA-DRB1, and more specifically HLA-DRB1*11:01.
Mutated RAS peptide sequence with substitution at glycine position 12
The mutated human RAS sequence recognized by the TCR comprises a wild-type KRAS, HRAS, or NRAS with a substitution of glycine at position 12 (defined relative to the wild-type protein), particularly substitution with cysteine.
TCR comprising sequences highly identical to specific variable regions
The TCR comprises amino acid sequences at least 95% identical to SEQ ID NOs: 15 and 16 or their functional subsequences, including combinations thereof.
TCR comprising substituted constant regions
The TCR includes α and β chain constant regions having amino acid sequences at least 95% identical to SEQ ID NOs: 30 and 31 respectively, with defined variability at specific positions, including cysteine substitutions.
Alternative TCR chains with defined variable and constant region sequences
The TCR can comprise α and β chains at least 95% identical to SEQ ID NOs: 36 and 37 respectively, with defined variability at specific positions including cysteine substitutions.
Isolated polypeptides representing functional portions of the TCR
Isolated or purified polypeptides comprising functional portions of the TCR containing the specified CDR sequences (SEQ ID NOs: 7-12), including polypeptides with sequences at least 95% identical to SEQ ID NOs: 15 and 16 or their corresponding regions.
Proteins comprising the paired α and β polypeptide chains with specified CDRs
Proteins comprising a first polypeptide chain with α chain CDR1, CDR2, and CDR3 of SEQ ID NOs: 7-9 and a second polypeptide chain with β chain CDR1, CDR2, and CDR3 of SEQ ID NOs: 10-12, including sequences with at least 95% identity to SEQ ID NOs: 15 and 16 and optionally with specified constant regions.
Pharmaceutical composition comprising the TCR and a carrier
A pharmaceutical composition comprising the TCR described and a pharmaceutically acceptable carrier.
Nucleic acids and vectors encoding the TCR
Isolated nucleic acids encoding the TCR, recombinant expression vectors comprising such nucleic acids, host cells transformed or transfected with the vectors, and populations of such host cells.
The claims cover a T-cell receptor with antigen specificity for mutated RAS (KRAS, HRAS, NRAS) peptides presented by HLA Class II molecules, particularly HLA-DRB1*11:01, with defined complementarity-determining regions and constant region substitutions, and related polypeptides, proteins, nucleic acids, vectors, host cells, and pharmaceutical compositions for use in cancer detection and treatment.
Stated Advantages
The inventive TCRs specifically target mutated RAS expressed by cancer cells but not by normal cells, reducing toxicity.
They may successfully treat or prevent mutated RAS-positive cancers resistant to chemotherapy, surgery, or radiation.
The TCRs provide highly avid recognition of mutated RAS allowing recognition of unmanipulated tumor cells.
Use of HLA-DRB1*07:01 and HLA-DRB1*11:01 alleles expands the population of immunotherapy-eligible patients.
Documented Applications
Methods of detecting the presence of cancer in a mammal using the inventive TCRs and related compositions.
Methods of treating or preventing cancer in a mammal by administering the inventive TCR materials, nucleic acids, vectors, or host cells.
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