HLA class II-restricted T cell receptors against mutated RAS
Inventors
Yoseph, Rami • Robbins, Paul F. • Rosenberg, Steven A.
Assignees
US Department of Health and Human Services
Publication Number
US-11306132-B2
Publication Date
2022-04-19
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 presented by human leukocyte antigen (HLA) Class II molecules. The mutated human RAS sequences include mutated forms of KRAS, HRAS, or NRAS, with particular focus on substitutions at position 12 from glycine (G12) to other amino acids such as valine (G12V) or cysteine (G12C). The TCRs are capable of recognizing these mutated RAS peptides presented in the context of HLA Class II molecules like HLA-DR, specifically alleles such as HLA-DRB1*07:01 or HLA-DRB1*11:01.
The invention addresses the medical need for new cancer treatments, especially for cancers with limited options such as metastatic and unresectable pancreatic, colorectal, lung, endometrial, ovarian, and prostate cancers. Mutated RAS proteins are involved in the oncogenesis of many cancers and are not expressed in normal cells. The TCRs described bind with high avidity to mutated RAS peptides presented by HLA Class II molecules, facilitating targeted immune responses.
The inventive TCRs consist of alpha and beta chains with defined complementarity determining regions (CDRs) provided by specific SEQ ID NOs. These TCRs can comprise murine or human constant regions, with modifications such as cysteine substitutions or hydrophobic amino acid substitutions in the transmembrane domain to enhance stability and expression. Nucleic acids encoding these TCRs, recombinant expression vectors, host cells expressing the TCRs, and pharmaceutical compositions comprising them are also disclosed. Methods for detecting cancer and for treating or preventing cancer by administering these TCRs or host cells expressing them are provided.
Claims Coverage
The patent includes multiple independent claims covering isolated T cell receptors, polypeptides, and proteins with antigenic specificity for mutated human RAS presented by HLA Class II molecules, as well as their nucleic acid sequences, recombinant expression vectors, host cells, and methods of detecting and treating cancer.
TCRs with antigenic specificity for mutated human RAS presented by HLA Class II molecules
The TCRs specifically recognize mutated human RAS proteins (mutated KRAS, HRAS, or NRAS) presented by HLA Class II molecules. The TCRs comprise defined CDR sequences of α and β chains (SEQ ID NOs: 1-6).
Specific amino acid sequences and high identity variants of TCR variable regions
TCRs comprising amino acid sequences at least 99% identical to SEQ ID NO: 13 and SEQ ID NO: 14, or defined segments thereof, including combinations thereof, providing specific antigen recognition.
TCRs comprising defined murine constant regions with amino acid variations
TCRs comprising α and β chain constant regions at least 99% identical to SEQ ID NO: 30 and 31 respectively, with specific residue variations (e.g., cysteine substitutions) enhancing function and expression.
TCRs comprising full-length α and β chains with specified variable and constant regions
TCRs including α chains and β chains having amino acid sequences at least 99% identical to SEQ ID NOs: 34 and 35 (including specified residue variations), alone or in combination with defined partial sequences.
Isolated polypeptides and proteins comprising functional portions of the TCRs
Polypeptides and proteins comprising functional portions of the TCRs with specified CDR sequences, variable regions, and optionally constant regions, retaining antigen specificity for mutated RAS.
Pharmaceutical compositions comprising the inventive TCRs
Pharmaceutical compositions comprising the isolated or purified TCRs and pharmaceutically acceptable carriers are claimed.
Nucleic acids encoding the inventive TCRs and host cells expressing them
Isolated nucleic acids encoding the TCRs, recombinant expression vectors containing these sequences, and host cells comprising the TCRs or vectors for expression.
Methods of detecting and treating KRAS G12V-expressing cancers using the TCRs
Methods involving contacting a sample with the TCR to detect KRAS G12V-expressing cancer, and methods of treating such cancers by administering the TCR in effective amounts.
The claims collectively cover isolated TCRs with defined specificity and sequences for mutated human RAS presented by HLA Class II molecules, their polypeptides and proteins, nucleic acids and vectors encoding them, host cells expressing these TCRs, pharmaceutical compositions, and methods for cancer detection and treatment using these TCRs.
Stated Advantages
Targeted destruction of cancer cells expressing mutated RAS while minimizing destruction of normal cells, thereby reducing toxicity.
Capability to treat or prevent cancers expressing mutated RAS mutations (e.g., G12V or G12C) that are resistant to chemotherapy, surgery, or radiation.
High avidity recognition of mutated RAS enabling recognition of unmanipulated tumor cells.
Expansion of immunotherapy eligibility to patients expressing certain HLA-DRB1 alleles, such as *07:01 and *11:01.
Documented Applications
Detecting the presence of cancer in a mammal by using the TCRs, polypeptides, proteins, nucleic acids, recombinant vectors, host cells, or pharmaceutical compositions to form detectable complexes with mutated RAS.
Treating or preventing cancers in mammals expressing mutated human RAS, particularly pancreatic, colorectal, lung (adenocarcinoma), endometrial, ovarian (epithelial ovarian cancer), and prostate cancers, by administering TCRs, host cells expressing the TCRs, or compositions thereof.
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