Mutated RAS-Specific TCRs for Targeted Cancer Immunotherapy
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Solution Overview
Problem
Current cancer treatments, such as surgery, chemotherapy, and radiation therapy, offer limited options for metastatic and unresectable cancers like pancreatic, colorectal, lung, endometrial, ovarian, and prostate cancers, resulting in poor prognosis.
Innovation Solution
Development of isolated or purified T-cell receptors (TCRs) with specific antigenic specificity for mutated human RAS proteins, presented by human leukocyte antigen (HLA) Class I molecules, targeting mutated KRAS, HRAS, or NRAS sequences, which are expressed in various cancer types, allowing for targeted immune response and reduced toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional cancer treatments (surgery, chemotherapy, radiation therapy) are used for metastatic and unresectable cancers, then treatment options are available, but prognosis remains poor and treatment efficacy is limited
Solution Approach 1:
The patent changes the fundamental parameter of cancer treatment from non-specific conventional therapies to highly specific TCR-based immunotherapy. The TCRs are engineered to recognize specific mutated RAS peptides (G12V, G12D, G12C, G12A) presented by HLA Class I molecules, transforming the treatment approach to target molecular characteristics of the cancer rather than using broad-spectrum therapies.
Solution Approach 2:
The patent segments the cancer treatment approach by developing distinct TCRs for different RAS mutation types (KRAS, HRAS, NRAS with various mutations). Each TCR is specifically designed to recognize a particular mutated RAS peptide-HLA complex, allowing tailored treatment for different cancer types and mutation profiles rather than using a single general approach.
2Measurement precision
If TCRs with high specificity for mutated RAS are developed, then targeted immune response increases, but complexity of developing specific TCRs increases
Solution Approach 1:
The patent performs preliminary action by identifying and characterizing specific TCR sequences (SEQ ID NOs: 1-6) that have proven specificity for mutated RAS peptides before clinical application. The TCR sequences have been pre-validated through screening and characterization to ensure they recognize their target peptides with high specificity, reducing the need for complex de novo development in clinical settings.
Solution Approach 2:
The patent uses copying by utilizing naturally occurring TCR sequences that have already evolved to recognize mutated RAS peptides. Instead of designing entirely new TCRs from scratch, the invention identifies and replicates naturally selected TCR sequences that have proven specificity, simplifying the development process while maintaining high antigen recognition precision.
3Object-affected harmful factors
If TCR-based immunotherapy is implemented, then toxicity to normal cells is reduced, but eligibility is limited to patients with specific HLA Class I molecules
Solution Approach 1:
The patent applies local quality by designing TCRs that specifically recognize mutated RAS peptides presented by certain HLA Class I molecules (HLA-A*11:01, HLA-A*02:01, HLA-B*44:02, HLA-B*07:02). The TCR specificity is localized to particular peptide-HLA combinations, allowing highly targeted recognition that spares normal cells while providing precise treatment for eligible patients with the required HLA types.
Data Source
AI summary
Disclosed is an isolated or purified T cell receptor (TCR), wherein the TCR has antigenic specificity for a mutated RAS amino acid sequence presented by a human leukocyte antigen (HLA) Class I 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.