G12D Mutant RAS-Specific TCRs for Selective Cancer Cell Targeting
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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, necessitating the development of additional therapeutic approaches.
Innovation Solution
Isolation and purification of T-cell receptors (TCRs) with antigenic specificity for mutated human RAS proteins, specifically targeting the G12D mutation in KRAS, HRAS, or NRAS, to elicit an immune response and selectively target cancer cells while sparing normal cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional cancer treatments (surgery, chemotherapy, radiation therapy) are used for metastatic and unresectable cancers, then some treatment effect is achieved, but treatment options remain limited and prognosis remains poor
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 (G12D, G12V, G12C, G13D) presented by HLA class II molecules, enabling selective targeting of cancer cells with mutated RAS while sparing normal cells. This parameter change from general to specific treatment mechanisms expands therapeutic options and improves prognosis for metastatic cancers.
2Measurement precision
If TCRs are designed to specifically target mutated RAS proteins, then cancer cell targeting is improved, but treatment complexity increases
Solution Approach 1:
The patent extracts and isolates the specific TCR sequences that recognize mutated RAS peptides from the complex immune system. By identifying and characterizing specific TCR alpha and beta chain variable region sequences (SEQ ID NOs: 1-36) that bind to HLA class II-mutated RAS complexes, the invention simplifies the treatment approach. Instead of using complex conventional chemotherapy that affects all rapidly dividing cells, the extracted TCRs provide precise targeting of only cancer cells expressing the specific RAS mutations.
3Reliability
If TCR therapy is developed for specific RAS mutations, then treatment effectiveness for resistant cancers is improved, but development time and resources increase
Solution Approach 1:
The patent performs preliminary action by identifying, isolating, and characterizing multiple TCR sequences specific to different RAS mutations (G12D, G12V, G12C, G13D) in advance. The TCR sequences are pre-engineered and tested for their ability to recognize mutated RAS peptides presented by various HLA class II molecules. This preliminary development of a library of mutation-specific TCRs allows for rapid deployment of appropriate therapy based on the patient's specific RAS mutation status, avoiding the need for time-consuming de novo TCR development for each patient.
Data Source
AI summary
Disclosed is an isolated or purified T cell receptor (TCR), wherein the TCR has antigenic specificity for a mutated human RAS amino acid sequence with a substitution of glycine at position 12 with aspartic acid. The TCRs may recognize G12D RAS presented by an HLA-DR heterodimer. 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.