Mutant RAS T-Cell Receptors for HLA-Specific Cancer Targeting
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current pharmacological inhibitors are ineffective against mutant RAS-associated cancers, which are driven by common somatic mutations like G12C, G12D, and G12R, leading to constitutive activation of intracellular GTPase signaling and tumor growth.
Innovation Solution
Development of T-cell receptors (TCRs) that specifically bind to mutant RAS (mRAS) peptides in the context of HLA-C*08:02 molecules, including specific CDR sequences and fusion polypeptides, and genetically modified immune cells to express these TCRs for targeted cancer treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If pharmacological inhibitors are used to target mutant RAS, then treatment approaches are available, but they are ineffective against mutant RAS-associated cancers
Solution Approach 1:
The patent replaces pharmacological inhibition (chemical approach) with immune system engagement (biological approach). Instead of using small molecule inhibitors that fail to effectively block mutant RAS, the invention uses T-cell receptors to recruit the immune system to recognize and destroy cancer cells expressing mutant RAS, thereby substituting a failed mechanical/chemical system with a biological system that achieves the desired therapeutic effect
Solution Approach 2:
The patent introduces T-cells as intermediary agents between the mutant RAS target and cancer cell destruction. The TCR acts as a mediator that recognizes mutant RAS peptides presented on HLA molecules, translating the presence of the target antigen into an immune response that eliminates cancer cells, thereby solving the problem of direct pharmacological inhibition failure
2Measurement precision
If TCRs are designed to specifically bind mutant RAS peptides, then high affinity and specificity are achieved, but complex molecular engineering is required
Solution Approach 1:
The patent applies local quality by focusing TCR recognition on specific local features of the mutant RAS peptide-HLA complex, particularly the mutation-induced changes at codon 12. The TCRs are engineered to recognize specific epitopes (e.g., residues 10-18 or 12-20 of KRAS) that contain the mutation, allowing high specificity through localized recognition rather than requiring the entire molecule to be uniquely specific
Solution Approach 2:
The patent uses parameter changes by modifying amino acid sequences in the TCR complementarity-determining regions (CDRs) to optimize binding affinity and specificity for mutant RAS peptides. By systematically varying CDR sequences and selecting those with optimal binding parameters, the invention achieves high specificity while managing molecular complexity through rational design
3Adaptability or versatility
If genetically modified immune cells are used to express TCRs, then targeted cancer treatment is achieved, but genetic modification complexity increases
Solution Approach 1:
The patent merges the TCR gene encoding sequence with immune cell genetic material through viral vector transduction or other gene delivery methods. By combining the exogenous TCR gene with the host immune cell genome, the invention creates genetically modified cells that express the desired TCR, thereby achieving targeted cancer treatment capability while managing genetic modification complexity through established molecular biology techniques
Solution Approach 2:
The patent enables genetically modified immune cells to self-sustain and self-proliterate with the introduced TCR. The modified cells can be expanded in culture, maintaining expression of the therapeutic TCR, and can autonomously recognize and kill target cancer cells, thereby achieving adaptability while the system serves itself rather than requiring continuous external intervention
Data Source
AI summary
The present invention provides compositions and methods of treating cancer associated with mutant RAS. In certain aspects, the present invention provides T-cell receptors that bind to specific mutant RAS peptide fragments in the context of specific HLA types. In certain aspects, the present invention provides multispecific (e.g., bispecific) antibodies comprising T-cell receptors that bind to specific mutant RAS peptide fragments in the context of specific HLA types.