Engineered TCRs for COL6A3 Cancer Targeting
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Solution Overview
Problem
Current cancer therapies lack specific targeting of cancer cells, with existing T-cell receptors exhibiting low affinity and limited specificity for tumor-associated antigens like COL6A3, necessitating the development of more effective and selective anti-cancer agents.
Innovation Solution
Engineered T cell receptor (TCR) constructs with mutated complementarity determining regions (CDRs) that enhance stability, recognition, and selectivity for COL6A3 antigens, specifically binding to COL6A3 peptides presented by HLA-A*02, thereby improving affinity and specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional T-cell receptors are used, then the therapy can be administered, but the affinity and specificity for tumor-associated antigens like COL6A3 remain low
Solution Approach 1:
The patent applies parameter changes by mutating the complementarity determining regions (CDRs) of the T-cell receptor to alter its binding parameters. Specifically, amino acid substitutions were made in CDR1 and CDR2 regions to enhance affinity for COL6A3 peptides while maintaining MHC class I restriction, thereby improving specificity without fundamentally changing the TCR's basic structure or mechanism of action
2Measurement precision
If TCR affinity for COL6A3 is increased through mutation, then recognition and selectivity improve, but the TCR structure becomes more complex
Solution Approach 1:
The patent applies local quality by making targeted mutations specifically in the complementarity determining regions (CDRs) of the TCR, particularly in CDR1 and CDR2. These localized changes in amino acid sequence enhance the binding interface's affinity for COL6A3 peptides while leaving the rest of the TCR structure intact, thereby improving recognition without unnecessarily increasing overall structural complexity
3Reliability
If engineered TCRs with mutated CDRs are developed, then affinity and specificity for COL6A3 increase, but the development process becomes more complex
Solution Approach 1:
The patent applies preliminary action by using phage display technology to pre-screen and select TCR variants with improved affinity for COL6A3 peptides before in vivo administration. This preliminary selection process in a controlled in vitro system identifies optimal CDR mutations that enhance selectivity, thereby simplifying the subsequent manufacturing and clinical implementation by avoiding the need for extensive trial-and-error optimization in patients
Data Source
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AI summary
The present invention pertains to antigen recognizing constructs against COL6A3 antigens. The invention in particular provides novel engineered T cell receptor (TCR) based molecules which are selective and specific for the tumor expressing antigen COL6A3. The TCR of the invention, and COL6A3 antigen binding fragments derived therefrom, are of use for the diagnosis, treatment and prevention of COL6A3 expressing cancerous diseases. Further provided are nucleic acids encoding the antigen recognizing constructs of the invention, vectors comprising these nucleic acids, recombinant cells expressing the antigen recognizing constructs and pharmaceutical compositions comprising the compounds of the invention.