High Affinity TCR for AFP Antigen Recognition
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Solution Overview
Problem
Current T cell receptors (TCRs) have limited affinity for the FMNKFIYEI-HLA A0201 complex, which hampers their effectiveness in targeting and treating AFP-related diseases, such as hepatocellular carcinoma.
Innovation Solution
Development of a TCR with enhanced affinity for the FMNKFIYEI-HLA A0201 complex by introducing specific mutations in the CDR regions of the TCR α and β chain variable domains, thereby increasing the receptor's binding capacity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type TCR is used, then the TCR can recognize AFP antigen, but the affinity is limited and insufficient for effective targeting
Solution Approach 1:
The patent applies parameter changes by systematically mutating amino acid residues in the CDR regions of the TCR. Specifically, multiple point mutations were introduced in CDR1α, CDR2α, CDR3α, CDR1β, CDR2β, and CDR3β to optimize the binding interface with the FMNKFIYEI-HLA A0201 complex. This resulted in a 2-fold or greater increase in binding affinity compared to wild-type TCR, directly resolving the contradiction between maintaining recognition capability and improving binding strength.
2Productivity
If TCR affinity for FMNKFIYEI-HLA A0201 complex is increased, then targeting effectiveness improves, but the complexity of TCR development and characterization increases
Solution Approach 1:
The patent applies local quality by focusing mutations specifically in the CDR (complementarity-determining region) loops of the TCR, which are the local regions directly responsible for antigen recognition. Rather than randomly mutating the entire TCR structure, the invention concentrates genetic modifications in the six CDR regions (CDR1α, CDR2α, CDR3α, CDR1β, CDR2β, CDR3β) that contact the peptide-MHC complex. This localized approach efficiently improved targeting effectiveness while managing development complexity.
Data Source
AI summary
Provided in the present invention is a T cell receptor (TCR) having the property of binding to a FMNKFIYEI-HLA A0201 complex; and the binding affinity of the TCR to the FMNKFIYEI-HLA A0201 complex is at least 2 times the binding affinity of the wild-type TCR to the FMNKFIYEI-HLA A0201 complex. Also provided in the present invention is a fusion molecule of such TCRs with therapeutic agents. Such TCRs can be used alone or in combination with therapeutic agents, so as to target tumor cells presenting the FMNKFIYEI-HLA A0201 complex.