TCR Binding HPV16 E6 Antigen Complex
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Solution Overview
Problem
Current technologies lack an effective T cell receptor (TCR) capable of specifically recognizing and binding to the TIHDIILECV-HLA A0201 complex, which is crucial for targeting HPV16 E6-related diseases such as cervical cancer.
Innovation Solution
Development of a TCR with an alpha chain variable domain and a beta chain variable domain that have specific amino acid sequences with high homology to SEQ ID NO: 1 and SEQ ID NO: 5, respectively, enabling specific binding to the TIHDIILECV-HLA A0201 complex, and its application in adoptive immunotherapy to target and destroy tumor cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional TCRs are used, then general immune recognition is achieved, but specific binding to TIHDIILECV-HLA A0201 complex is not obtained
Solution Approach 1:
The patent applies local quality by specifically modifying the CDR3 regions of the TCR alpha and beta chains to optimize binding to the TIHDIILECV-HLA A0201 complex. The CDR3 alpha sequence (ALRAGANNLF) and CDR3 beta sequence (ASGPWGSSGNTIY) are specifically designed to recognize the unique epitope structure, while other regions maintain general TCR functionality. This localized optimization enables specific antigen recognition without compromising overall TCR function.
Solution Approach 2:
The patent employs parameter changes by systematically optimizing the amino acid sequences in the CDR regions, particularly CDR3 alpha and CDR3 beta. The specific sequence parameters (e.g., ALRAGANNLF for CDR3 alpha, ASGPWGSSGNTIY for CDR3 beta) were selected to maximize binding affinity and specificity to the TIHDIILECV-HLA A0201 complex, transforming a general TCR into a highly specific antigen recognizer.
2Reliability
If TCR with high sequence homology to SEQ ID NO: 1 and SEQ ID NO: 5 is developed, then specific binding to TIHDIILECV-HLA A0201 is achieved, but development complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the TCR development process into distinct modular components: identifying the target epitope (TIHDIILECV), determining HLA restriction (HLA A0201), optimizing CDR1, CDR2, and CDR3 regions separately, and assembling them into functional TCR alpha and beta chains. This modular approach to sequence design and validation systematically manages development complexity while achieving high binding specificity.
3Productivity
If TCR is applied in adoptive immunotherapy, then tumor cell killing function is enhanced, but treatment complexity increases
Solution Approach 1:
The patent applies self-service by engineering TCR-expressing T cells that autonomously recognize and kill HPV16 E6-positive tumor cells without requiring additional external targeting molecules or complex delivery systems. The TCR (with sequences ALRAGANNLF and ASGPWGSSGNTIY) provides built-in specificity for the TIHDIILECV-HLA A0201 complex, enabling the therapeutic cells to self-direct to tumor targets and execute killing functions independently.
Data Source
AI summary
The present invention provides a T cell receptor (TCR) capable of specifically binding to HPV 16 E6 antigen short peptide complex TIHDIILECV-HLA A0201. Moreover, an effector cell transducing the TCR of the present disclosure also has a strong killing function. Such TCR can be used separately or in combination with other therapeutic agents, and can also be used in adoptive cellular immunotherapy to target a tumor cell presenting the complex TIHDIILECV-HLA A0201.