Constant UNI-Tabs for Precise rTCR Quality Control
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Solution Overview
Problem
Current methods for quality control of recombinant T cell receptors (rTCRs) in adoptive immune therapy are complex and inaccurate, often leading to incorrect evaluation and potential immune responses due to the use of pHLA-multimers, TCR-Vß specific antibodies, and additional tagging molecules, which complicate the identification and assessment of rTCR-T cell levels.
Innovation Solution
The insertion of epitope tags in specific adaptable positions within the constant regions of rTCRs, particularly in the alpha and beta constant regions (TRAC and TRBC), maintains structural integrity and functionality, allowing for precise identification and tracking of rTCRs without interfering with TCR specificity or expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Difficulty of detecting and measuring
If pHLA-multimers, TCR-Vß specific antibodies, or additional tagging molecules are used for quality control, then identification capability is improved, but device complexity and measurement precision deteriorate
Solution Approach 1:
The patent merges the identification function directly into the TCR molecule by integrating an epitope tag sequence into the constant region of the TCR alpha or beta chain. This eliminates the need for separate identification systems like pHLA-multimers or Vß-specific antibodies, as the TCR itself now carries the identification marker. The merging of detection function into the target molecule simplifies the overall quality control system while maintaining identification capability.
Solution Approach 2:
The epitope-tagged TCR serves multiple functions simultaneously: it maintains antigen recognition capability through the variable regions while the integrated epitope tag provides universal identification through antibody binding. This multi-functional design allows a single molecule to perform both immune recognition and quality control identification tasks, reducing the need for multiple separate components.
2Difficulty of detecting and measuring
If additional tagging molecules are expressed alongside rTCR, then identification capability is improved, but manufacturing precision deteriorates due to expression level disparities
Solution Approach 1:
The identification epitope is merged into the TCR molecule itself rather than being expressed as a separate molecule. This ensures that the epitope and the functional TCR are always co-expressed in identical stoichiometric ratios, eliminating the expression level disparities that plague separate tagging approaches. The unified structure guarantees that every TCR molecule carries exactly one epitope tag, enabling accurate quantification.
3Difficulty of detecting and measuring
If epitope tags are inserted into TCR constant regions, then identification capability is improved, but structural integrity may deteriorate
Solution Approach 1:
The patent applies local quality by selectively inserting the epitope tag into specific positions within the constant regions of the TCR alpha or beta chains. These positions are chosen to minimize disruption to the overall TCR structure and function. The constant regions serve as appropriate locations because they are less critical for antigen binding compared to the variable regions, allowing local modification without compromising global structural integrity.
Data Source
Figure 1
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Figure 3A)~3C)
AI summary
The present invention covers a T cell receptor (TCP) comprising at least one epitope tag. An isolated polypeptide comprising at least one epitope tag and functional portion of the TCP is also described. Moreover, a multivalent TCP complex, nucleic acid molecules, vectors, cells as well as medical uses and pharmaceutical compositions relating to the TCP as well as a method of modifying a TCP or a fragment thereof comprising such that the TCP comprises at least one epitope tag are defined.