TCR Locus DNA Constructs for Safer Functional T Cell Engineering
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Solution Overview
Problem
Current techniques for modifying ex vivo or intravitally gene edited cells for therapeutic use are limited to correcting single mutations or integrating new synthetic genes, lacking flexibility and efficiency in genomic modifications, particularly for T cells in adoptive cellular therapeutics.
Innovation Solution
Human T cells are modified by inserting nucleic acids encoding polypeptides and heterologous T cell receptors or synthetic antigen receptors into specific genomic sites, such as the TCR locus, to alter specificity and function, thereby generating T cells with altered functionality and reduced side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If current techniques are used to modify ex vivo or intravitally gene edited cells, then correction of existing mutations is achieved, but therapeutic applicability is limited to conditions caused by single mutations
Solution Approach 1:
The patent applies universality by creating a standardized genomic modification platform that can serve multiple therapeutic functions. The nucleic acid construct system allows correction of single mutations, integration of synthetic genes, and modification of T cell receptors through a unified approach, making the system versatile across different disease conditions and modification types rather than requiring separate techniques for each application.
Solution Approach 2:
The patent segments the genomic modification process into modular components: a standardized nucleic acid construct with homology arms, a selectable marker, and the desired genetic modification. This segmentation allows flexible assembly of different modification types (point mutations, insertions, deletions) using the same basic framework, expanding therapeutic applicability without proportionally increasing overall system complexity.
2Productivity
If entirely new synthetic genes are integrated into cells, then new therapeutic functions are achieved, but extensive research and development into creating synthetic DNA sequences is required
Solution Approach 1:
The patent applies preliminary action by pre-designing and validating the nucleic acid construct framework, including homology arms for targeted integration and selectable markers for identification. This preliminary preparation of the modification system allows rapid implementation of different synthetic gene integrations without repeating the extensive R&D process for each new therapeutic application, significantly reducing development time.
Solution Approach 2:
The patent uses copying by utilizing the same standardized nucleic acid construct design and integration methodology across different synthetic gene implementations. Once the construct framework is established, it can be copied and adapted for different therapeutic genes without requiring extensive new research and development, accelerating the generation of new therapeutic functions.
3Reliability
If T cells are modified to produce edited T cells with desirable functions, then antigen specificity and functionality are improved, but side effects associated with T cell therapies may occur
Solution Approach 1:
The patent applies local quality by using targeted genomic integration at specific loci (such as the TCR locus) rather than random integration throughout the genome. This localized modification approach ensures that desired functions are introduced with precise control over expression patterns, reducing off-target effects and improving the reliability of T cell function while minimizing unintended side effects.
Data Source
AI summary
Provided herein are methods and compositions for modifying the genome of human T cells. Further, the compositions and methods described herein can be used to generate human T cells with altered specificity and functionality, while limiting the side effects associated with T cell therapies. Provided herein is a human T cell that heterologously expresses one or more polypeptides. In some embodiment, the one or more polypeptides, for example, two or more polypeptides, are encoded by a nucleic acid construct inserted into the TCR locus of the cell.