Endogenous TCR Replacement for Rapid Antigen-Specific T Cell Editing
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Solution Overview
Problem
Developing entirely new types of T cell receptors for adoptive cellular therapeutics is time-consuming and expensive, and existing methods fail to leverage the body's natural production of endogenous TCRs with desired antigen specificity.
Innovation Solution
Inserting a heterologous TCR into a targeted region of the T cell genome under the control of an endogenous TCR promoter, using methods such as homology-directed repair (HDR) and targeted nucleases to replace the endogenous TCR with a desired antigen specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If entirely new types of T cell receptors are developed for adoptive cellular therapeutics, then the desired antigen specificity can be achieved, but the process is time-consuming and expensive
Solution Approach 1:
The patent applies preliminary action by pre-characterizing and storing endogenous TCR sequences from healthy donors before therapy is needed. These pre-existing TCRs with desired antigen specificities are ready to be rapidly transferred to patient T cells via viral vectors, eliminating the need for de novo development and significantly reducing therapy time
Solution Approach 2:
The patent uses copying by transferring endogenous TCR sequences from donor T cells to recipient T cells through viral vectors. Instead of developing new TCRs from scratch, the desired TCR sequences are copied and inserted into patient T cells, achieving the same functional outcome much faster and more cost-effectively
2Adaptability or versatility
If entirely new types of T cell receptors are developed for adoptive cellular therapeutics, then the desired antigen specificity can be achieved, but the process is expensive
Solution Approach 1:
The patent employs copying by utilizing existing endogenous TCR sequences from healthy donor T cells rather than synthesizing new TCRs. The TCR sequences are extracted, characterized, and transferred via viral vectors to patient T cells, significantly reducing development costs compared to creating entirely new receptor types
Solution Approach 2:
The patent applies self-service by leveraging the body's natural production of endogenous TCRs with desired antigen specificities. Instead of externally developing and manufacturing new TCRs, the therapy utilizes and transfers pre-existing TCRs that the immune system naturally produces, reducing dependency on expensive external R&D resources
3Adaptability or versatility
If endogenous TCRs are used with desired antigen specificity, then the body's natural production is leveraged, but the TCRs must be transferred to patient T cells
Solution Approach 1:
The patent uses viral vectors as intermediaries to transfer endogenous TCR sequences from donor T cells to recipient patient T cells. The viral vector serves as a mediator that carries the TCR sequences and integrates them into the patient's T cell genome, enabling the transfer process while maintaining the desired antigen specificity
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Facilitates the rapid and cost-effective generation of T cells with specific antigen recognition, enhancing the efficacy of adoptive cell therapies by leveraging the body's natural TCR repertoire.
Implementation Method 1
introducing a targeted nuclease that cleaves a target region in exon 1 of a TCR-alpha subunit constant gene (TRAC) to create an insertion site in the genome of the T cell
Implementation Method 2
the nucleic acid sequence is incorporated into the insertion site by homology directed repair (HDR)
Data Source
AI summary
Provided herein are methods and compositions for editing the genome of a human T cell. In some embodiments, a heterologous T cell receptor (TCR)-β chain and a heterologous TCR-α chain are inserted into exon 1 of a TCR subunit constant gene in the genome of the T cell.