Engineered Host Cells for TCR Discovery
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Solution Overview
Problem
There is a need for novel T cell receptors (TCRs) that specifically bind to desired peptide-MHC complexes, particularly those associated with cancer-specific peptides, and technologies to discover such TCRs for effective cancer immunotherapy.
Innovation Solution
Engineered host cells are developed to express functional TCRs, allowing for the identification of TCRs that specifically bind to desired peptide-MHC complexes by using recombinant co-receptors and regulatable surface expression systems, enabling the selection and isolation of TCRs with desired characteristics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional T cell screening methods are used, then existing T cell repertoire can be analyzed, but novel TCRs specific to cancer peptides cannot be identified due to negative selection in the thymus
Solution Approach 1:
The invention segments the T cell system into two distinct parts: (1) a library of diverse TCRs expressed on host cells, and (2) a separate peptide-MHC complex target. This allows independent optimization of TCR diversity in the library while maintaining specific binding capability through screening against cancer peptides, thereby identifying novel specific TCRs that would not exist in conventional thymus-selected T cells.
Solution Approach 2:
The patent introduces engineered host cells as intermediary carriers that express diverse TCR libraries. These host cells serve as a bridge between the abstract concept of TCR diversity and the specific binding requirement, enabling systematic screening to identify TCRs with high affinity for cancer-specific peptide-MHC complexes without being constrained by thymic selection.
2Reliability
If TCRs are introduced into patient T cells for adoptive immunotherapy, then cancer-specific immunity can be achieved, but suitable TCRs with high affinity binders are difficult to obtain
Solution Approach 1:
The invention enables the system to self-optimize by allowing the TCR library to be screened and selected based on their binding characteristics to cancer peptides. The host cells expressing the TCR library serve their own purpose of identifying high-affinity binders through the screening process, eliminating the need for manual selection or complex acquisition procedures.
Solution Approach 2:
The patent changes the key parameter of TCR diversity from the natural thymic distribution to an engineered library composition. This allows the TCR pool to be enriched for specific binding capabilities while maintaining the structural and functional parameters needed for T cell activation and cancer targeting.
3Reliability
If endogenous co-receptors are expressed on T cells, then natural T cell function is maintained, but recombinant co-receptors are needed to ensure proper TCR signaling and function in engineered cells
Solution Approach 1:
The invention extracts the co-receptor function from the natural T cell context and places it into the engineered host cell system. By removing endogenous co-receptors and replacing them with recombinant versions, the patent achieves precise control over co-receptor expression to ensure proper TCR signaling while simplifying the overall system design.
Solution Approach 2:
The recombinant co-receptors expressed in the host cells serve multiple functions: they provide necessary signaling for TCR activation, enable proper peptide-MHC complex binding, and facilitate the screening process. This multi-functionality reduces the need for separate systems and simplifies the overall engineered cell design.
Data Source
AI summary
Provided herein are engineered host cells suitable for expression of functional T cell receptors (TCR) and methods of using these cells to identify TCRs that specifically bind to a desired peptide-major histocompatibility complex (MHC) complex.