T-Cell Receptor Screening Using Barcoded Antigen Pairing
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Solution Overview
Problem
Identifying and redesigning T-cell receptors for therapeutic applications is difficult and inefficient, requiring significant effort to match specific antigens and ligands.
Innovation Solution
A high-throughput analysis method using compositions and methods to screen diverse immune cell receptor repertoires against ligand libraries, associating each nucleic acid with barcodes to identify interacting pairs, and engineering receptors with intracellular activation domains for macrophage phagocytosis or trogocytosis to segregate antigens/ligands.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional methods are used to identify and redesign T-cell receptors for therapeutic applications, then the process is thorough and reliable, but the process is time-consuming and inefficient
Solution Approach 1:
The patent segments the T-cell receptor identification process into distinct functional modules: (1) displaying diverse TCR repertoires on phagocytic cells, (2) presenting antigen libraries on target cells, (3) performing high-throughput screening through phagocytosis or trogocytosis, and (4) recovering and characterizing interacting pairs. This segmentation enables parallel processing of multiple TCR-antigen combinations simultaneously, dramatically reducing identification time while maintaining reliability through systematic validation at each stage.
Solution Approach 2:
The patent replaces traditional mechanical sorting and manual characterization methods with high-throughput functional screening. By using phagocytic or trogocytic activity as a natural selection mechanism, the system automatically identifies interacting TCR-antigen pairs without manual intervention. The intrinsic biological function of phagocytosis serves as the selection criterion, eliminating the need for time-consuming manual sorting and enrichment steps while preserving identification accuracy.
2Productivity
If diverse immune cell receptor repertoires are screened against ligand libraries using high-throughput analysis, then the identification efficiency is improved, but the complexity of the screening system increases
Solution Approach 1:
The patent employs self-service mechanisms where the biological systems perform the screening function inherently. Phagocytic cells automatically engulf target cells presenting matching antigens, and trogocytosis naturally occurs when TCRs bind to MHC-antigen complexes. These intrinsic biological behaviors serve as the screening criterion, eliminating the need for complex external sorting devices or artificial selection systems. The system uses the cells' own functional properties to drive the screening process, simplifying the overall apparatus while enabling high-throughput analysis.
Solution Approach 2:
The patent uses universal phagocytic or trogocytic mechanisms that can screen against diverse TCR repertoires and various antigen types simultaneously. The same basic screening platform works for different immune cell types, different MHC classes, and different antigen presentations. This multi-functionality allows a single system design to handle multiple screening scenarios without requiring separate specialized equipment for each case, reducing overall system complexity while maintaining high productivity.
3Measurement precision
If barcodes are associated with each nucleic acid encoding receptors and ligands, then the identification precision of interacting pairs is improved, but the complexity of data analysis increases
Solution Approach 1:
The patent creates physical copies of identification information by associating barcodes directly with the nucleic acids encoding TCRs and antigens. Each TCR gene is linked to a unique barcode sequence, and each antigen gene is linked to its corresponding barcode. When TCR-antigen interactions occur, the barcodes are physically present in the same cell or nucleic acid pool, enabling direct correlation without complex computational mapping. The barcode information is copied into the biological system itself, allowing precise identification through simple sequence matching rather than complex data analysis.
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 rapid identification and characterization of receptor-ligand pairs, enabling efficient therapeutic applications by enhancing the immune response through engineered immune cells.
Implementation Method 1
engineered receptors with intracellular activation domains for macrophage phagocytosis or trogocytosis to segregate antigens/ligands
Implementation Method 2
engineered receptors with intracellular activation domains for macrophage phagocytosis or trogocytosis to segregate antigens/ligands
Data Source
AI summary
The disclosure relates generally to the field of T-cell receptors or T-cell receptor mimics, and methods for obtaining novel T-cell receptors or novel T-cell receptor mimics. The compositions and methods described identify pairs of T-cell receptors and antigens. The compositions and methods allow high throughput analysis so that many antigens can be paired with a large repertoire of T-cell receptors.