Single-Chain TRβC Chimeric Polypeptides for Specific Antigen Binding
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Solution Overview
Problem
Current technologies do not effectively utilize the T cell receptor β-chain constant region domains (TRβC1 and TRβC2) as scaffolds for chimeric polypeptides to target specific antigens, limiting the therapeutic potential for immune cell stimulation and cancer treatment.
Innovation Solution
Development of single-chain chimeric polypeptides comprising a first target-binding domain, a soluble T cell receptor β-chain constant region (TRβC) domain, and a second target-binding domain, which can be used to stimulate immune cells and treat various diseases, including cancer, by specifically binding to target antigens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cell receptor β-chain constant region domains are used as scaffolds for chimeric polypeptides, then immune cell stimulation and cancer treatment efficacy are improved, but the structural complexity and manufacturing difficulty increase
Solution Approach 1:
The chimeric polypeptide is divided into distinct functional domains: a target-binding domain (such as antibody variable regions or single-chain variable fragments) and a T cell receptor β-chain constant region domain. This segmentation allows each domain to perform its specific function independently while maintaining overall structural organization, thereby improving therapeutic efficacy without overwhelming complexity
Solution Approach 2:
The T cell receptor β-chain constant region domain serves multiple functions: it provides structural stability, enables immune cell recognition and binding, and facilitates signal transduction. This multi-functionality reduces the need for additional separate components, balancing therapeutic efficacy with manageable structural complexity
2Measurement precision
If single-chain chimeric polypeptides are developed with multiple target-binding domains, then specificity and affinity for target antigens are improved, but the manufacturing precision requirements increase
Solution Approach 1:
Multiple target-binding domains are merged into a single polypeptide chain connected by flexible linkers. This merging approach maintains high antigen binding specificity through the combined affinity of multiple domains while using the linker regions to absorb some manufacturing variability, thereby reducing the strict precision requirements compared to separate multi-component systems
Solution Approach 2:
The design allows for variation in linker length and composition parameters without significantly impacting the overall binding specificity. By making these linker parameters adjustable, the system can tolerate certain manufacturing variations while maintaining the required antigen binding precision through optimization of other critical parameters
Data Source
AI summary
Provided herein are single-chain chimeric polypeptides that include: (i) a first target-binding domain; (ii) a soluble T cell receptor β-chain constant region (TRβC) domain; and (iii) a second target-binding domain. Also provided here are methods of making and using these single-chain chimeric polypeptides and nucleic acids encoding these single-chain chimeric polypeptides.