N-terminal Fused Bifunctional Polypeptides for pMHC Binding
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Solution Overview
Problem
Existing bifunctional molecules with therapeutic agents fused to the C-terminus of pMHC-binding partners, such as antibodies or T cell receptors, face reduced binding efficiency due to interference with the variable regions, limiting their effectiveness in immune response induction.
Innovation Solution
Bifunctional molecules with immune effector parts fused to the N-terminus of pMHC-binding partners, utilizing linker sequences for flexibility and correct folding, enhance immune response efficacy without compromising binding affinity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic agents are fused to the C-terminus of pMHC-binding partners, then the molecules can deliver therapeutic agents to target cells, but the binding efficiency is reduced due to interference with the variable regions
Solution Approach 1:
The patent inverts the conventional fusion strategy by attaching the immune effector to the N-terminus of the pMHC-binding partner instead of the C-terminus. This reversal positions the therapeutic agent away from the variable regions, eliminating steric interference while maintaining target cell delivery capability. The N-terminal fusion preserves both binding efficiency and therapeutic function simultaneously.
2Productivity
If immune effector parts are fused to enhance immune response efficacy, then the potency in activating cytotoxic T lymphocytes increases, but the structural complexity and potential interference with binding increases
Solution Approach 1:
The patent introduces a linker sequence as an intermediary element between the pMHC-binding partner and the immune effector. This linker acts as a flexible connector that reduces structural complexity by providing a standardized interface, while simultaneously allowing the immune effector to function effectively without interfering with the binding partner's variable regions. The linker mediates between the two functional domains, enabling enhanced immune response with manageable structural complexity.
Data Source
AI summary
A bifunctional polypeptide comprising a specific binding partner for a peptide-MHC epitope, such as an antibody or T cell receptor, and an immune effector, such as an antibody or a cytokine, the immune effector part being linked to the N-terminus of the peptide-MHC binding part.