Natural-State Polypeptide Fusion Molecule Without Flexible Linkers
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Solution Overview
Problem
Current biopharmaceutical macromolecules derived from antibody molecules through protein engineering face risks of immunogenicity due to the use of flexible peptides connecting protein domains, necessitating a method to create molecules closer to their natural state.
Innovation Solution
A fusion protein structure is developed with a polypeptide sequence that connects an antibody single-chain molecule without immune effects to a polypeptide receptor molecule via a flexible linker, forming a multi-domain fusion protein complex molecule that mimics its natural state, using a shorter peptide segment to avoid immunogenicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If flexible peptides are used to connect protein domains in biopharmaceutical macromolecules, then the expression and downstream preparation are facilitated, but the risk of immunogenicity increases
Solution Approach 1:
The patent extracts and removes the flexible peptide linker from the fusion protein structure. Instead of using traditional flexible peptides to connect the scFv domain to other protein domains, the invention directly fuses the C-terminus of scFv to the N-terminus of the next domain, eliminating the immunogenic flexible peptide while maintaining the desired structural connection and facilitating expression.
2Adaptability or versatility
If traditional protein engineering techniques are used to combine multiple protein domains, then the functional versatility is improved, but the natural state of the molecule is lost and immunogenicity increases
Solution Approach 1:
The patent merges multiple protein domains (scFv and other functional domains) into a single continuous polypeptide chain through direct fusion without flexible peptide linkers. This merging approach maintains the functional versatility of combining different domains while creating a molecule that is closer to its natural state, thereby reducing immunogenicity risk.
3Ease of operation
If flexible peptides are used to form scFv structure, then the heavy and light chains are expressed as a single polypeptide, but the structure becomes artificial and immunogenic
Solution Approach 1:
The patent extracts and removes the flexible peptide component from the scFv structure. Instead of relying on flexible peptides to link the variable heavy and light chains, the invention uses direct fusion or alternative linking methods that eliminate the artificial flexible peptide segment, thereby maintaining single-chain expression capability while reducing immunogenicity.
Data Source
AI summary
A multi-domain fusion protein molecule is composed of an antibody single-chain molecule without an immune effect and a polypeptide receptor molecule, which specifically binds to pMHC epitope, or component part thereof or fragment thereof. These protein domains is close to the natural state, can be mixed to form a fusion protein complex molecule having a biological function, and can avoid the risk of immunogenicity caused by introducing artificial flexible peptide chains to link each domain into a single polypeptide chain molecule.