Bispecific TNF-α/IL-17A Fusion Protein With Reduced Aggregation
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Solution Overview
Problem
Existing bispecific fusion proteins face challenges such as low expression levels, poor stability, and a tendency to form aggregates, limiting their efficacy in treating inflammation-related diseases like rheumatoid arthritis.
Innovation Solution
A bispecific fusion protein with a bilaterally symmetrical structure, comprising a soluble TNF receptor, a human IgG Fc fragment, and a functional domain binding to IL-17A, is developed to enhance stability and specificity, effectively blocking the signal pathways of both TNF-α and IL-17A.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If existing bispecific fusion proteins are used to target TNF-α and IL-17A, then dual-target therapeutic effect is achieved, but expression levels are low and stability is poor
Solution Approach 1:
The patent employs asymmetric structure design where the Fc region contains amino acid substitutions (e.g., L234A, L235A, P236H) that create structural asymmetry to reduce aggregate formation while maintaining dual-target binding capability. This asymmetric modification specifically addresses the stability issue without compromising the dual-target therapeutic effect.
Solution Approach 2:
The patent modifies specific amino acid parameters in the Fc region (substitutions at positions 234, 235, and 236) to change the physical-chemical properties of the fusion protein. These parameter changes improve stability and reduce aggregation while preserving the ability to bind both TNF-α and IL-17A targets.
2Adaptability or versatility
If existing bisspecific fusion proteins are used, then dual-target binding capability is achieved, but they tend to form aggregates
Solution Approach 1:
The asymmetric amino acid substitutions in the Fc region (L234A, L235A, P236H) create structural features that prevent improper intermolecular interactions, thereby reducing aggregate formation while maintaining the dual-target binding capability.
Solution Approach 2:
The patent converts the potential harm of Fc region interactions into a benefit by introducing specific mutations that redirect the Fc region's properties to reduce aggregation. The modified Fc region now serves to stabilize the fusion protein rather than promote aggregation.
3Adaptability or versatility
If existing bispecific fusion proteins are used, then therapeutic potential is achieved, but production efficiency is limited due to low expression levels
Solution Approach 1:
The amino acid substitutions in the Fc region change the biophysical parameters of the fusion protein, improving its expression levels in mammalian cell systems. These parameter changes enhance productivity while preserving the therapeutic potential of dual-target inhibition.
Data Source
AI summary
The present invention relates to a bispecific fusion protein targeting TNF-α and IL-17A, a polynucleotide encoding same, a preparation method therefor, the use thereof, etc. The bispecific fusion protein targeting TNF-α and IL-17A is a dimer which has a bilaterally symmetrical structure, and comprises, in the order from N-terminal to C-terminal, three structural functional regions: a soluble TNF receptor or a portion thereof, a human IgG Fc fragment, and a functional domain competitively binding to IL-17A or against IL-17A. The fusion protein can effectively bind to both TNF-α and IL-17A, and has the effect of blocking the signal pathway thereof. The fusion protein has a good stability, specificity and biological activity.