Bispecific TNF-α/IL-17A Fusion Protein to Reduce 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 effectiveness 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, designed to inhibit both TNF-α and IL-17A signaling pathways, featuring improved stability and specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing bispecific fusion proteins are used to target TNF-α and IL-17A, then dual-pathway inhibition is achieved, but expression levels are low and stability is poor
Solution Approach 1:
The patent combines TNF-α and IL-17A binding domains into a single fusion protein molecule, creating a bispecific protein that simultaneously targets both inflammatory pathways. This merging approach allows dual functionality while improving overall protein stability and expression levels compared to separate single-specific proteins
Solution Approach 2:
The fusion protein employs a composite structure combining different domain types (TNF-α binding domain, IL-17A binding domain, and Fc region) to create a molecule with enhanced stability and expression characteristics that surpass individual domains
2Reliability
If existing bispecific fusion proteins are used to target TNF-α and IL-17A, then dual-pathway inhibition is achieved, but aggregate formation increases
Solution Approach 1:
The patent optimizes critical parameters including domain sequence selection, linker region design, and Fc region configuration to minimize hydrophobic interactions and promote proper folding. These parameter changes reduce aggregate formation while maintaining dual-pathway inhibition capability
Solution Approach 2:
The Fc region serves as an intermediary element that mediates proper protein folding and solubility. This intermediary domain helps prevent aggregate formation by providing a stable structural framework that facilitates correct conformation of the binding domains
3Reliability
If single-target biologic drugs are used for treatment, then specific pathway inhibition is achieved, but response is lost over time and efficacy diminishes
Solution Approach 1:
The bisspecific fusion protein performs multiple functions by simultaneously inhibiting both TNF-α and IL-17A pathways. This multi-functionality addresses the limitation of single-target drugs by providing broader and more sustained therapeutic effect, reducing the likelihood of secondary loss of response
Solution Approach 2:
By targeting two parallel inflammatory pathways concurrently, the fusion protein ensures continuous therapeutic action even if one pathway becomes less relevant over time. This continuous dual-pathway inhibition maintains treatment efficacy throughout the duration of therapy
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
The fusion protein effectively blocks the synergistic effects of TNF-α and IL-17A, exhibiting good biological activity, stability, and reduced aggregate formation, making it suitable for treating inflammation-related diseases.
Implementation Method 1
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
Data Source
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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.