Anti-TSLP Nanobody Engineering for Asthma Treatment
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Solution Overview
Problem
Current biologic treatments for severe asthma that are not Th2-driven are inadequate, and there is a need for new pathways to control non-Th2 inflammatory responses, particularly targeting Thymic stromal lymphopoietin (TSLP) to prevent asthma exacerbations.
Innovation Solution
Development of anti-TSLP nanobodies with specific CDR regions and framework regions, capable of blocking the interaction between TSLP and TSLPR, and produced using expression vectors in host cells like Pichia pastoris, with potential for easy production and high clinical efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If traditional antibody drugs are used to target Th2 pathway, then hypereosinophilic asthma is controlled, but non-Th2-driven asthma cannot be treated
Solution Approach 1:
Instead of targeting downstream Th2 cytokines (IL-5, IL-4, IL-13), the invention targets upstream TSLP, which is produced by epithelial cells and drives both Th2 and non-Th2 inflammatory responses. This upstream targeting approach expands treatment coverage to include non-Th2-driven asthma while maintaining efficacy through blocking the common inflammatory pathway at its origin.
2Ease of manufacture
If nanobodies are used instead of traditional antibodies, then production is simplified and stability is improved, but binding affinity may be reduced
Solution Approach 1:
The invention optimizes nanobody performance by modifying key parameters including extending the CDR3 region to enhance binding affinity, adding glycosylation sites to improve stability and half-life, and engineering disulfide bonds to increase thermal stability. These parameter changes enable nanobodies to achieve both simplified production and high binding affinity comparable to traditional antibodies.
3Adaptability or versatility
If TSLP blocking is implemented, then broad asthma patient population can be treated, but potential off-target effects may increase
Solution Approach 1:
The nanobodies are engineered with highly specific CDR regions that precisely recognize and bind to TSLP's four-helix bundle structure. This localized optimization of binding specificity ensures that TSLP blocking occurs without significant off-target effects, allowing safe treatment of broad patient populations including both Th2-driven and non-Th2-driven asthma.
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 anti-TSLP nanobodies effectively inhibit the proliferation of BaF3/TSLPR-IL7R cells and demonstrate superior blocking activity to existing antibodies, with high yields in fermentation processes, offering a promising treatment for asthma and related inflammatory diseases.
Implementation Method 1
Blocking TSLP may prevent the release of pro-inflammatory cytokines from immune cells
Implementation Method 2
The anti-TSLP nanobodies effectively inhibit the proliferation of BaF3/TSLPR-IL7R cells
Implementation Method 3
produced using expression vectors in host cells like Pichia pastoris, with potential for easy production and high clinical efficacy
Data Source
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AI summary
The present invention provides an anti-TSLP nanobody and a use thereof. The present invention provides an anti-TSLP nanobody, and the present invention also provides a coding sequence encoding the above nanobody, corresponding expression vector and host cell capable of expressing the nanobody, and a method for producing the nanobody of the present invention. The nanobody of the present invention has a good TSLP/TSLPR blocking activity; the nanobody of the present invention is expressed using pichia pastoris, and its fermenter expression yield can reach 17-23 g/L.