IL-21 Variants with Altered Receptor Binding
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Solution Overview
Problem
Current methods lack IL-21 variants with modulated activity for treating diseases and disorders, particularly in terms of altered binding to the common gamma chain (γc) of the IL-21 receptor, which is crucial for designing effective agonists and antagonists for therapeutic applications.
Innovation Solution
Development of isolated IL-21 peptides with specific mutations in amino acid residues involved in binding to the γc of the IL-21 receptor, allowing for altered activation and binding properties, enabling the creation of both agonists and antagonists for therapeutic use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If IL-21 variants with mutations in amino acid residues are developed to alter binding to γc, then therapeutic options for autoimmune diseases and cancers are provided, but the complexity of protein engineering and characterization increases
Solution Approach 1:
The patent applies parameter changes by systematically mutating specific amino acid residues (e.g., R121D, Y124D in helix D) to alter the binding properties of IL-21 to the common gamma chain. This enables the creation of variants with modified activation levels, providing a range of therapeutic options from agonists to antagonists while managing engineering complexity through focused mutagenesis at key positions.
2Reliability
If IL-21 variants with altered binding to γc are created, then selective modulation of IL-21 receptor activation is achieved, but the difficulty of detecting and measuring binding changes increases
Solution Approach 1:
The patent employs feedback mechanisms by using biacore analysis and other binding assays to measure and characterize the binding properties of IL-21 variants to the common gamma chain. This allows for the optimization of mutations to achieve desired activation levels while providing quantitative data to guide further variant development and ensure reliable selective modulation.
3Reliability
If mutations are introduced in helix D residues corresponding to R121 and Y124, then antagonistic properties are generated similar to IL-4 antagonists, but the loss of agonist activity reduces therapeutic flexibility
Solution Approach 1:
The patent applies local quality by making specific localized mutations in helix D (such as R121D, Y124D) to generate antagonistic properties, while the rest of the protein structure remains intact. This localized approach allows for the creation of variants with specific functions (agonist or antagonist) while maintaining the ability to generate different therapeutic options by modifying only the critical binding region.
Data Source
AI summary
The invention is concerned with IL-21 polypeptide variants having an altered binding to the common gamma chain (c) of the IL-21 receptor and the use thereof in therapy.