Split Interleukin Mimetics for Targeted Receptor Binding
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Solution Overview
Problem
Existing approaches to enhance the therapeutic properties of central immune cytokines like IL-2 and IL-4 for cancer treatment are limited by issues such as low stability and undesirable binding to specific receptor subunits.
Innovation Solution
Development of non-naturally occurring conditionally active receptor agonists comprising two polypeptide components (X1 and X2, X3 and X4) that interact to form active agonists of IL-2 or IL-4 receptors, overcoming individual receptor binding limitations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mutation and chemical modification approaches are used to improve therapeutic properties of IL-2 and IL-4, then therapeutic potential is enhanced, but undesirable binding to receptor subunits (IL-2Rα, IL-4Rα, IL-13Rα) cannot be eliminated
Solution Approach 1:
The patent divides the interleukin molecule into separate polypeptide components (e.g., IL-2 divided into components that bind to IL-2Rβ and IL-2Rγ separately). This segmentation allows each component to be optimized for specific receptor subunit binding, eliminating unwanted binding to other subunits like IL-2Rα while maintaining therapeutic activity through reconstitution of the complete receptor complex.
2Stability of the object's composition
If native IL-2 or IL-4 structures are used, then natural receptor binding is maintained, but stability is low
Solution Approach 1:
The patent modifies physical and chemical parameters of the interleukin molecules, including amino acid sequence mutations, peptide bond modifications, and structural conformational changes. These parameter changes enhance molecular stability and resistance to degradation while preserving or optimizing binding affinity for target receptor subunits through rational design of the separate polypeptide components.
3Adaptability or versatility
If fusion protein approaches are used to create conditionally active agonists, then specificity is improved, but device complexity increases
Solution Approach 1:
Instead of creating complex fusion proteins, the patent uses segmentation to divide the agonist into separate polypeptide components that can independently function and then reconstitute activity. This approach achieves conditional activation and targeting specificity through the modular nature of the separate components binding to different receptor subunits, rather than through complex fused structures.
Data Source
AI summary
Conditionally active receptor agonists that, when activated, bind to IL-2 receptor βc heterodimer (IL-2Rβc), IL-4 receptor αcheterodimer (IL-4Rαc), or IL-13 receptor α subunit (IL-13Rα) are disclosed, as are components of the conditionally active receptor agonists and methods for using the conditionally active receptor agonists.