Modified IL-2 Heterodimer for Reduced IL2Rα Toxicity
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Solution Overview
Problem
Current cancer treatments like surgery, chemotherapy, and radiotherapy have limitations, and immunomodulatory factors such as interleukins face systemic toxic side effects, necessitating a more effective and less toxic therapy.
Innovation Solution
A modified IL-2 molecule is developed by substituting regions in the IL-2 molecule that bind to IL2Rα with corresponding regions in IL-15 that bind to IL15Rα, reducing affinity for IL2Rα and enhancing stability, allowing it to form a heterodimer with IL15Rα or its Sushi domain, thereby reducing toxic side effects and promoting NK cell proliferation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immunomodulatory factors (such as interleukins) are used to treat cancer, then antitumor effect is improved, but systemic toxic side effects increase
Solution Approach 1:
The patent applies local quality by modifying specific regions of the IL-2 molecule (substituting residues in the IL2Rα binding region with corresponding IL-15 residues) to change its binding properties locally. This allows the modified IL-2 to selectively bind to IL2/15Rβ and IL2/15Rγ chains while reducing binding to IL2Rα, thereby concentrating its antitumor effect on target cells while minimizing systemic toxicity to other tissues.
Solution Approach 2:
The patent segments the receptor binding function by analyzing and modifying specific residue regions responsible for binding to different receptor chains. By separately optimizing binding to IL2/15Rβ and IL2/15Rγ while reducing binding to IL2Rα, the patent creates a modified IL-2 with segmented binding properties that achieve selective targeting and reduced systemic toxicity.
2Reliability
If IL-2 binds to IL2Rα, then Treg cell proliferation is enhanced, but toxic side effects increase
Solution Approach 1:
The patent applies parameter changes by systematically modifying amino acid residues in the IL-2 molecule structure. Specifically, it substitutes residues in the IL2Rα binding region with corresponding IL-15 residues, which changes the binding affinity parameters. This results in reduced binding to IL2Rα (lowering Treg cell proliferation and associated toxicity) while maintaining binding to IL2/15Rβ and IL2/15Rγ (preserving antitumor activity).
Data Source
AI summary
A modified interleukin-2 (IL-2) molecule is obtained by being subjected to a modification as follows: substituting a region in an IL-2 molecule that mediates the binding of the IL-2 molecule to interleukin-2 receptor alpha (IL2Rα) with a region in an interleukin-15 (IL-15) molecule that mediates the binding of the IL-15 molecule to interleukin-15 receptor alpha (IL15Rα). The region in the IL-15 molecule that mediates the binding of the IL-15 molecule to the IL15Rα includes 9 or more amino acid residues. Furthermore, a protein heterodimer including the modified IL-2 molecule and IL15Rα (a Sushi domain) or a variant thereof is provided. The modified IL-2 molecule and/or the protein heterodimer including the modified IL-2 significantly reduce(s) an affinity of IL2Rα to greatly reduce its side effects in clinical treatment and is promising drug candidate.