Decoy-Resistant IL-18 Variants for IL-18BP-Blocked Signaling
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Solution Overview
Problem
The clinical efficacy of interleukin-18 (IL-18) as an immunotherapeutic agent for cancer treatment is limited due to its sensitivity to IL-18 binding protein (IL-18BP), which inhibits its signaling activity.
Innovation Solution
Development of modified IL-18 polypeptides with specific mutations, such as substitutions at Cysteine-38 and Cysteine-68, and additional amino acid changes, to create decoy-resistant (DR) IL-18 variants that specifically bind to IL-18 receptor but exhibit reduced binding to IL-18BP, thereby promoting effective signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type IL-18 is used as an immunotherapeutic agent, then it can stimulate anti-tumor immune cells, but its clinical efficacy is limited due to inhibition by IL-18 binding protein
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of IL-18 through specific mutations (such as C38S/C68S, C38S/C68G, and other combinations listed in SEQ ID NOs: 89-91). These mutations alter the binding characteristics of IL-18, reducing its affinity for IL-18BP while maintaining or enhancing its affinity for the IL-18 receptor, thereby overcoming the inhibitory effect of IL-18BP and improving clinical efficacy
Solution Approach 2:
The patent applies local quality by making specific localized changes at particular amino acid positions (Cysteine-38 and Cysteine-68) within the IL-18 molecule. These localized mutations specifically affect the interaction interface with IL-18BP, creating a differentiated binding profile that selectively reduces inhibition while preserving receptor activation capability
2Reliability
If modified IL-18 polypeptides with mutations at Cysteine-38 and Cysteine-68 are developed, then binding to IL-18BP is reduced, but the molecular structure becomes more complex
Solution Approach 1:
The patent applies parameter changes by introducing specific point mutations at defined positions (C38 and C68) rather than extensive modifications. These targeted changes achieve the desired functional outcome (reduced IL-18BP binding) with minimal structural alteration, maintaining relatively simple polypeptide structures that are easier to produce and characterize
Solution Approach 2:
The patent applies local quality by confining mutations to specific critical residues (Cysteine-38 and Cysteine-68) that are key to IL-18BP interaction. This localized approach achieves high decoy resistance through minimal structural changes, avoiding the need for complex extensive modifications throughout the molecule
Data Source
AI summary
The present disclosure provides compositions and methods comprising stabilized IL-18 polypeptides for use in therapeutic and non-therapeutic applications. In some cases, the stabilized IL-18 proteins provide IL-18 signaling activity even in the presence of an inhibitory molecule such as IL-18BP. Also provide are methods of administration and methods for making active polypeptides.