IL-18 Variant Polypeptides That Evade IL-18BP Neutralization
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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 neutralization by IL-18 binding protein (IL-18BP).
Innovation Solution
Development of IL-18 variant polypeptides that specifically bind to IL-18 receptor (IL-18R) while exhibiting substantially reduced binding to IL-18BP, or IL-18BP inhibitors that bind to IL-18BP to prevent its neutralization of endogenous IL-18.
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 neutralization by IL-18BP
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of IL-18 to create variants with altered binding properties. Specifically, mutations are introduced to reduce affinity for IL-18BP while maintaining or enhancing affinity for IL-18R, thereby changing the interaction parameters between IL-18 and its binding partners to overcome neutralization and improve clinical efficacy
Solution Approach 2:
The patent applies local quality by making specific localized changes to the IL-18 molecule at particular amino acid positions (such as residues in the binding interface regions). These localized mutations affect only specific interaction surfaces - reducing binding to IL-18BP at certain sites while preserving or enhancing binding to IL-18R at other sites, thus achieving differential binding properties through local modifications
2Duration of action of stationary object
If IL-18 variant polypeptides with reduced binding to IL-18BP are developed, then sustained IL-18 signaling activity is achieved, but the complexity of developing and characterizing variants increases
Solution Approach 1:
The patent applies preliminary action by pre-selecting and testing multiple IL-18 variant sequences in vitro before clinical use. The inventors performed preliminary screening of variants with specific mutations to identify those with desirable binding properties (reduced IL-18BP binding, maintained IL-18R binding) and sustained signaling activity, thereby resolving the complexity issue through advance characterization and selection
Solution Approach 2:
The patent applies copying by creating multiple copies of IL-18 with different amino acid substitutions and systematically evaluating them. Rather than developing one complex variant through trial and error, multiple variant copies were generated with predicted beneficial mutations, allowing parallel evaluation and selection of the most effective variant with sustained signaling activity
Data Source
AI summary
The present invention provides compositions and methods comprising an activator of interleukin-18 (IL-18) activity for use in therapeutic and non-therapeutic applications. The activator provides IL-18 signaling activity even in the presence of an inhibitory molecule 5 such as IL-18 binding protein (IL-18BP).