IL-18 Mimic Decoy-Resistant Variants Overcome IL-18BP Inhibition

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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 signaling activity being inhibited by the IL-18 binding protein (IL-18BP).

Innovation Solution

Development of IL-18 mimics, specifically decoy-resistant (DR) and decoy-to-the-decoy (D2D) variants that either bind to the IL-18 receptor while resisting IL-18BP inhibition or bind to IL-18BP to antagonize its effect, thereby enhancing IL-18 signaling activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If IL-18 is used as an immunotherapeutic agent to stimulate anti-tumor immune cells, then immune activity and anti-tumor responses are enhanced, but signaling activity is inhibited by IL-18BP

Engineering Contradiction:

Improveclinical efficacyVSAvoidinhibition by IL-18BP

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent creates IL-18 mimics that are structurally unrelated to native IL-18 but replicate its binding properties and binding sites. These mimics copy the functional characteristics of IL-18 variants while avoiding recognition by IL-18BP, thereby achieving therapeutic efficacy without decoy-mediated inhibition

Inventive Principle:

Principle #26Copying

Solution Approach 2:

The patent develops IL-18 mimics with altered structural parameters compared to native IL-18. By changing the protein topology and amino acid sequence while maintaining key binding properties, the mimics achieve resistance to IL-18BP inhibition while preserving immune cell stimulation capability

Inventive Principle:

Principle #35Parameter changes

2Reliability

If IL-18 variants with high sequence identity to wild type IL-18 are used, then binding properties are maintained, but they remain susceptible to IL-18BP inhibition

Engineering Contradiction:

Improvebinding propertiesVSAvoiddecoy binding

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

Instead of using IL-18 variants with high sequence identity, the patent employs IL-18 mimics that are structurally unrelated to native IL-18. These mimics copy only the essential binding properties and sites required for immune cell activation, thereby decoupling binding function from decoy recognition

Inventive Principle:

Principle #26Copying

Solution Approach 2:

The IL-18 mimics are designed to preserve local binding properties at the interaction interface with immune cells while having globally different structure and sequence. This localized preservation of binding capability allows maintenance of therapeutic function without the penalty of overall sequence similarity that leads to decoy binding

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS20240374679A1Interleukin-18 mimics and methods of use

Publication Date: 2024.11.14 YALE UNIVERSITY

AI summary

The present disclosure provides methods of making and methods of using IL-18 mimic polypeptides for use in therapeutic and non-therapeutic applications. The synthetic IL-18 mimics an increase IL-18R signaling activity even in the presence of an inhibitory molecule such as IL-18BP.