Stabilized IL-18 Variants That Resist IL-18BP Inhibition

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), leading to reduced signaling activity.

Innovation Solution

Development of modified IL-18 polypeptides with specific mutations at cysteine residues and additional amino acid substitutions to enhance binding to IL-18 receptor while reducing binding to IL-18BP, resulting in decoy-resistant (DR) and decoy-to-the-decoy (D2D) variants that maintain signaling activity.

Engineering Contradictions & Design Principles

VSEngineering 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 sensitivity to IL-18 binding protein (IL-18BP)

Engineering Contradiction:

Improveclinical efficacyVSAvoidsensitivity to IL-18BP

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by modifying the amino acid sequence of IL-18 at specific positions (including Cysteine-38 and Cysteine-68) to alter its binding characteristics. These sequence modifications change the physical-chemical parameters of the protein, enabling it to resist binding to IL-18BP while maintaining or enhancing binding to the IL-18 receptor, thereby resolving the contradiction between clinical efficacy and sensitivity to IL-18BP

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent applies local quality by making targeted mutations at specific amino acid positions within the IL-18 molecule rather than modifying the entire structure. The mutations at particular locations (Cys-38, Cys-68, and other positions) locally alter the protein's interaction properties with IL-18BP versus the IL-18 receptor, allowing differential binding characteristics that resolve the efficacy-sensitivity contradiction

Inventive Principle:

Principle #3Local quality

2Reliability

If modified IL-18 polypeptides with mutations at Cysteine-38 and Cysteine-68 are developed, then binding to IL-18 receptor is enhanced and binding to IL-18BP is reduced, but the complexity of the protein engineering increases

Engineering Contradiction:

Improvesignaling activityVSAvoidprotein engineering complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent systematically changes amino acid parameters at specific positions to achieve the desired binding profile. By focusing mutations at key positions (Cys-38, Cys-68, and other strategically selected positions), the patent achieves enhanced signaling activity and reduced IL-18BP binding without requiring extensive global modification of the protein structure, thus managing engineering complexity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent applies local quality by making targeted mutations at specific amino acid positions within the IL-18 molecule rather than modifying the entire structure. The mutations at particular locations (Cys-38, Cys-68, and other positions) locally alter the protein's interaction properties with IL-18BP versus the IL-18 receptor, allowing differential binding characteristics that resolve the efficacy-sensitivity contradiction

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS12582701B2Interleukin-18 variants and methods of use

Publication Date: 2026.03.24 SIMCHA IL-18 INC

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.