IL-18 Variants and Fusion Proteins with Reduced IL-18BP Binding
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Solution Overview
Problem
Existing IL-18 treatments for cancer are hindered by the high expression of IL-18 binding protein (IL-18BP) in the tumor microenvironment, which acts as a decoy receptor, inhibiting IL-18-mediated TIL activation and reducing treatment efficacy.
Innovation Solution
Development of variant human IL-18 proteins and fusion proteins with reduced binding to IL-18BP, incorporating specific amino acid substitutions and an albumin binding domain to enhance IL-18 activity and serum half-life, potentially synergizing with IL-12 for enhanced anti-tumor effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type IL-18 is used for cancer treatment, then IL-18 activity is achieved, but binding to inhibitory IL-18BP occurs which reduces treatment efficacy
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid residues in the IL-18 protein sequence (e.g., positions 38, 68, 76, 127, and other variable positions) to create variant IL-18 proteins. These substitutions alter the binding parameters of IL-18 to IL-18BP, reducing the affinity and thereby decreasing the harmful decoy receptor effect while maintaining beneficial IL-18 activity.
Solution Approach 2:
The patent applies local quality by making targeted amino acid substitutions at specific positions within the IL-18 protein structure rather than altering the entire molecule. This allows modification of the binding interface with IL-18BP while preserving the overall structure and function of IL-18, achieving selective reduction of harmful binding without compromising therapeutic activity.
2Object-affected harmful factors
If amino acid substitutions are made to reduce IL-18BP binding, then binding affinity to IL-18BP decreases, but IL-18 activity must be maintained
Solution Approach 1:
The patent systematically varies amino acid parameters at multiple positions in the IL-18 sequence to find substitutions that simultaneously reduce IL-18BP binding affinity while preserving IL-18 receptor binding and biological activity. The patent tests various amino acid types (e.g., hydrophobic, charged, polar) at variable positions to optimize this balance.
Solution Approach 2:
The patent creates IL-18 variants that maintain multiple functions: (1) binding to IL-18 receptor with high affinity, (2) inducing IFN-γ production, (3) activating immune cells, and (4) reduced binding to IL-18BP. The variant proteins are designed to perform multiple therapeutic functions while avoiding the harmful decoy receptor interaction.
Data Source
AI summary
Provided herein are variant human IL-18 (hIL-18) proteins and fusion proteins comprising the variant hIL-18 proteins. Such variant hIL-18 proteins exhibit biological IL-18 activity while having reduced or no detectable binding to inhibitory IL-18BP. Thus, in some embodiments, the variant hIL-18 proteins advantageously retain IL-18 biological activity in the presence of IL-18BP. Such variant hIL-18 and related fusion proteins find use, for example, in the treatment of cancer.