IL-18 Binding Molecules Selective Neutralization
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Solution Overview
Problem
Developing therapeutic molecules that target IL-18 is challenging due to the presence of IL-18 binding protein (IL-18BP), which forms a complex with IL-18, making it difficult to selectively neutralize biologically active IL-18. This requires high doses of therapeutic compounds, leading to potential side effects and increased production costs.
Innovation Solution
A binding molecule that specifically binds to IL-18 without binding to the IL-18/IL-18BP complex, allowing for selective neutralization of biologically active IL-18. This molecule is designed to inhibit IL-18-dependent interferon gamma (INF-γ) production and has a dissociation constant (KD) of 100 pM or less.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic compounds are used to neutralize IL-18, then the biological activity of IL-18 is inhibited, but high doses are required due to the presence of IL-18BP, leading to potential side effects and increased production costs
Solution Approach 1:
The antibody is engineered to recognize a specific local epitope on IL-18 that is sterically hindered when IL-18 is bound to IL-18BP. This localized binding specificity allows the antibody to selectively neutralize free IL-18 while ignoring the IL-18/IL-18BP complex, thereby achieving effective neutralization at lower doses without the need to compete with the abundant IL-18BP inhibitor.
2Reliability
If high doses of therapeutic compounds are administered to overcome IL-18BP inhibition, then IL-18 neutralization is achieved, but side effects and production costs increase
Solution Approach 1:
The antibody's binding specificity is directed toward a particular region of IL-18 that remains accessible only in the free state. This localized recognition ensures that the antibody selectively binds and neutralizes bioactive free IL-18 while leaving the IL-18/IL-18BP complex untouched, thereby achieving therapeutic efficacy at lower doses and minimizing off-target effects and toxicity associated with high-dose therapy.
3Reliability
If therapeutic compounds bind to IL-18 in complex with IL-18BP, then total IL-18 is neutralized, but the cost and complexity of production increase
Solution Approach 1:
The antibody is designed to bind a specific epitope on IL-18 that is occluded or sterically hindered when IL-18 is complexed with IL-18BP. This localized binding preference enables the antibody to selectively target free IL-18, the biologically active form, without requiring binding to the IL-18/IL-18BP complex. This selective mechanism simplifies the therapeutic approach and reduces production costs by avoiding the need to develop compounds capable of displacing or binding to the stable IL-18/IL-18BP complex.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The binding molecule effectively inhibits IL-18-dependent INF-γ production, reducing the biological activity of IL-18 while minimizing the risk of side effects and production costs associated with high-dose therapies.
Implementation Method 1
A binding molecule which binds IL-18 and does not bind the IL-18/IL-18 binding protein (IL-18 BP) complex
Implementation Method 2
This molecule is designed to inhibit IL-18-dependent interferon gamma (INF-γ) production
Data Source
AI summary
IL-18 participates in both innate and acquired immunity. The bioactivity of IL-18 is negatively regulated by the IL-18 binding protein (IL18BP), a naturally occurring and highly specific inhibitor. This soluble protein forms a complex with free IL-18 preventing its interaction with the IL-18 receptor, thus neutralizing and inhibiting its biological activity. The present invention discloses binding molecules, in particular antibodies or fragments thereof, which bind IL-18 and do not bind IL-18 bound to IL-18BP (IL-18/IL-18BP complex). Apart from its physiological role, IL-18 has been shown to mediate a variety of autoimmune and inflammatory diseases. The binding molecules of the inventions may be used as therapeutic molecules for treating IL-18-related autoimmune and inflammatory diseases or as diagnostic tools for characterizing, detecting and/or measuring IL-18 not bound to IL-18BP as component of the total IL-18 pool.