IL-10 Mutein Engineering for Enhanced Receptor Binding
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Solution Overview
Problem
IL-10 therapies have shown poor clinical efficacy due to low levels of IL-10 reaching the gastrointestinal tract and weak affinity for the IL-10Rβ subunit, limiting its anti-inflammatory and anti-tumor activities.
Innovation Solution
Development of an IL-10 variant with enhanced binding affinity for IL-10Rβ, achieved through yeast surface display engineering, which includes specific amino acid substitutions at positions 18, 92, and 99, resulting in a 1000-fold better receptor binding compared to wild-type IL-10.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type IL-10 is used for therapy, then it can elicit anti-inflammatory responses, but it has weak affinity for IL-10Rβ and low levels reach the gastrointestinal tract, resulting in poor clinical efficacy
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of IL-10 at specific positions (18, 92, and 99) to alter its binding properties. The mutein form with substitutions such as Y18F, I92L, and N99S changes the physical-chemical parameters of the protein, resulting in 1000-fold improved affinity for IL-10Rβ while preserving anti-inflammatory activity
Solution Approach 2:
The patent applies local quality by making targeted amino acid substitutions at specific local positions (18, 92, 99) within the IL-10 molecule. These localized changes in the protein structure specifically enhance receptor binding affinity without compromising the overall function of the cytokine
2Duration of action of moving object
If high doses of PEGylated IL-10 are used to ensure prolonged retention in circulation, then anti-tumor response is boosted, but the treatment complexity and cost increase
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of IL-10 at specific positions (18, 92, and 99) to alter its binding properties. The mutein form with substitutions such as Y18F, I92L, and N99S changes the physical-chemical parameters of the protein, resulting in 1000-fold improved affinity for IL-10Rβ while preserving anti-inflammatory activity
Solution Approach 2:
The patent applies preliminary action by pre-modifying the IL-10 molecule during production to create a mutein with inherently improved pharmacokinetic properties. This preliminary engineering of the cytokine structure eliminates the need for post-administration PEGylation, providing prolonged circulation retention as an intrinsic property of the modified molecule
3Reliability
If IL-10 is administered to treat autoimmune disorders, then anti-inflammatory activity is achieved, but weak binding to IL-10Rβ limits the effective dose and response
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of IL-10 at specific positions (18, 92, and 99) to alter its binding properties. The mutein form with substitutions such as Y18F, I92L, and N99S changes the physical-chemical parameters of the protein, resulting in 1000-fold improved affinity for IL-10Rβ while preserving anti-inflammatory activity
Solution Approach 2:
The patent applies local quality by making targeted amino acid substitutions at specific local positions (18, 92, 99) within the IL-10 molecule. These localized changes in the protein structure specifically enhance receptor binding affinity without compromising the overall function of the cytokine
Data Source
AI summary
The present disclosure relates to modified forms, or muteins, of IL-10, as well as variants thereof, which display improved features as compared to wild-type IL-10. The present invention further relates to the use of such modified forms, or muteins, of IL-10, as well as variants thereof in methods, including therapeutic methods.