Modified IdeS Polypeptide Reducing Immunogenicity
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Solution Overview
Problem
IdeS, a cysteine protease with high IgG cleaving activity, is immunogenic, leading to reduced efficacy and potential harmful immune responses due to the production of anti-drug antibodies, limiting its therapeutic use for diseases mediated by IgG.
Innovation Solution
A novel polypeptide with enhanced IgG cysteine protease activity, derived from IdeS and IdeZ sequences, is developed, which is less immunogenic and maintains or exceeds the cleaving efficiency of IdeS, allowing for effective treatment of IgG-mediated diseases with reduced immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If IdeS is used as a therapeutic agent, then IgG cleaving activity is achieved, but immunogenicity increases leading to reduced efficacy and harmful immune responses
Solution Approach 1:
The patent creates a modified copy of the IdeS protein by introducing specific amino acid substitutions (H84N, N138R, A147E, D150R, N162E, N171Y, N205K, D226N, Q251E, E255K, A312K, S349N) to reduce immunogenicity while preserving IgG cleaving activity. This modified polypeptide is a variant copy that maintains therapeutic function but reduces harmful immune responses
Solution Approach 2:
The patent changes the amino acid sequence parameters of IdeS through multiple substitutions to alter its immunogenic properties. By modifying specific residues (e.g., H84N, N138R), the protein's antigenic characteristics are changed while maintaining its catalytic function, thus reducing immunogenicity without sacrificing therapeutic efficacy
2Reliability
If higher doses of IdeS are administered to overcome immunogenicity, then therapeutic effect may be maintained, but quantity of anti-drug antibodies increases precluding further administration
Solution Approach 1:
The modified polypeptide serves as an improved copy that inherently produces fewer anti-drug antibodies compared to wild-type IdeS. This allows for repeat administrations at effective doses without the accumulating antibody problem that would preclude further treatment
3Adaptability or versatility
If IdeS is used for in vivo treatment, then IgG-mediated diseases can be treated, but immune complexes of ADA and IdeS trigger hyper-inflammatory response
Solution Approach 1:
The modified polypeptide copy reduces the formation of harmful immune complexes by being less recognizable to the immune system. This prevents the hyper-inflammatory response that would otherwise be triggered by immune complex formation, enabling safe in vivo therapeutic use
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 novel polypeptide effectively cleaves IgG molecules, reducing the need for higher doses and minimizing immune reactions, thereby improving therapeutic outcomes for autoimmune diseases and organ transplantation by efficiently cleaving IgG antibodies.
Implementation Method 1
IdeS catalyses a single proteolytic cleavage in the lower hinge region of the heavy chains of all subclasses of human IgG
Data Source
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AI summary
The present invention relates to a novel polypeptide which displays IgG cysteine protease activity, and in vivo and ex vivo uses thereof. Uses of the polypeptide include methods for the prevention or treatment of diseases and conditions mediated by IgG, and methods for the analysis of IgG.