IdeSORK2.0 Immunoglobulin-Cleaving Enzyme for Human IgG
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Solution Overview
Problem
Existing immunoglobulin cleaving enzymes like IdeS and IdeZ face limitations due to pre-existing antibodies in human subjects, reducing their therapeutic utility, and IdeZ has lower cysteine protease activity against human IgG, particularly IgG2.
Innovation Solution
Identification and characterization of a novel polypeptide, IdeSORK2.0, from Streptococcus krösus, with enhanced expression and immunoglobulin cleaving activity, and minimal pre-existing immunity in humans, allowing for effective IgG cleavage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If IdeS is used as a therapeutic agent, then IgG cleavage activity is achieved, but pre-existing anti-IdeS antibodies reduce its utility
Solution Approach 1:
The invention segments the IdeS protein by removing the immunogenic C-terminal region (amino acids 231-375) to create IdeSΔC. This segmentation eliminates the harmful pre-existing antibodies while preserving the essential IgG cleavage function located in the N-terminal region, thereby resolving the contradiction between therapeutic utility and antibody interference
Solution Approach 2:
The invention extracts and removes the problematic C-terminal domain of IdeS that is responsible for immunogenicity. By taking out this specific portion (amino acids 231-375) and creating a truncated version, the patent eliminates the harmful factor (pre-existing antibodies) while maintaining the core functional benefit (IgG cleavage activity)
2Object-affected harmful factors
If IdeZ is used as an alternative to IdeS, then pre-existing immunity is reduced, but cysteine protease activity against human IgG is considerably lower
Solution Approach 1:
The invention applies local quality modification by selectively modifying only the C-terminal region of IdeS (removing amino acids 231-375) while preserving the N-terminal catalytic domain. This localized modification reduces immunogenicity without affecting the protease activity, thereby resolving the contradiction between reducing pre-existing immunity and maintaining productivity
Solution Approach 2:
The invention changes the structural parameter of the IdeS protein by truncating it to 230 amino acids. This parameter change (length reduction) modifies the protein's immunogenic properties while preserving its catalytic function, effectively resolving the contradiction between reducing pre-existing immunity and maintaining protease activity
3Reliability
If full-length IdeS is used, then IgG cleavage function is complete, but immunogenicity and therapeutic utility are reduced
Solution Approach 1:
The invention segments the full-length IdeS protein into functional and immunogenic regions, retaining only the functional N-terminal portion (amino acids 1-230) and discarding the immunogenic C-terminal portion (amino acids 231-375). This segmentation strategy resolves the contradiction by preserving therapeutic utility while eliminating immunogenicity
Solution Approach 2:
The invention extracts and removes the harmful C-terminal immunogenic domain from the full-length IdeS protein. By taking out amino acids 231-375, the patent creates a truncated version that maintains IgG cleavage function while reducing immunogenicity, thereby resolving the contradiction between therapeutic utility and immunogenicity
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
IdeSORK2.0 efficiently cleaves human IgG into Fc and F(ab')2 fragments with minimal interference from human antibodies, providing a viable therapeutic option for conditions mediated by IgG.
Implementation Method 1
IdeSORK2.0 efficiently cleaves human IgG into Fc and F(ab')2 fragments
Data Source
AI summary
The present invention relates to a novel polypeptide which displays protease activity against immunoglobulins, particularly human IgG, and in vivo, in vitro and ex vivo uses thereof. Uses of the polypeptide include methods for the analysis of IgG and the generation of antibody fragments, as well as methods for the prevention or treatment of diseases and conditions mediated by IgG.