Modified IdeZ Polypeptides for Low-Immunogenic IgG Cleavage
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Solution Overview
Problem
Existing cysteine proteases like IdeS and IdeZ have immunogenicity issues and lower activity against human IgG, particularly IgG1 and IgG2, limiting their therapeutic efficacy and requiring higher doses or immune-suppressive co-administration.
Innovation Solution
Modified IdeZ polypeptides with specific amino acid modifications, such as deletions and substitutions, enhance IgG cysteine protease activity and reduce immunogenicity, achieving higher potency and lower immunogenicity compared to IdeS and IdeZ.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If IdeS or IdeZ is used as a therapeutic agent, then IgG cleavage activity is achieved, but immunogenicity increases leading to anti-drug antibody production
Solution Approach 1:
The patent applies parameter changes by modifying amino acid residues in the IdeZ polypeptide sequence. Specifically, it introduces substitutions at positions 93, 97, 137, 139, 140, 147, 150, 162, 165, 166, 171, 174, 205, 226, 237, 239, 243, 250, 251, 254, 255, 282, 288, 312, 315, 347, and 349, and deletions at positions 64-65 and 71-72. These parameter changes in the protein structure reduce immunogenicity while preserving IgG cleavage activity, thereby resolving the contradiction between therapeutic efficacy and immunogenicity.
2Reliability
If IdeZ is used for IgG cleavage, then activity against IgG1 and IgG2 is achieved, but potency is lower compared to IdeS
Solution Approach 1:
The patent improves potency by introducing specific amino acid substitutions and deletions in the IdeZ polypeptide. The modifications at positions 93 (K→N), 97 (Y→F), 137 (R→K), 139 (Q→R), 140 (E→Q), 147 (E→D), 150 (R→K), 162 (E→K), 165 (K→D), 166 (E→K), 171 (Y→H), 174 (T→N), 205 (K→R), 226 (D→N), 237 (F→Y), 239 (E→K), 243 (K→R), 250 (S→T), 251 (E→K), 254 (E→K), 255 (K→R), 282 (D→E), 288 (K→R), 312 (K→R), 315 (K→R), 347 (Q→N), and 349 (N→K), along with deletions at 64-65 and 71-72, enhance the catalytic efficiency and binding affinity of IdeZ for IgG1 and IgG2, thereby increasing productivity while maintaining activity against these subclasses.
3Reliability
If higher doses of IdeS are administered to overcome immunogenicity, then therapeutic effect is maintained, but adverse immune responses increase
Solution Approach 1:
The patent resolves this contradiction by fundamentally changing the immunogenicity parameter of the therapeutic agent through amino acid modifications. The modified IdeZ polypeptide with substitutions and deletions at multiple positions exhibits reduced immunogenicity, allowing administration at lower doses while maintaining therapeutic effect and minimizing adverse immune responses such as anti-drug antibody production and hyper-inflammatory reactions.
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 modified IdeZ polypeptides effectively cleave human IgG, particularly IgG1 and IgG2, with increased potency and reduced immunogenicity, allowing for lower doses and fewer adverse immune responses.
Implementation Method 1
IdeS is an extracellular cysteine protease produced by the human pathogen S. pyogenes. IdeS catalyses a single proteolytic cleavage in the lower hinge region of the heavy chains of all subclasses of human IgG.
Data Source
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 and in vitro generation of F(ab′)2 fragments.