Humanized Anti-Stx2 Monoclonal Antibody for Toxin Neutralization
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Solution Overview
Problem
Current therapeutic interventions against Shiga toxin-producing Escherichia coli (STEC) infections, particularly those targeting Shiga toxin (Stx)2, are ineffective and can induce toxin overproduction, and there is a need for humanized antibodies that can effectively neutralize Stx2 without adverse reactions.
Innovation Solution
Development of a humanized monoclonal antibody (Hu-mAb 2-5) with specific VH and VL CDR sequences that effectively bind to Stx2, demonstrating low immunogenicity and high neutralizing efficacy, capable of protecting against hemolytic uremic syndrome (HUS) by mitigating kidney damage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If human and humanized antibodies against Stx2 are used for therapeutic intervention, then neutralization of toxin is achieved, but they have not shown effectiveness in clinical trials and may induce toxin overproduction
Solution Approach 1:
The patent applies parameter changes by modifying the antibody structure through humanization - changing the framework regions from murine to human sequences while preserving the CDR regions. This structural parameter change reduces immunogenicity and improves therapeutic effectiveness, resolving the contradiction between achieving neutralization and avoiding adverse reactions
Solution Approach 2:
The patent creates a humanized copy of the murine antibody by grafting CDR regions onto human framework sequences. This copying approach with modification allows the antibody to maintain its neutralizing function while reducing immunogenicity, thereby improving reliability without inducing harmful effects
2Reliability
If antibiotics are administered to treat STEC infection, then bacterial growth is controlled, but toxin overexpression is induced
Solution Approach 1:
The patent introduces a humanized antibody as an intermediary substance that directly neutralizes the toxin. This intermediary approach bypasses the harmful effect of antibiotics by providing a alternative mechanism - the antibody binds to and neutralizes Stx2 toxin, controlling the infection without inducing toxin overexpression
3Reliability
If mouse monoclonal antibodies are used to neutralize Stx2, then high neutralizing efficacy is achieved, but high immunogenicity causes adverse reactions
Solution Approach 1:
The patent changes the immunological parameters of the antibody by humanizing the framework regions. This parameter change reduces the immunogenicity difference between the antibody and human immune system, allowing high neutralizing efficacy to be maintained while reducing adverse reactions
Solution Approach 2:
The patent applies local quality by preserving the CDR regions (which provide neutralizing function) while changing only the framework regions to human sequences. This localized modification maintains efficacy in the critical binding regions while reducing immunogenicity in the framework regions
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
Hu-mAb 2-5 shows significant in vitro and in vivo neutralization of Stx2, reducing mortality and kidney damage in mouse models, with low potential for adverse reactions, suggesting a promising therapeutic candidate for STEC infections.
Implementation Method 1
Hu-mAb 2-5 shows significant in vitro and in vivo neutralization of Stx2
Data Source
AI summary
The disclosure relates to humanized antibodies (Hu mAb) or antigen-binding fragments thereof that bind to or recognize Shiga toxin (Stx)2, compositions comprising such antibodies or antigen-binding fragments, methods comprising such antibodies or antigen-binding fragments, and methods of using such antibodies or antigen-binding fragments. The Hu mAb or antigen binding fragments thereof that bind to or recognize Stx2 may be used for treating a subject in need thereof to prevent or ameliorate one or more symptoms of Shiga toxin-producing Escherichia coli (STEC) infection in the subject, or to prevent or ameliorate one or more symptoms of hemolytic uremic syndrome (HUS) in the subject.