Humanized Antibodies Neutralizing C. difficile Toxins
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Solution Overview
Problem
There is an unmet need for effective, non-invasive treatments for C. difficile infections, particularly against antibiotic-resistant strains and high-toxin producing strains, with a requirement for therapeutic antibodies that have reduced immunogenicity while providing high binding affinity and potent neutralization activity for C. difficile toxin A or toxin B.
Innovation Solution
Development of human monoclonal antibodies that bind specifically to C. difficile toxin A or toxin B, with characteristics such as low dissociation constants, potent neutralization activity in vitro, and broad spectrum binding to various toxinotypes, including toxinotypes 0, III, V, XII, and XV, and the creation of bispecific antibodies targeting both toxins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic antibodies are developed to treat C. difficile infections, then treatment effectiveness against toxin-producing strains is improved, but immunogenicity of the antibodies increases
Solution Approach 1:
The patent applies parameter changes by humanizing non-human primate antibodies through modifying amino acid sequences in the variable regions. This involves changing specific parameters (amino acid composition, glycosylation patterns) to reduce immunogenicity while preserving binding affinity and neutralization activity against C. difficile toxins
Solution Approach 2:
The patent uses humanized antibody sequences as an intermediary between non-human primate antibodies (high affinity) and human immune system (low immunogenicity). The humanized variants serve as a mediator that maintains therapeutic effectiveness while reducing harmful immune responses
2Reliability
If antibodies with high binding affinity are developed, then neutralization activity against toxins is improved, but complexity of antibody development increases
Solution Approach 1:
The patent applies preliminary action by first generating antibodies in non-human primates that naturally have high binding affinity, then using phage display technology to select and humanize these antibodies. This preliminary generation of high-affinity antibodies simplifies subsequent humanization efforts compared to de novo design
Solution Approach 2:
The patent uses copying by creating humanized versions of non-human primate antibodies through sequence alignment and transfer of complementarity-determining regions (CDRs). This copying approach preserves the proven high-affinity binding characteristics while adapting the antibody for human use
Data Source
AI summary
Monoclonal antibodies, or antigen-binding fragments thereof, that bind to Clostridium difficile (C. difficile) toxin A or toxin B and methods of using the same to detect or treat C. difficile infections and/or C. difficile-associated disease.