Antigen-Binding Molecules with Hinge Mutations for P. gingivalis Neutralization
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Solution Overview
Problem
Porphyromonas gingivalis infections lead to chronic inflammation and systemic diseases, with existing treatments failing to effectively target the bacteria and its exotoxins, resulting in persistent inflammation and associated health issues.
Innovation Solution
Development of human or humanized antigen-binding molecules (ABMs) that specifically bind to Porphyromonas gingivalis, including mutations in the hinge region to resist protease cleavage, allowing effective targeting and neutralization of bacterial virulence factors such as gingipains and hemagglutinins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing treatments are used to target Porphyromonas gingivalis, then some binding activity is achieved, but the treatments fail to effectively neutralize virulence factors and result in persistent inflammation
Solution Approach 1:
The patent modifies the antibody molecule by introducing hinge region mutations (e.g., K22A, K22R) that change the biochemical properties of the antibody to resist protease cleavage. This parameter change in the antibody's structural stability allows it to maintain functional integrity in the presence of bacterial proteases, thereby improving neutralization effectiveness and reducing persistent inflammation.
Solution Approach 2:
The patent exploits the harmful proteolytic environment created by bacterial virulence factors (gingipains) by designing antibodies with modified hinge regions that specifically resist this protease activity. The antibody's modified structure converts the previously harmful proteolytic environment into a beneficial selective pressure, allowing the antibody to stand out and function effectively where ordinary antibodies would be degraded.
2Measurement precision
If antibodies are designed to bind Porphyromonas gingivalis, then binding specificity is improved, but the antibodies are susceptible to protease cleavage that degrades their function
Solution Approach 1:
The patent applies local quality modification by introducing specific mutations only in the hinge region of the antibody molecule while maintaining the integrity of the binding sites (CDR regions). This localized structural change provides protease resistance without compromising the binding specificity achieved through the variable regions, thus resolving the contradiction between binding precision and proteolytic stability.
Solution Approach 2:
The patent segments the antibody molecule into functional regions (variable regions for binding, constant regions for stability, hinge region for flexibility and protease resistance). By independently optimizing each segment - maintaining CDR sequences for specificity while modifying the hinge region for stability - the patent achieves both binding precision and protease resistance simultaneously.
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 ABMs effectively reduce Porphyromonas gingivalis infections, decrease inflammation, and prevent associated systemic diseases by specifically binding to the bacteria and neutralizing key virulence factors, providing a therapeutic solution for conditions like cardiovascular disease, diabetes, and Alzheimer's disease.
Implementation Method 1
human or humanized antigen-binding molecules (ABMs) that specifically bind to Porphyromonas gingivalis
Implementation Method 2
mutations in the hinge region to resist protease cleavage
Data Source
AI summary
Antigen-binding molecules (ABMs) that bind to Porphyromonas gingivalis are described. The ABMs may be human or humanized ABMs. The ABMs find use in treating infections involving P. gingivalis, such as periodontal disease. Also provided are methods of treating or preventing a disorder or disease by administering the ABM.