Antigen-Binding Molecule pH-Dependent Recycling for Reduced Dose
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Solution Overview
Problem
Current antibody pharmaceuticals face challenges in reducing the required dose and prolonging the neutralization effect due to limitations in affinity enhancement and pharmacokinetics, with existing methods unable to completely neutralize antigens with a smaller amount of antibody, and catalytic antibodies have not shown comparable or prolonged effects as pharmaceutical agents.
Innovation Solution
Development of antigen-binding molecules with improved pharmacokinetics and antigen-binding activity by impairing antigen-binding activity at acidic pH compared to neutral pH, specifically through histidine substitution or insertion, allowing for multiple antigen bindings and prolonged retention in plasma, enabling superior in vivo effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antibody affinity to antigen is enhanced through affinity maturation, then antigen-binding ability is improved, but the antibody still cannot neutralize more than a stoichiometric amount of antigen molecules
Solution Approach 1:
The patent introduces pH-dependent binding characteristics by substituting histidine residues into the antibody's antigen-binding region. This causes the antibody to bind strongly at neutral pH (plasma conditions) but dissociate at acidic pH (endosomal conditions), enabling a single antibody molecule to neutralize multiple antigen molecules sequentially rather than being limited to stoichiometric neutralization
Solution Approach 2:
The patent creates a continuous neutralization cycle where the antibody binds antigen in plasma, is internalized into endosomes, dissociates due to acidic pH, and is recycled back to plasma to bind new antigen molecules. This continuous cycle allows one antibody molecule to repeatedly perform its neutralization function, dramatically increasing productivity beyond stoichiometric limits
2Productivity
If catalytic antibodies are used to hydrolyze peptide bonds and inactivate antigens, then multiple antigens can be neutralized, but sufficient catalytic activity has not been achieved for pharmaceutical application
Solution Approach 1:
Instead of trying to create catalytic antibodies that break down antigens (which have proven difficult to achieve with sufficient activity), the patent inverts the approach by creating antibodies that repeatedly bind and release intact antigens through pH-dependent dissociation. This recycling mechanism achieves multiple neutralizations per antibody molecule without requiring catalytic bond-breaking activity
Solution Approach 2:
The patent uses pH as an intermediary mechanism to control antibody-antigen binding and dissociation. The pH change from neutral (plasma) to acidic (endosome) acts as a switch that triggers release of the antigen, allowing the antibody to be recycled without direct catalytic interaction with the antigen's peptide bonds
3Quantity of substance
If the dose of antibody pharmaceutical is reduced to lower production cost and improve subcutaneous formulation, then manufacturing cost is reduced, but the neutralization effect duration is insufficient
Solution Approach 1:
The patent extends the duration of neutralization effect by creating a continuous recycling cycle. Antibodies that would normally be degraded after one binding event are instead released in endosomes and recycled back to plasma for additional binding events. This multiplies the effective duration of action per administered antibody molecule, allowing lower doses to maintain therapeutic effects longer
4Reliability
If conventional antibody pharmaceuticals are administered at high doses to ensure sufficient neutralization, then neutralization efficacy is maintained, but production cost increases and subcutaneous formulation becomes difficult
Solution Approach 1:
The patent modifies the pH sensitivity parameter of the antibody through histidine substitution, enabling the antibody to undergo conformational changes or binding affinity changes at different pH levels. This allows the antibody to be released from antigen in endosomes and recycled, multiplying its neutralization capacity and reducing the required dose for maintaining efficacy
Solution Approach 2:
By establishing a continuous binding-dissociation-recycling cycle, the patent increases the total number of neutralization events per antibody molecule. This reduces the quantity of antibody needed to achieve and maintain therapeutic efficacy, thereby lowering production costs and improving formulation options including subcutaneous administration
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 approach enables antigen-binding molecules to repeatedly bind to multiple antigens, improving pharmacokinetics and exerting more superior in vivo effects than ordinary antigen-binding molecules, allowing for reduced antibody doses and prolonged durability.
Implementation Method 1
antigen-binding molecules with improved pharmacokinetics and antigen-binding activity by impairing antigen-binding activity at acidic pH compared to neutral pH, specifically through histidine substitution or insertion
Data Source
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AI summary
The present inventors discovered that antibodies having weaker antigen-binding activity at the early endosomal pH in comparison with that at the pH of plasma are capable of binding to multiple antigen molecules with a single antibody molecule, have long half-lives in plasma, and have improved durations of time in which they can bind to antigen.