Antigen-Binding Molecule pH-Dependent Dynamics Plasma Clearance
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Solution Overview
Problem
Current antibody drugs face challenges in efficiently promoting antigen clearance from plasma, as they often require high doses and have limited affinity, leading to incomplete neutralization and increased antigen plasma retention, which complicates pharmacokinetic improvements and antigen-neutralizing effects.
Innovation Solution
Development of an antigen-binding molecule with an antigen-binding domain, an FcRn binding domain, and a sugar chain receptor-binding domain, designed to have altered binding activities based on ion-concentration conditions, particularly pH and calcium-ion concentrations, to enhance antigen uptake into cells and decrease plasma antigen concentrations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional antibodies are used for antigen neutralization, then antigen-binding ability is achieved, but the amount of antibody required exceeds the amount of antigen produced in vivo, limiting dose reduction
Solution Approach 1:
The patent applies pH-dependent binding dynamics to enable antibodies to bind antigens strongly at neutral pH in plasma and dissociate at acidic pH in endosomes. This dynamic binding behavior allows one antibody molecule to neutralize multiple antigen molecules over time, reducing the required antibody dose while maintaining reliable neutralization effect
Solution Approach 2:
The patent changes the binding parameter of the antibody by engineering pH-dependent binding characteristics. The antibody is designed to exhibit strong binding affinity at neutral pH (plasma condition) and weak binding affinity at acidic pH (endosome condition), enabling repeated antigen neutralization cycles and reducing the quantity of antibody needed
2Duration of action of stationary object
If antibodies with long plasma retentivity bind to antigens, then plasma retention time increases, but antigen clearance from plasma is inhibited
Solution Approach 1:
The patent exploits pH parameter changes between plasma (neutral pH) and endosome (acidic pH) environments. The antibody binds antigen at neutral pH but dissociates at acidic pH, enabling the antibody to remain in plasma with long retentivity while simultaneously promoting antigen clearance through endosomal uptake and dissociation cycles
3Reliability
If affinity maturation techniques are used to enhance antigen-binding ability, then antigen-neutralizing ability improves, but the stoichiometric limitation remains at one antigen molecule per antibody molecule
Solution Approach 1:
The patent introduces pH-dependent dynamic binding behavior that allows the antibody to release and rebind antigen molecules multiple times. This overcomes the stoichiometric limitation of conventional antibodies by enabling one antibody molecule to neutralize multiple antigen molecules through repeated binding-dissociation cycles in different pH environments
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 antigen-binding molecule effectively increases the number of antigens bound per molecule, promotes antigen clearance from plasma, and improves pharmacokinetics by altering binding activities in response to environmental conditions, allowing for repeated antigen binding and efficient plasma antigen reduction.
Implementation Method 1
an antibody binding to an antigen in a pH-dependent manner has been reported recently as a novel approach (Patent Literature 1). This pH-dependent antigen-binding antibody is strongly associated with an antigen under the neutral condition in plasma and dissociated from the antigen under the acidic condition in endosome.
Implementation Method 2
The pH dependent antigen-binding antibody thus dissociated from the antigen can be reassociated with an antigen after being recycled into plasma by FcRn.
Implementation Method 3
an antigen-binding molecule containing a binding domain to a sugar chain receptor... can promote uptake of an antigen into a cell
Data Source
AI summary
Disclosed are an antigen-binding molecule containing a sugar chain receptor-binding domain and having a weak antigen-binding activity in the pH of early-stage endosome compared to the antigen-binding activity in the pH of plasma; a pharmaceutical composition containing the antigen-binding molecule; and a method for producing these. Use of the antigen-binding molecule of the invention enables to promote uptake of an antigen into a cell and increase the number of antigens that a single antibody molecule can bind. Administration of the antibody enables to reduce the number of antigens in plasma more and more and improve pharmacokinetics of the antibody.