pH-Dependent Antibody Library for Antigen Clearance
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Solution Overview
Problem
Current antibody drugs face challenges in subcutaneous administration, high production costs, and limited ability to neutralize antigens below the antigen's amount, with existing methods unable to completely clear antigens from plasma efficiently.
Innovation Solution
Development of a library of antigen-binding molecules with calcium-dependent or pH-dependent antigen-binding activity, allowing for enhanced cellular uptake and reduced antigen concentration in plasma, utilizing amino acid residues in specific positions of the antigen-binding domain to change binding activity based on ion concentration conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional antibodies are used for antigen neutralization, then antigen-binding activity is achieved, but the ability to neutralize antigens below the antigen's amount is limited
Solution Approach 1:
The patent applies dynamics by making the antibody's binding activity conditional rather than static. The antibody exhibits high affinity for antigen at neutral pH (plasma conditions) but low affinity at acidic pH (endosome conditions), allowing it to dynamically adjust its binding state based on environmental pH. This enables one antibody molecule to bind multiple antigen molecules sequentially during circulation, overcoming the stoichiometric limitation of conventional antibodies.
Solution Approach 2:
The patent changes the binding parameter (affinity) based on pH conditions. By introducing histidine residues at specific positions in the antigen-binding domain, the antibody's binding affinity becomes pH-dependent. At neutral pH 7.4, the antibody binds antigen with high affinity, while at acidic pH 5.0-6.0, the binding affinity decreases, allowing dissociation. This parameter change enables enhanced antigen neutralization efficiency.
2Ease of manufacture
If antibody doses are reduced to lower production cost, then production cost decreases, but pharmacokinetics and antigen-neutralizing effect are compromised
Solution Approach 1:
The patent modifies the binding parameter (affinity) to be pH-dependent through histidine residue introduction, allowing the antibody to maintain high antigen-neutralizing effectiveness at lower doses. The pH-dependent binding enables extended functional activity during circulation.
Solution Approach 2:
The patent achieves continuity of useful action by enabling the antibody to repeatedly bind and release antigens during circulation. The antibody binds antigen at neutral pH in plasma, gets internalized into endosomes, releases antigen at acidic pH, and is recycled back to plasma to bind more antigens. This continuous cycle allows one antibody molecule to neutralize multiple antigen molecules over time, improving pharmacokinetic efficiency.
3Reliability
If affinity maturation is performed to enhance antigen-binding ability, then antigen-binding activity increases, but the stoichiometric limitation remains
Solution Approach 1:
The patent applies dynamics by making the binding activity conditional rather than static. The antibody exhibits high affinity at neutral pH but low affinity at acidic pH, allowing it to dynamically switch between bound and unbound states. This enables one antibody to sequentially neutralize multiple antigens during circulation, overcoming the stoichiometric limitation of conventional high-affinity antibodies.
Solution Approach 2:
The patent implements periodic action through cyclic binding and release of antigens. The antibody binds antigen during circulation at neutral pH, is internalized into endosomes, releases antigen at acidic pH, and is recycled back to plasma. This periodic bind-release-recycle cycle allows continuous antigen neutralization beyond the initial stoichiometric ratio.
4Ease of operation
If subcutaneous administration is implemented to reduce dosage, then administration convenience improves, but preparation difficulty increases due to high required doses
Solution Approach 1:
The patent changes the binding parameter to be pH-dependent, enabling enhanced antigen-neutralizing efficiency at lower doses. This dose reduction makes subcutaneous administration feasible, improving administration convenience while overcoming the preparation difficulty associated with high-dose formulations.
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
This approach enables the antigen-binding molecules to effectively promote antigen clearance from plasma, reducing the amount of antibodies needed and improving pharmacokinetics, while also addressing the limitations of conventional antibodies in antigen neutralization and plasma retention.
Implementation Method 1
an amino acid residue that changes the antigen-binding activity of the antigen-binding molecule depending on ion concentration conditions
Implementation Method 2
an amino acid residue that changes the antigen-binding activity of the antigen-binding molecule depending on ion concentration conditions
Data Source
AI summary
Disclosed is a library consisting essentially of a plurality of antigen-binding molecules differing in sequence from each other, wherein an antigen-binding domain in each of the antigen-binding molecules comprises at least one amino acid residue that changes the antigen-binding activity of the antigen-binding molecule depending on ion concentration conditions. Also disclosed are a composition comprising a plurality of polynucleotide molecules each encoding the antigen-binding molecules, a composition comprising a plurality of vectors each comprising the polynucleotide molecules, a method for selecting the antigen-binding molecules, a method for isolating the polynucleotide molecules, a method for producing the antigen-binding molecules, and a pharmaceutical composition comprising any of the antigen-binding molecules.