pH-Responsive Antigen-Binding Molecules for Repeated Antigen Elimination
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Solution Overview
Problem
Existing antibody pharmaceuticals face limitations in reducing the required dose due to stoichiometric neutralization limits and plasma retention issues, and there is a lack of methods to enhance Fcγ-receptor-binding activity for antibodies targeting soluble antigens.
Innovation Solution
Development of antigen-binding molecules with human-FcRn-binding activity in acidic pH and Fcγ-receptor-binding activity in neutral pH, utilizing specific amino acid modifications in the Fc region to enhance intracellular uptake, antigen binding capacity, and pharmacokinetics, and reduce plasma antigen concentration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If affinity maturation is used to enhance antigen-binding ability, then antigen-neutralizing activity is improved, but the required antibody dose cannot be reduced below stoichiometric neutralization limits
Solution Approach 1:
The patent applies pH-dependent binding dynamics to enable antibodies to bind antigens in neutral plasma conditions and dissociate in acidic endosomal conditions. This dynamic behavior allows a single antibody to neutralize multiple antigens sequentially, breaking the stoichiometric limitation where one antibody can only bind one antigen at a time. The dynamic pH-responsive binding/unbinding cycle enables sub-stoichiometric dosing while maintaining neutralizing activity.
Solution Approach 2:
The patent modifies the binding parameter by introducing pH-dependency to the antibody-antigen interaction. By engineering antibodies that exhibit strong binding at neutral pH (plasma conditions) and weak binding at acidic pH (endosome conditions), the system changes the binding parameter dynamically based on environmental pH. This parameter change enables the antibody to release antigens in endosomes for cellular uptake while maintaining plasma retention, thereby reducing the required antibody dose below stoichiometric levels.
2Duration of action of moving object
If pH-dependent antigen-binding antibodies are used to enable repeated binding cycles, then antigen-neutralizing effect is prolonged, but plasma retention of antigen increases
Solution Approach 1:
The patent applies local quality differentiation by creating distinct binding behaviors in different physiological compartments: strong binding in neutral plasma environment and weak binding in acidic endosomal environment. This spatial differentiation of binding strength ensures that antibodies retain antigens in plasma for prolonged neutralizing effect while facilitating antigen release and cellular uptake in endosomes, thereby preventing plasma antigen accumulation.
Solution Approach 2:
The patent uses pH as an intermediary parameter to mediate the binding interaction between antibody and antigen. The pH gradient between plasma (neutral) and endosomes (acidic) serves as a switching mechanism that controls antibody-antigen binding affinity. This intermediary pH-dependent mechanism enables selective retention in plasma versus selective release in endosomes, resolving the contradiction between prolonged neutralizing effect and plasma antigen retention.
3Duration of action of stationary object
If Fc region modifications are made to enhance plasma retention, then antibody half-life is extended, but intracellular uptake of bound antigen is reduced
Solution Approach 1:
The patent employs dynamic pH-responsive behavior to resolve the contradiction between plasma retention and intracellular uptake. The antibody exhibits strong binding to FcRn at acidic pH (enhancing plasma retention and half-life) but reduced binding at neutral pH (allowing endosomal release and intracellular uptake). This dynamic pH-dependent switching enables the antibody to achieve both extended half-life through FcRn recycling and efficient intracellular antigen delivery through endosomal release.
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 molecules achieve enhanced intracellular antigen uptake, increased antigen binding per molecule, improved pharmacokinetics, and reduced plasma antigen concentration, facilitating more effective antigen elimination and potentially lower dosing requirements.
Implementation Method 1
an antigen-binding molecule having human-FcRn-binding activity in an acidic pH range condition
Implementation Method 2
an antigen-binding domain having antigen-binding activity which changes depending on an ion-concentration condition
Implementation Method 3
contacting the antigen-binding molecule with an Fcγ-receptor-expressing cell
Implementation Method 4
dissociate from the antigen under acidic conditions in the endosome
Data Source
AI summary
The present inventors created antigen-binding molecules containing an antigen-binding domain and an Fcγ-receptor-binding domain, wherein the molecules have human-FcRn-binding activity in an acidic pH range condition, the antigen-binding domain changes the antigen-binding activity of the antigen-binding molecules depending on the ion-concentration condition, and the Fcγ receptor-binding domain has higher binding activity to the Fcγ receptor in a neutral pH range condition than an Fc region of a native human IgG in which the sugar chain bound at position 297 (EU numbering) is a fucose-containing sugar chain.