Antigen-Binding Molecule with pH-Dependent FcRn Binding
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Solution Overview
Problem
Current antigen-binding molecules are ineffective in inhibiting the multiple physiological activities of antigens with two or more activities, as they cannot simultaneously neutralize all activities, leading to difficulties in treating diseases caused by such antigens.
Innovation Solution
Development of antigen-binding molecules with specific properties, including binding to human neonatal Fc receptor under acidic pH, stronger binding to human Fc receptors than native IgG under neutral pH, and altered antigen-binding activity based on ion concentration, allowing for the inhibition of some physiological activities while maintaining others, thereby promoting antigen elimination from plasma.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If a single type of neutralizing antibody is used to inhibit one physiological activity of an antigen, then the binding specificity is improved, but the ability to inhibit multiple physiological activities deteriorates
Solution Approach 1:
The patent applies multi-functionality by designing an antibody molecule with two distinct antigen-binding sites that can simultaneously recognize and bind to different epitopes on the same antigen. This dual-specificity antibody can inhibit multiple physiological activities of the antigen (such as HMGB1 binding to both RAGE and TLR4) with a single molecule, eliminating the need for multiple separate antibodies while maintaining high binding specificity for each target
2Duration of action of stationary object
If an antibody binds strongly to FcRn under neutral pH to extend plasma retention, then the plasma half-life is improved, but the antigen elimination effect deteriorates
Solution Approach 1:
The patent applies dynamics by engineering the antibody's Fc region to exhibit pH-dependent binding behavior to FcRn. The antibody binds weakly to FcRn at physiological pH 7.4 (allowing rapid antigen elimination) but binds strongly at the acidic pH of endosomes (enabling recycling and extended plasma half-life). This dynamic pH-sensitive binding mechanism allows the antibody to optimize both antigen elimination efficiency and plasma retention duration
Solution Approach 2:
The patent changes the binding parameter of the antibody-FcRn interaction based on pH conditions. By introducing specific amino acid substitutions in the Fc region (such as L238Q, N297Q), the antibody's affinity for FcRn is modulated: low affinity at neutral pH promotes antigen elimination, while high affinity at acidic pH enables endosomal recycling and extended circulation
3Reliability
If conventional antibodies are used to neutralize antigens, then the in vitro neutralization is improved, but the in vivo therapeutic effect deteriorates due to inability to eliminate antigen from plasma
Solution Approach 1:
The patent uses FcRn as an intermediary to achieve a dual effect: the engineered antibody exploits FcRn's pH-dependent binding properties to first eliminate antigen from plasma through rapid dissociation at neutral pH, then uses FcRn-mediated endosomal recycling at acidic pH to extend the antibody's plasma half-life. This intermediary mechanism bridges the gap between in vitro neutralization capability and in vivo therapeutic efficacy
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
These molecules effectively reduce plasma antigen concentration and decrease in vivo physiological activities of antigens with multiple functions, offering a more comprehensive therapeutic approach compared to traditional antibodies.
Implementation Method 1
under an acidic pH range condition, the receptor-binding domain has human neonatal Fc Receptor (FcRn)-binding activity
Implementation Method 2
under a neutral pH range condition, the human Fc receptor-binding activity of the receptor-binding domain is higher than human Fc receptor-binding activity of native human IgG
Implementation Method 3
an antigen-binding activity of the antigen-binding domain is altered according to the ion concentration condition
Implementation Method 4
Antibodies (IgGs) bind to neonatal Fc receptor (FcRn), and have long plasma retention. The binding of IgG to FcRn is observed only under an acidic condition (pH 6.0)
Data Source
AI summary
The present inventors newly discovered that even if an antigen-binding molecule inhibits in vitro some of the physiological activities of an antigen having two or more physiological activities without inhibiting the remaining physiological activities, the molecule can promote elimination of the antigen from blood (from serum or plasma) and as a result reduce the physiological activities in vivo, when the antigen-binding molecule is conferred with the properties: (i) of binding to human FcRn under an acidic pH range condition; (ii) of binding under a neutral pH range condition to human Fc receptor stronger than native human IgG, and (iii) that its antigen-binding activity alters according to the ion concentration.