FcRn Antigen-Binding Molecules for Sustained IgG Depletion
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Solution Overview
Problem
Current FcRn-binding molecules, such as efgartigimod, require frequent administration and can negatively impact serum albumin levels and cholesterol levels, necessitating the development of improved agents that antagonize FcRn binding to IgG with a longer half-life, lower dose, and better maintenance of albumin levels.
Innovation Solution
Development of FcRn/antigen-binding molecules comprising a variant IgG Fc region with one antigen-binding domain, specifically designed to reduce serum IgG levels while maintaining FcRn and albumin levels, featuring enhanced stability and FcRn occupancy, and a molecular weight between 60 kDa to 104 kDa.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If FcRn-binding molecules like efgartigimod are used to reduce serum IgG levels, then IgG levels decrease, but serum albumin levels and cholesterol levels are negatively impacted
Solution Approach 1:
The patent applies local quality by engineering the Fc region with specific localized mutations (e.g., at positions 252, 254, 256, 433, 434, 436 in EU numbering) that enhance FcRn binding affinity selectively, while the rest of the molecule structure remains intact to preserve normal FcRn physiology and avoid adverse effects on albumin and cholesterol
Solution Approach 2:
The patent changes the binding parameters of the Fc region by introducing mutations that increase affinity for FcRn at both acidic and physiological pH, thereby enhancing IgG depletion efficacy while maintaining selective FcRn interaction that does not disrupt albumin homeostasis
2Reliability
If FcRn-binding molecules are administered frequently to maintain IgG reduction, then treatment efficacy is maintained, but treatment complexity and patient burden increase
Solution Approach 1:
The patent creates a dynamic system where the engineered Fc region continuously binds and recycles IgG through FcRn at an enhanced rate, creating a self-sustaining mechanism that maintains IgG depletion over extended periods without requiring frequent external intervention
Solution Approach 2:
The patent achieves continuous useful action by designing the Fc region to maintain high FcRn occupancy and recycling activity throughout the dosing interval, ensuring sustained IgG depletion efficacy without treatment interruptions or frequent re-administration
3Quantity of substance
If higher doses of FcRn-binding molecules are used to enhance IgG reduction, then treatment efficacy increases, but adverse effects on albumin and cholesterol levels worsen
Solution Approach 1:
The patent changes the binding affinity parameter of the Fc region through mutations, enabling higher FcRn occupancy and more potent IgG depletion at lower doses, thereby achieving enhanced efficacy without proportionally increasing adverse effects on albumin and cholesterol
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 FcRn/antigen-binding molecules achieve a significant reduction of serum IgG by up to 55% without affecting FcRn and albumin levels, with a clearance rate less than 0.2 l/h and a terminal half-life exceeding 3 days, providing a more effective and less frequent treatment option for antibody-mediated disorders.
Implementation Method 1
This recycling is facilitated by the pH-dependent binding of IgG to FcRn, where the IgG/FcRn interaction is stronger at acidic endosomal pH than at extracellular physiological pH
Implementation Method 2
Agents that antagonize the binding of IgG to FcRn, such as FcRn-binding molecules, are useful for regulating, treating, or preventing antibody-mediated disorders
Data Source
AI summary
Provided herein are binding molecules comprising a human neonatal Fc receptor (FcRn) binding molecule and at least one antigen-binding domain linked to the FcRn binding molecule. Polynucleotides, vectors, host cells, and methods of production are also provided herein. Methods of treating an antibody-mediated disorder with an FcRn/antigen-binding molecule are further provided.