Fc-fragment Loop Insertions for pH-Dependent FcRn Binding
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Solution Overview
Problem
Current therapeutic antibodies have limited in vivo half-lives, requiring frequent dosing and higher amounts, which increases costs and reduces patient compliance.
Innovation Solution
Development of variant Fc-fragments with increased affinity for the neonatal Fc receptor (FcRn) at slightly acidic pHs, allowing for longer in vivo half-lives by incorporating specific amino acid insertions within or adjacent to Loop 5 or Loop 10, while maintaining low affinity at physiological pH.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If Fc-fragments are modified to increase affinity for FcRn at acidic pH, then in vivo half-life is extended, but dosing frequency must be reduced and manufacturing complexity increases
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid residues in the Fc-fragment sequence to alter its binding properties. Specific substitutions (e.g., position 238, 242, 356, 382, 429) change the chemical characteristics of the Fc-region, enabling enhanced affinity for FcRn at acidic pH while maintaining selectivity and avoiding non-specific binding at physiological pH.
Solution Approach 2:
The invention applies local quality by making targeted modifications at specific locations within the Fc-fragment structure rather than global changes. The amino acid substitutions are localized to particular positions (e.g., loop regions, complementarity-determining regions) that directly influence FcRn binding affinity, allowing precise control over binding characteristics at different pH levels.
2Reliability
If higher amounts of antibodies are administered, then therapeutic effect is maintained, but healthcare costs increase
Solution Approach 1:
The patent applies continuity of useful action by extending the in vivo half-life of the antibody through enhanced FcRn binding. This allows the therapeutic antibody to remain active in the bloodstream for longer periods, maintaining continuous therapeutic effect and enabling less frequent dosing, thereby reducing the total quantity of antibody required over time.
3Reliability
If dosing frequency is increased, then therapeutic effect is maintained, but patient compliance decreases
Solution Approach 1:
By engineering Fc-fragments with enhanced FcRn binding affinity at acidic pH, the patent achieves extended circulating half-life of the antibody. This continuous presence in the bloodstream maintains therapeutic efficacy over longer periods, allowing less frequent dosing intervals and significantly improving patient compliance without compromising treatment effectiveness.
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 variant Fc-polypeptides exhibit extended in vivo half-lives, enabling lower and less frequent dosing, thereby improving patient convenience and reducing healthcare costs.
Implementation Method 1
binds to the neonatal Fc receptor with higher affinity and/or greater binding activity compared to a control Fc-fragment at a slightly acidic pH and binds to the neonatal Fc receptor with about the same affinity or lower than a control Fc-fragment, i.e., little or no binding activity, at a physiologic pH
Data Source
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AI summary
Described herein are variant Fc-fragments that contain an insertion within or adjacent to a loop that bind to the neonatal Fc receptor (FcRn) with higher affinity and/or higher binding activity at pH 5-6 and approximately the same or lower affinity at a physiologic pH as compared to a control Fc-fragment, that is, little or no binding activity at a physiologic pH. Also described are variant Fc-polypeptides that comprise these variant Fc-fragments. Further described are methods of making and identifying such Fc-fragments and methods for making and using such Fc-polypeptides.