IgG1 Fc Mutations Extend Antibody Half-Life
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Solution Overview
Problem
Therapeutic antibodies have a short half-life, requiring frequent dosing and increasing healthcare costs, necessitating methods to enhance their half-life for improved patient compliance and cost-effectiveness.
Innovation Solution
Development of variant Fc polypeptides with specific amino acid substitutions in the human IgG1 Fc domain, such as M252Y/S254T/T256E (YTE) and M428L/N434S (LS), which alter the affinity to FcRn at different pH levels, thereby extending the in vivo half-life of antibodies and Fc fusion proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If therapeutic antibodies are administered with standard Fc domains, then the treatment can be provided, but the half-life is short requiring frequent dosing
Solution Approach 1:
The patent applies parameter changes by modifying the Fc domain amino acid sequence to alter its binding affinity to FcRn at different pH levels. Specific amino acid substitutions (e.g., M252Y/S254T/T256E YTE mutation, M428L/N434S LS mutation) change the biochemical parameters of the Fc domain, enabling enhanced half-life through improved pH-dependent recycling without requiring frequent dosing adjustments
2Duration of action of moving object
If the affinity to FcRn is increased at both pH 6.0 and pH 7.4, then the half-life may be extended, but the antibody may not release properly from FcRn at endosomal pH
Solution Approach 1:
The patent applies dynamics by creating pH-dependent dynamic binding behavior. The Fc domain variants are designed to exhibit strong binding to FcRn at acidic pH 6.0 (in endosomes) for protective recycling, while automatically releasing at neutral pH 7.4 (in blood circulation). This dynamic pH-responsive switching is achieved through specific amino acid mutations that alter the ionization states and interaction interfaces at different pH levels
Solution Approach 2:
The patent uses parameter changes by modifying the Fc domain's pH-sensitive binding parameters through amino acid substitutions. These mutations change the electrostatic and hydrogen bonding characteristics of the Fc-FcRn interface, enabling the binding affinity to vary dynamically with pH, thus achieving both extended half-life and proper release functionality
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 significantly increase the half-life of antibodies and Fc fusion proteins, leading to enhanced therapeutic efficacy and reduced dosing frequency, while maintaining or improving their binding affinity to target antigens.
Implementation Method 1
alter the affinity to FcRn at different pH levels, thereby extending the in vivo half-life of antibodies and Fc fusion proteins
Data Source
AI summary
The present disclosure relates generally to antibodies and Fc fusion proteins comprising Fc variants, and uses thereof. The Fc variants disclosed herein exhibit elevated affinity towards FcRn at pH 6.0, and/or rapidly disassociate from FcRn at pH 7.4 compared to a parent Fc domain