Fc Domain Variants Optimizing Receptor Binding and Expression
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Solution Overview
Problem
Current Fc engineering efforts have not successfully created Fc variant domain polypeptides with enhanced efficacy and improved manufacturability for treating various diseases.
Innovation Solution
Development of Fc domain variant polypeptides with specific amino acid substitutions at positions 251, 267, 268, 298, 314, 330, 339, 373, and 376, which exhibit increased binding to Fc receptors, high protein expression, and high protein purity profiles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Fc engineering is performed to enhance affinity to Fc receptors, then ADCC activity is improved, but manufacturability and protein expression remain insufficient
Solution Approach 1:
The patent applies parameter changes by systematically modifying amino acid positions in the Fc domain (specifically positions 251, 267, 268, 298, 314, 330, 339, 373, and 376 according to EU numbering) to optimize both ADCC activity and manufacturability. Multiple substitution combinations are tested to find the optimal balance between binding affinity and production characteristics.
Solution Approach 2:
The patent applies local quality by making specific localized amino acid substitutions at particular positions within the Fc domain rather than global modifications. This allows targeted enhancement of Fc receptor binding affinity while maintaining overall protein structure and manufacturability characteristics.
2Reliability
If multiple amino acid substitutions are introduced to enhance Fc receptor binding, then binding affinity is improved, but protein purity and expression levels may deteriorate
Solution Approach 1:
The patent systematically evaluates multiple amino acid substitution combinations at specific Fc domain positions to optimize the balance between Fc receptor binding affinity and protein purity/expression levels. The substitutions are designed to enhance binding while maintaining manufacturability.
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 Fc domain variant polypeptides demonstrate enhanced binding to Fc receptors, improved protein expression, and purity, potentially leading to more effective disease treatment and streamlined manufacturing processes.
Implementation Method 1
The Fc domain variant polypeptides have increased binding to a Fc receptor relative to the Fc domain parent polypeptide
Implementation Method 2
The Fc region also interacts with the neonatal Fc receptor (FcRn). This interaction has been shown to extend the half-life of IgG by reducing lysosomal degradation in endothelial cells.
Data Source
AI summary
The present disclosure provides Fc domain variant polypeptides, including effector-competent Fc domain variants. The present disclosure also provides Fc domain variant polypeptides comprising at least one substitution or at least two substitutions at amino acid positions 251, 267, 268, 298, 314, 330, 339, 373, and 376, according to EU numbering, as compared to a Fc domain parent polypeptide. The present disclosure also provides nucleic acids encoding Fc domain variant polypeptides and host cells for making Fc domain variant polypeptides. Methods for increasing the yield of Fc domain variant polypeptides, and methods of using Fc domain variant polypeptides to treat disease, are also provided.