Fc-region mutation for controlled FcRn binding affinity
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Solution Overview
Problem
Existing methods for modifying antibody pharmacokinetic properties, such as half-life, are inadequate in predicting and adjusting the in vivo clearance of therapeutic antibodies, leading to unpredictable clinical utility due to fast clearance rates.
Innovation Solution
A method combining FcRn affinity chromatography and heparin affinity chromatography is used to modify the Fc-region of antibodies, optimizing FcRn binding by introducing mutations that adjust retention times within specific thresholds, thereby enhancing in vivo half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If FcRn binding is increased to extend antibody half-life, then in vivo half-life is improved, but clearance reduction becomes unpredictable due to lack of precise control methods
Solution Approach 1:
The patent changes the binding parameters of the antibody Fc-region to FcRn by introducing specific amino acid mutations. These mutations modify the biochemical properties of the Fc-region, thereby adjusting the binding affinity to FcRn in a controlled manner to achieve predictable half-life extension
Solution Approach 2:
The patent replaces traditional mechanical or empirical optimization methods with a rational design approach based on structural analysis and binding energy calculations. This substitution allows for precise prediction and control of clearance rates through computational modeling of FcRn interactions
2Adaptability or versatility
If Fc-region engineering is performed to modify pharmacokinetic properties, then half-life can be adjusted, but the method complexity increases due to multiple mutation options
Solution Approach 1:
The patent focuses mutations on specific local regions of the Fc-region that are known to be critical for FcRn binding. By concentrating engineering efforts on key residues rather than the entire Fc-region, the method achieves effective pharmacokinetic modulation while reducing overall complexity
Solution Approach 2:
The patent divides the Fc-region into functional segments and identifies specific residues within these segments that govern FcRn binding. This segmentation allows for targeted modification of pharmacokinetic properties without requiring comprehensive engineering of the entire antibody structure
3Duration of action of moving object
If clearance rate is reduced to extend circulation time, then systemic circulation duration is improved, but prediction accuracy of in vivo behavior deteriorates due to fast clearance variability
Solution Approach 1:
The patent performs preliminary in silico screening and in vitro validation of Fc-region variants before in vivo testing. By pre-selecting candidates with predicted optimal binding properties and validating them in controlled in vitro assays, the method improves prediction accuracy of in vivo clearance behavior
Solution Approach 2:
The patent employs feedback loops where in vitro FcRn binding data and in vivo pharmacokinetic results are continuously integrated to refine the predictive model. This feedback mechanism allows for iterative optimization and improved accuracy in predicting clearance rates and circulation times
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
This approach allows for the precise adjustment of antibody pharmacokinetic properties, reducing clearance and increasing half-life, making antibodies more suitable for therapeutic applications by defining a two-dimensional retention time region for slow clearance and long systemic circulation.
Implementation Method 1
The affinity between the FcRn and the Fc-region is pH dependent, showing nanomolar affinity at endosomal pH of 5-6 and rather weak binding at a physiological pH of 7.4
Implementation Method 2
Analytical FcRn affinity chromatography for functional characterization of monoclonal antibodies
Implementation Method 3
heparin binding, e.g. in ELISA format (see, e.g., Datta-Mannan, A., et al., MAbs 7 (2015) 1084-1093) is disclosed as a surrogate parameter to quantify non-specific interactions with cell surface structures
Data Source
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AI summary
Herein is reported a method for providing a modified antibody with improved in vivo half-live, comprising the modification of the Fc-region of the antibody by introducing one or more mutations that change the binding of the Fc-region to human FcRn until the (relative) retention time of the modified antibody in an FcRn affinity chromatography is increased for more than 1 minute but not more than 5 minutes compared to the parent antibody.