Fc Region Mutations for Antibody Stability
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Solution Overview
Problem
Current immunoglobulin-based therapies face challenges in maintaining the stability of engineered antibodies, particularly in the Fc region, which can affect thermostability and pharmacokinetics, leading to adverse effects such as aggregation and reduced serum half-life.
Innovation Solution
Introduction of specific stability-enhancing mutations at positions 250, 287, 308, 309, and 428 in the Fc region, along with cysteine substitutions at positions 242 and 336, to increase the CH2 domain melting temperature and reduce aggregation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If modifications are made to antibody Fc regions to improve pharmacokinetics, enhance ADCC activity, or improve heterodimeric Fc formation, then these functions are improved, but thermostability deteriorates
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions at defined positions (250, 287, 308, 309, 428) within the Fc region while leaving the rest of the antibody structure unchanged. This localized modification approach allows improvement of thermostability without compromising the overall functionality and pharmacokinetic properties of the antibody
Solution Approach 2:
The patent employs parameter changes by substituting specific amino acids at predetermined positions in the Fc region with alternative residues that have different physical-chemical properties. These parameter changes at the molecular level result in enhanced thermostability while maintaining the antibody's functional characteristics
2Stability of the object's composition
If mutations are introduced to improve antibody stability, then thermostability is improved, but aggregation increases
Solution Approach 1:
The patent introduces specific amino acid substitutions at defined positions (250, 287, 308, 309, 428) within the Fc region while leaving the rest of the antibody structure unchanged. This localized modification approach allows improvement of thermostability without compromising the overall functionality and pharmacokinetic properties of the antibody
Solution Approach 2:
The patent converts the potential harm of amino acid mutations (which could cause aggregation) into a benefit by carefully selecting specific substitutions at predetermined positions that enhance thermostability while actually reducing aggregation tendency through optimized local interactions
3Stability of the object's composition
If mutations are introduced to improve antibody stability, then thermostability is improved, but serum half-life is reduced
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions at defined positions (250, 287, 308, 309, 428) within the Fc region while leaving the rest of the antibody structure unchanged. This localized modification approach allows improvement of thermostability without compromising the overall functionality and pharmacokinetic properties of the antibody
Solution Approach 2:
The patent employs parameter changes by substituting specific amino acids at predetermined positions in the Fc region with alternative residues that have different physical-chemical properties. These parameter changes at the molecular level result in enhanced thermostability while maintaining the antibody's functional characteristics including serum half-life
Data Source
AI summary
Fc variants are described comprising one or more amino acid mutations that increase the stability of the Fc variant as compared to a parental Fc that does not include the one or more amino acid mutations, as well as polypeptides comprising an Fc variant and polynucleotides encoding an Fc variant.