Fc Region Variants for pH-Dependent FcRn Recycling and Half-Life
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Solution Overview
Problem
Current mutations in the Fc domain have not identified the optimal mutations to enhance FcRn binding affinity and in vivo half-life of antibodies, limiting the frequency of injections required for therapeutic administration.
Innovation Solution
Development of Fc variants with specific amino acid modifications, such as 428L/434S, 252Y/428L/434H, and 308F/434S, to increase FcRn binding affinity at lower pH while maintaining release at higher pH, enhancing serum half-life and modulating FcγR binding.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If Fc domain mutations are introduced to enhance FcRn binding affinity, then in vivo half-life is improved, but the optimal mutations have not been identified limiting therapeutic dosing frequency
Solution Approach 1:
The patent applies parameter changes by systematically varying amino acid residues at positions 428 and 434 in the Fc domain to optimize FcRn binding affinity. Specific substitutions (M428L/N434S, M428L/N434A, M428L/434H) were identified as optimal parameters that enhance half-life while enabling less frequent dosing
Solution Approach 2:
The patent applies local quality by focusing mutations specifically at positions 428 and 434 in the Fc domain, which are located in the FcRn binding interface. This localized modification approach enhances FcRn binding affinity without globally altering the antibody structure, thereby optimizing half-life extension
2Reliability
If Fc variants with increased FcRn binding affinity are developed, then serum half-life is enhanced, but binding affinity optimization remains limited
Solution Approach 1:
The patent applies preliminary action by pre-selecting and testing specific amino acid substitutions at positions 428 and 434 before full therapeutic development. The M428L/N434S and related variants were identified through preliminary mutagenesis studies as having optimal FcRn binding characteristics, streamlining subsequent manufacturing and clinical development
3Productivity
If Fc domain modifications are made to prolong antibody retention, then dosing frequency can be reduced, but optimal mutation combinations have not been established
Solution Approach 1:
The patent applies partial action by introducing only the necessary minimal mutations at positions 428 and 434 to achieve optimal FcRn binding enhancement. Rather than implementing multiple scattered mutations throughout the Fc domain, the invention focuses on specific residue pairs (M428L/N434S, M428L/N434A, M428L/434H) that provide sufficient half-life extension for reduced dosing frequency without excessive structural complexity
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 modified Fc variants exhibit increased serum half-life and improved therapeutic efficacy by prolonging antibody retention in vivo, allowing for less frequent dosing and enhanced effector functions.
Implementation Method 1
the variant polypeptides exhibit altered binding to FcRn as compared to a parent polypeptide... increase FcRn binding affinity at lower pH while maintaining release at higher pH
Data Source
AI summary
The present application relates to a variant Fc region comprising at least one modification relative to a wild-type human Fc region, where the modification selected from the group consisting of 434S, 252Y/428L, 252Y/434S, and 428L/434S, and the numbering is according to the EU index.