Fc-gamma receptor mutants for extended protein half-life
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Solution Overview
Problem
Current protein drugs face challenges with short in vivo half-life and residence time, limiting their clinical applications, and existing methods for extending serum half-life, such as PEGylation and Fc-fusion, have limitations in efficacy and stability.
Innovation Solution
Development of an Fc-gamma receptor mutant with improved IgG binding ability by optimizing the amino acid sequence, specifically through substitution, deletion, or insertion of amino acids, to enhance the receptor's binding affinity and stability, thereby increasing the serum half-life of peptide drugs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If Fc-gamma receptor wild-type is used, then binding ability to IgG is achieved, but serum half-life is short and expression level is low
Solution Approach 1:
The patent applies parameter changes by systematically modifying amino acid residues at positions 23, 41, 42, and 43 of the Fc-gamma receptor sequence. These specific parameter changes in the primary structure result in mutants with dramatically improved IgG binding affinity (up to 1000-fold increase) while maintaining stable expression levels and extended serum half-life compared to the wild-type receptor.
Solution Approach 2:
The patent applies local quality by making targeted modifications only at specific binding interface residues (positions 23, 41, 42, 43) rather than globally modifying the entire receptor structure. This localized approach optimizes the binding interface while preserving the overall structural integrity and functional properties of the Fc-gamma receptor, achieving enhanced binding affinity without compromising stability.
2Duration of action of stationary object
If PEG polymer is conjugated to increase serum half-life, then in vivo retention time is extended, but molecular weight increases and production becomes difficult
Solution Approach 1:
The patent applies the taking out principle by removing the need for PEG conjugation or Fc-fusion strategies. Instead of adding external molecules to extend half-life, the invention extracts the essential function by creating Fc-gamma receptor mutants that naturally achieve extended serum half-life through improved IgG binding affinity alone, thereby simplifying the manufacturing process and avoiding the complexities of PEGylation.
3Duration of action of stationary object
If Fc-fusion is used to extend serum half-life, then in vivo retention is improved, but binding ability to target antigen may be reduced
Solution Approach 1:
The patent applies the taking out principle by removing the Fc-fusion component entirely. The invention demonstrates that Fc-gamma receptor mutants alone, with optimized amino acid sequences, can achieve both extended serum half-life and high binding affinity to IgG without requiring fusion to the Fc region of antibodies, thus avoiding potential steric hindrance or binding interference.
Data Source
AI summary
The present disclosure relates to a polypeptide including an Fc-gamma receptor mutant. The Fc-gamma receptor mutant of the present disclosure is optimized by substituting a part of an amino acid sequence of an Fc-gamma receptor with a different amino acid sequence, so as to provide an excellent selective binding ability to immunoglobulins. Therefore, it can be usefully used for increasing in vivo half-life of drugs, detecting and purifying immunoglobulins, inhibiting organ transplant rejections, or preventing or treating autoimmune diseases.