Chimeric Fc Binding Protein for FcεRI Targeting and Longer Half-Life
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Solution Overview
Problem
Natural IgE antibodies have limitations for drug development due to high affinity for FcεRI, short plasma half-life, difficulty in purification, and challenges in quality control, which can lead to severe allergic reactions.
Innovation Solution
A binding protein is developed with modified IgG Fc regions, incorporating amino acid substitutions and replacements from IgE Fc regions to enhance binding to FcεRI and FcRn, allowing for easy purification with Protein A/G, reduced glycosylation sites, and improved expression quality.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If natural IgE is used as a drug, then binding activity to FcεRI is strong, but affinity is too high causing severe allergic reactions
Solution Approach 1:
The patent modifies the Fc region of IgE by introducing amino acid substitutions and deletions at specific positions (e.g., positions 84-85 in the DE-TURN region, positions 105-117 in the FG-LOOP region) to change the binding affinity parameter. This reduces the affinity from 10^-7 M to a safer range while maintaining therapeutic binding activity to FcεRI.
Solution Approach 2:
The patent extracts and removes specific amino acid sequences from the IgE Fc region that are responsible for excessive binding affinity. By deleting residues in the DE-TURN and FG-LOOP regions, the patent eliminates the harmful high-affinity binding characteristic while preserving the necessary FcεRI binding function for therapeutic effect.
2Reliability
If natural IgE is used as a drug, then FcεRI binding activity is achieved, but plasma half-life is short
Solution Approach 1:
The patent creates a chimeric Fc region that combines IgE's FcεRI binding capability with IgG's FcRn binding capability. By incorporating IgG-like Fc region structures (particularly in the CH2 and CH3 domains) while retaining IgE's FcεRI binding motifs, the protein achieves dual functionality: binding to both FcεRI for therapeutic effect and FcRn for extended half-life.
3Reliability
If natural IgE is used as a drug, then FcεRI binding is achieved, but purification is difficult
Solution Approach 1:
The patent applies local modifications to the Fc region by introducing specific amino acid substitutions at defined positions (e.g., positions 84-85, 105-117) while maintaining the overall IgG Fc region structure. This localized modification enables the protein to bind FcεRI effectively while retaining compatibility with standard IgG purification systems like Protein A.
4Reliability
If natural IgE is used as a drug, then FcεRI binding activity is achieved, but quality control is challenging due to multiple glycosylation sites
Solution Approach 1:
The patent removes or reduces the number of potential glycosylation sites from the IgE Fc region by deleting specific amino acid sequences (particularly in the DE-TURN and FG-LOOP regions) that serve as glycosylation motifs. This simplifies the glycosylation profile to a manageable number of sites, enabling better quality control and batch consistency.
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 binding protein achieves stable binding to FcεRI, prolonged half-life, and ease of purification, while maintaining good druggability properties, suitable for therapeutic applications.
Implementation Method 1
The binding protein includes an IgG Fc region or a fragment thereof, the IgG Fc region or the fragment thereof includes BC-LOOP, DE-TURN and/or FG-LOOP or a fragment thereof derived from CH3 in an IgE Fc region, and regions in CH2 in the IgG Fc region corresponding to BC-LOOP, DE-TURN and/or FG-LOOP or the fragment thereof in CH3 in the IgE Fc region are substituted or replaced
Implementation Method 2
the binding protein of the present application has one or more of the following properties: (2) being capable of binding to FcRn
Implementation Method 3
the binding protein of the present application has one or more of the following properties: (4) being capable of being purified directly with Protein A or G
Data Source
AI summary
Provided in the present application is a binding protein. The binding protein contains an IgG Fc region or a fragment thereof, and can bind to FcεRI. Also provided in the present application are a nucleic acid molecule encoding the binding protein; a vector and a cell which contain the nucleic acid molecule; a pharmaceutical composition containing the binding protein; and a use of the binding protein in the preparation of a drug.