FcεRI Alpha ECD Dimer for High-Affinity IgE Binding
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Solution Overview
Problem
Current treatments for allergic diseases, such as allergic rhinitis and asthma, are inadequate due to high costs, side effects, and inability to address the underlying cause, with existing anti-IgE antibodies like omalizumab causing severe side effects and having limited efficacy.
Innovation Solution
A polypeptide dimer composed of two monomers, each containing an extracellular domain of an IgE Fc receptor alpha subunit linked via a modified Fc region through an IgD antibody hinge, which binds strongly to IgE without activating Fc gamma receptors, reducing side effects and extending administration cycles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If omalizumab is administered at high doses to maintain therapeutic effects, then therapeutic efficacy is improved, but cost burden and side effects increase
Solution Approach 1:
The invention uses a dimeric structure composed of two monomeric units, each containing an extracellular domain of IgE Fc receptor alpha subunit linked to a modified Fc region. This segmentation allows the protein to bind IgE with high affinity while avoiding activation of Fc gamma receptors, thereby reducing side effects while maintaining therapeutic efficacy
Solution Approach 2:
The invention modifies the Fc region to have selective binding properties - it binds IgE with high affinity through the extracellular domain while the modified Fc region prevents binding to Fc gamma receptors. This local quality differentiation eliminates harmful interactions with Fc gamma receptors while preserving beneficial IgE binding, thus reducing side effects
2Reliability
If conventional anti-IgE antibodies are used, then IgE-mediated allergic diseases are treated, but antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity occur
Solution Approach 1:
The invention extracts and utilizes only the extracellular domain of the IgE Fc receptor alpha subunit, separating the IgE binding function from the cytotoxic functions mediated by Fc gamma receptors. By using a modified Fc region that does not bind Fc gamma receptors, the patent removes the source of antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity while preserving IgE binding capability
Solution Approach 2:
The invention converts the potentially harmful Fc region into a beneficial component by modifying it to specifically bind IgE without activating Fc gamma receptors. This transformation turns what could be a source of cytotoxicity into a selective IgE binding platform, eliminating harmful cytotoxic effects while maintaining therapeutic benefit
3Reliability
If high-dose omalizumab administration is used, then therapeutic effects are maintained, but administration frequency and cost increase
Solution Approach 1:
The dimeric structure merges two monomeric units with IgE binding capability, creating a protein with doubled binding capacity compared to monomeric antibodies. This merging effect enhances the pharmacological activity and persistence of the therapeutic agent, allowing for extended administration intervals and reduced dosing frequency
Solution Approach 2:
The invention creates a composite protein structure combining the extracellular domain of IgE Fc receiver alpha subunit with a modified Fc region. This composite structure exhibits enhanced stability and binding affinity, leading to prolonged half-life and reduced administration frequency, thereby reducing time loss and cost burden
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 polypeptide dimer provides enhanced safety and persistence, minimizing side effects like anaphylaxis by reducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, and exhibits a 70-fold higher binding capacity to IgE than omalizumab, allowing extended treatment intervals.
Implementation Method 1
The abnormally increased number of IgE can bind to high-affinity IgE Fc receptors (FcεRIs) which are expressed on the surface of mast cells, basophils, and the like. Such binding causes mast cells or basophils to release chemical mediators
Implementation Method 2
the polypeptide dimeric protein according to the present invention is a substance obtained by applying a modified Fc, which has IgE alone as a single target and does not bind to an Fc gamma receptor, and thus lacks antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) functions
Data Source
AI summary
The present invention provides a polypeptide dimeric protein containing two monomers, each of which contains an extracellular domain (FcεRIa-ECD) of an alpha subunit of an IgE Fc receptor. The dimeric protein according to the present invention has advantages that an excellent binding ability to IgE is exhibited as compared with a conventional therapeutic agent containing an anti-IgE antibody, and less other side effects are exhibited due to lack of ADCC and CDC functions. Thus, the dimeric protein can be applied to a medical product for treating or preventing an IgE-mediated allergic disease.