Multi-module Polypeptide Complement Inhibitor Design
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Solution Overview
Problem
Current complement inhibitors, such as eculizumab and rEV576, have limitations in effectively regulating inappropriate complement activation, particularly in diseases associated with overactivation of the complement system, highlighting the need for improved regulatory mechanisms.
Innovation Solution
A multi-module polypeptide comprising an Fc receptor binding module, a first complement control protein repeat (CCP) module, and a second CCP module that binds to host cell surface markers, complement factors C3b, C4b, and their degradation products, with the second CCP module positioned C-terminal to the Fc receptor binding module and first CCP module, enhancing regulatory activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current complement inhibitors (eculizumab, rEV576) are used, then complement activation is inhibited, but regulatory activity is insufficient and plasma half-life is limited
Solution Approach 1:
The patent combines multiple functional modules into a single polypeptide: an Fc receptor binding module (for extended circulation via FcRn recycling) and CCP modules (for complement regulation). This merging creates a multifunctional inhibitor that simultaneously achieves extended plasma half-life through FcRn interaction and enhanced complement regulatory activity through multiple CCP domains, directly resolving the contradiction between duration of action and regulatory efficacy
Solution Approach 2:
The invention creates a composite polypeptide structure integrating different functional domains: the Fc portion (providing long circulation half-life through FcRn binding) and CCP modules (providing complement regulatory function). This composite architecture allows the molecule to exhibit both extended pharmacokinetic properties and enhanced therapeutic activity, overcoming the limitations of single-function complement inhibitors
2Reliability
If multi-module polypeptide with Fc receptor binding and CCP modules is constructed, then regulatory activity and plasma half-life are enhanced, but molecular complexity increases
Solution Approach 1:
The Fc portion of the polypeptide serves multiple functions: it provides structural framework, enables FcRn binding for extended circulation, and facilitates dimerization. By making this portion multifunctional, the invention reduces the need for additional separate components, thereby managing molecular complexity while achieving enhanced regulatory activity and prolonged half-life
Data Source
AI summary
The present invention relates to a multi-module polypeptide comprising (i) an Fc receptor binding module; (ii) a first complement control protein repeat (CCP) module; and (iii) a second CCP module binding to at least one host cell surface marker, to complement factor C3b, to complement factor C4b, to a degradation product of complement factor C3b, and/or to a degradation product of complement factor C4b; wherein said second CCP module is C-terminal of said Fc receptor binding module and of said first CCP module. The present invention also relates to a polynucleotide encoding said multi-module polypeptide, and to said multi-module polypeptide for use in medicine, in particular for use in treating and/or preventing inappropriate complement activation and/or a disease having inappropriate complement activation as a symptom. Moreover, the present invention relates to an in vitro method for preventing or reducing the degree of complement activation comprising applying a multi-module polypeptide to a reaction mixture, a tissue, and/or an organ comprising complement factors, thereby preventing or reducing the degree of complement activation in said reaction mixture, tissue, and/or organ.