Multi-Domain Complement Inhibitor for Broad Pathway Control
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Solution Overview
Problem
Existing complement inhibitors, such as eculizumab and mini-FH, have limitations in effectively inhibiting all three complement activation pathways, particularly the alternative pathway, and there is a need for improved regulators to manage inappropriate complement activation in diseases.
Innovation Solution
A multi-domain polypeptide comprising a first CCP-comprising domain with convertase decay accelerating activity, a host cell recognition domain, and a second CCP-comprising domain with Factor I cofactor activity, designed to inhibit convertases of the classical and alternative pathways of complement activation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing complement inhibitors (eculizumab, mini-FH) are used, then complement activation is inhibited to some extent, but they fail to effectively inhibit all three complement activation pathways, particularly the alternative pathway
Solution Approach 1:
The patent combines multiple functional domains (first CCP domain with convertase decay accelerating activity, second CCP domain with Factor I cofactor activity, and host cell recognition domain) into a single multi-domain polypeptide. This merging enables the inhibitor to simultaneously target multiple complement activation pathways (classical, lectin, and alternative) through integrated mechanisms, resolving the limitation of existing inhibitors that could not effectively inhibit all three pathways.
Solution Approach 2:
The multi-domain polypeptide is designed with universal inhibitory capabilities across all three complement activation pathways. The first CCP domain provides decay accelerating activity against C3 convertases of classical and alternative pathways, while the second CCP domain provides Factor I cofactor activity for C3b degradation. This multi-functionality allows a single inhibitor to regulate complement activation broadly, achieving pathway-specific inhibition without requiring separate inhibitors for each pathway.
2Reliability
If a multi-domain polypeptide with broad-spectrum complement inhibition is designed, then all three complement activation pathways are effectively inhibited, but the structural and functional complexity increases
Solution Approach 1:
The inhibitor is segmented into distinct functional domains: a first CCP-comprising domain with convertase decay accelerating activity, a second CCP-comprising domain with Factor I cofactor activity, and a host cell recognition domain. Each domain performs a specific function, and their modular arrangement allows for systematic design and optimization. This segmentation enables the complex broad-spectrum inhibition to be achieved through coordinated action of simpler, well-defined functional units.
Solution Approach 2:
The multi-domain polypeptide functions as a composite biological molecule, integrating different functional domains (CCP domains with specific activities, host cell recognition domains) into a unified structure. This composite approach allows the inhibitor to combine multiple mechanisms (convertase decay acceleration, Factor I cofactor activity, host cell targeting) within a single molecular entity, achieving broad-spectrum complement inhibition through synergistic integration of specialized functional modules.
Data Source
AI summary
The present invention relates to a multi-domain polypeptide comprising (i) a first complement control protein repeat (CCP)-comprising domain being a convertase decay accelerating domain for convertases of the classical and alternative pathways of complement activation, (ii) a host cell recognition domain, and (iii) a second CCP-comprising domains with cofactor activity. The present invention further relates to a polynucleotide encoding said multi-domain polypeptide, to a vector comprising said polynucleotide, and to a host cell comprising said polynucleotide and/or said vector. Further, the present invention relates to the multi-domain polypeptide, the polypeptide, and the vector for use in medicine and for treating and/or preventing inappropriate complement activation and/or a disease having inappropriate complement activation as a symptom. Moreover, the present invention relates to methods and uses related to multi-domain polypeptide, the polypeptide, and the vector.