Multi-domain Polypeptide Complement Inhibitor
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Solution Overview
Problem
There is a need for improved complement inhibitors that can effectively regulate all three pathways of complement activation, avoiding the limitations of existing technologies.
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, which together inhibit complement activation across the classical, lectin, and alternative pathways.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If a single-domain complement inhibitor is used, then the structure is simple and ease of manufacture is improved, but the ability to regulate all three pathways of complement activation is insufficient
Solution Approach 1:
The complement inhibitor is divided into multiple functional domains: a first CCP-comprising domain with convertase decay accelerating activity, a host cell recognition domain, and a second CCP-comprising domain with cofactor activity. Each domain regulates specific complement pathways, enabling comprehensive control of classical, lectin, and alternative pathways through modular functional segmentation.
Solution Approach 2:
The multi-domain polypeptide performs multiple functions simultaneously: it accelerates decay of convertases in classical and alternative pathways, recognizes host cell surfaces via the host cell recognition domain, and provides cofactor activity for Factor I-mediated degradation of C3b. This multi-functionality enables regulation of all three complement activation pathways through a single inhibitor molecule.
2Adaptability or versatility
If a multi-domain polypeptide is used to regulate all three pathways, then complement activation control is improved, but the structural complexity increases
Solution Approach 1:
The patent combines three distinct functional domains into a single polypeptide molecule: the first CCP-comprising domain for convertase decay acceleration, the host cell recognition domain, and the second CCP-comprising domain for cofactor activity. This merging of functions into one molecular entity achieves comprehensive pathway regulation while managing structural complexity through integrated domain architecture.
3Device complexity
If existing complement inhibitors are used, then the mechanism is simple, but inappropriate complement activation and associated diseases are not effectively prevented
Solution Approach 1:
The multi-domain polypeptide performs preliminary protective actions by pre-accelerating the decay of complement convertases and pre-providing cofactor activity for C3b degradation before inappropriate activation can occur. The host cell recognition domain ensures this protective action is directed specifically at host cell surfaces, preventing complement-mediated damage to self-tissues while maintaining effectiveness against pathogen-derived complement activation.
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.