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A C3-specific nanobody that blocks all three activation pathways in the human and murine complement system
Henrik Pedersen1, Rasmus K Jensen1, Annette G Hansen2
1Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
The Journal of Biological Chemistry
|May 8, 2020
Summary
A novel nanobody, hC3Nb2, effectively inhibits complement component C3 deposition across all pathways in humans and mice. This versatile inhibitor shows potential for studying complement activation in disease models.
Area of Science:
- Immunology
- Proteolytic cascades
- Innate immunity
Background:
- The complement system is crucial for innate immunity, tagging pathogens and cellular debris for clearance.
- Complement component C3 is central to complement activation.
- Dysregulated complement activation is linked to various human diseases, driving therapeutic development.
Purpose of the Study:
- To characterize a novel nanobody, hC3Nb2, as an inhibitor of complement component C3.
- To investigate the mechanism of inhibition and cross-reactivity of hC3Nb2.
Main Methods:
- Biochemical assays
- Surface plasmon resonance
- Negative stain electron microscopy
- Functional assays
Main Results:
- hC3Nb2 binds human C3 and its degradation products with low nanomolar affinity.
- hC3Nb2 inhibits C3 deposition across all complement pathways without interfering with Factor H/I regulation.
- The nanobody binds MG3 and MG4 domains of C3/C3b, inhibiting substrate-convertase interaction.
- hC3Nb2 demonstrates cross-reactivity, inhibiting lectin and alternative pathways in murine serum.
Conclusions:
- hC3Nb2 is a potent, general, and versatile inhibitor of human and murine complement cascades.
- Its cross-reactivity makes it valuable for analyzing complement activation in animal models of disease.
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