MAP‐2:CD55 chimeric construct effectively modulates complement activation

The complement system is a complex, tightly regulated protein cascade involved in pathogen defense and the pathogenesis of several diseases. Thus, the development of complement modulators has risen as a potential treatment for complement‐driven inflammatory pathologies. The enzymatically inactive MA...

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Veröffentlicht in:The FASEB journal 2023-11, Vol.37 (11), p.e23256-n/a
Hauptverfasser: González‐del‐Barrio, Lydia, Pérez‐Alós, Laura, Cyranka, Leon, Rosbjerg, Anne, Nagy, Simon, Prohászka, Zoltán, Garred, Peter, Bayarri‐Olmos, Rafael
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Sprache:eng
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Zusammenfassung:The complement system is a complex, tightly regulated protein cascade involved in pathogen defense and the pathogenesis of several diseases. Thus, the development of complement modulators has risen as a potential treatment for complement‐driven inflammatory pathologies. The enzymatically inactive MAP‐2 has been reported to inhibit the lectin pathway by competing with its homologous serine protease MASP‐2. The membrane‐bound complement inhibitor CD55 acts on the C3/C5 convertase level. Here, we fused MAP‐2 to the four N‐terminal domains of CD55 generating a targeted chimeric inhibitor to modulate complement activation at two different levels of the complement cascade. Its biological properties were compared in vitro with the parent molecules. While MAP‐2 and CD55 alone showed a minor inhibition of the three complement pathways when co‐incubated with serum (IC50MAP‐2+CD551‐4 = 60.98, 36.10, and 97.01 nM on the classical, lectin, and alternative pathways, respectively), MAP‐2:CD551‐4 demonstrated a potent inhibitory activity (IC50MAP‐2:CD551‐4 = 2.94, 1.76, and 12.86 nM, respectively). This inhibitory activity was substantially enhanced when pre‐complexes were formed with the lectin pathway recognition molecule mannose‐binding lectin (IC50MAP‐2:CD551‐4 = 0.14 nM). MAP‐2:CD551‐4 was also effective at protecting sensitized sheep erythrocytes in a classical hemolytic assay (CH50 = 13.35 nM). Finally, the chimeric inhibitor reduced neutrophil activation in full blood after stimulation with Aspergillus fumigatus conidia, as well as phagocytosis of conidia by isolated activated neutrophils. Our results demonstrate that MAP‐2:CD551‐4 is a potent complement inhibitor reinforcing the idea that engineered fusion proteins are a promising design strategy for identifying and developing drug candidates to treat complement‐mediated diseases. MAP‐2:CD551‐4 is a potent complement inhibitor capable of being targeted to the inflammation site via complex formation with the pattern recognition molecule MBL. Results show great inhibitory activity over the three complement activation pathways, being more efficient over the lectin pathway. This reinforces the idea of engineered fusion proteins as a promising design strategy for identifying and developing drug candidates to treat complement‐mediated diseases.
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.202300571R