A novel complement inhibitor sMAP‐FH targeting both the lectin and alternative complement pathways

Inhibition of the complement activation has emerged as an option for treatment of a range of diseases. Activation of the lectin and alternative pathways (LP and AP, respectively) contribute to the deterioration of conditions in certain diseases such as ischemia‐reperfusion injuries and age‐related m...

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Bibliographic Details
Published in:The FASEB journal 2020-05, Vol.34 (5), p.6598-6612
Main Authors: Takasumi, Mika, Omori, Tomoko, Machida, Takeshi, Ishida, Yumi, Hayashi, Manabu, Suzuki, Toshiyuki, Homma, Yoshimi, Endo, Yuichi, Takahashi, Minoru, Ohira, Hiromasa, Fujita, Teizo, Sekine, Hideharu
Format: Article
Language:English
Subjects:
alternative complement pathway
Animals
Complement Activation - immunology
Complement Factor H - immunology
Complement Factor H - metabolism
Complement Inactivating Agents - immunology
Complement Inactivating Agents - metabolism
Complement Pathway, Alternative - immunology
factor H
Female
Humans
lectin complement pathway
Lectins - immunology
Lectins - metabolism
Mannose-Binding Lectin - immunology
Mannose-Binding Lectin - metabolism
Mannose-Binding Protein-Associated Serine Proteases - immunology
Mannose-Binding Protein-Associated Serine Proteases - metabolism
MAp44
Mice
Mice, Inbred C57BL
small mannose‐binding lectin‐associated protein
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Summary:Inhibition of the complement activation has emerged as an option for treatment of a range of diseases. Activation of the lectin and alternative pathways (LP and AP, respectively) contribute to the deterioration of conditions in certain diseases such as ischemia‐reperfusion injuries and age‐related macular degeneration (AMD). In the current study, we generated dual complement inhibitors of the pathways MAp44‐FH and sMAP‐FH by fusing full‐length MAp44 or small mannose‐binding lectin‐associated protein (sMAP), LP regulators, with the N‐terminal five short consensus repeat (SCR) domains of complement factor H (SCR1/5‐FH), an AP regulator. The murine forms of both fusion proteins formed a complex with endogenous mannose‐binding lectin (MBL) or ficolin A in the circulation when administered in mice intraperitoneally. Multiple complement activation assays revealed that sMAP‐FH had significantly higher inhibitory effects on activation of the LP and AP in vivo as well as in vitro compared to MAp44‐FH. Human form of sMAP‐FH also showed dual inhibitory effects on LP and AP activation in human sera. Our results indicate that the novel fusion protein sMAP‐FH inhibits both the LP and AP activation in mice and in human sera, and could be an effective therapeutic agent for diseases in which both the LP and AP activation are significantly involved.
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.201902475R