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

Area of Science:

• Immunology
• Biotechnology

Background:

• Complement activation via lectin pathway (LP) and alternative pathway (AP) exacerbates diseases like ischemia-reperfusion injury and age-related macular degeneration (AMD).
• Targeting these pathways offers a therapeutic strategy for various inflammatory and autoimmune conditions.

Purpose of the Study:

• To develop and evaluate novel dual inhibitors targeting both LP and AP complement activation.
• To assess the efficacy of fusion proteins MAp44-FH and sMAP-FH in inhibiting complement pathways.

Main Methods:

• Generation of fusion proteins by combining LP regulators (MAp44, sMAP) with AP regulator domains (SCR1/5-FH).
• Administration of murine fusion proteins in mice to assess complex formation with endogenous lectins.
• In vitro and in vivo complement activation assays to evaluate inhibitory effects on LP and AP.

Main Results:

• Both MAp44-FH and sMAP-FH fusion proteins formed complexes with endogenous lectins in mice.
• sMAP-FH demonstrated significantly stronger inhibition of LP and AP activation compared to MAp44-FH, both in vitro and in vivo.
• The human form of sMAP-FH effectively inhibited LP and AP activation in human sera.

Conclusions:

• The novel fusion protein sMAP-FH acts as a potent dual inhibitor of both LP and AP complement activation.
• sMAP-FH shows therapeutic potential for diseases where aberrant activation of both complement pathways plays a significant role.