The inappropriate activation of
complement may contribute to various
immune diseases. The alternative pathway (AP) predominates during complement activation regardless of the initiating pathways. Hence, the main AP regulator
factor H (FH) holds great potential as an attractive therapeutic intervention. In addition,
complement receptor of the
immunoglobulin superfamily (CRIg) has been demonstrated to inhibit AP and, more notably, still specifically binds to C3b/
iC3b. We thus developed novel CRIg-targeted
complement inhibitors by connecting the functional domains of CRIg and FH, which we termed CRIg-FH and CRIg-L-FH. CRIg-L-FH, slightly more potent than CRIg-FH, considerably inhibited both AP- and also classical pathway (CP)-mediated
hemolysis and successfully eliminated the deposition of C3b/
iC3b. Kinetic analysis further revealed that the binding affinity constant (KD) of CRIg/FH was in the micromolar range, consistent with its long-lasting binding to
complement-attacked cells. CRIg-L-FH efficiently protected aberrant erythrocytes of patients with
paroxysmal nocturnal hemoglobinuria (PNH) from AP- and CP-mediated
complement damage (IC50 was 22.43 and 64.69 nM, respectively). Moreover, CRIg-L-FH was found to inhibit complement activation induced by the anti-Thy1 antibody in a mesangioproliferative
glomerulonephritis (MPGN) rat model. Hence, CRIg-L-FH protects glomerular mesangial cells (GMCs) from
complement-mediated injury and proliferative lesions. These findings strongly suggest that CRIg/FH is a potential therapeutic
drug candidate for a range of
complement-mediated diseases.