Improved therapeutic efficacy of a bifunctional anti-C5 mAb-FH SCR1-5 fusion protein over anti-C5 mAb in an accelerated mouse model of C3 glomerulopathy.

C3 glomerulopathy (C3G), a rare kidney disease caused by dysregulation of alternative pathway complement activation, is characterized by glomerular C3 deposition, proteinuria, crescentic glomerulonephritis, and renal failure. The anti-C5 monoclonal antibody (mAb) drug eculizumab has shown therapeutic effects in some but not all patients with C3G, and no approved therapy is currently available. Here, we developed and used a triple transgenic mouse model of fast progressing lethal C3G (FHm/mP-/-hFDKI/KI) to compare the therapeutic efficacy of a bifunctional anti-C5 mAb fused to a functional factor H (FH) fragment (short consensus repeat 1-5 [SCR1-5]) and the anti-C5 mAb itself. The new C3G mouse model is derived by humanizing factor D (hFDKI/KI) in a previously described FHm/mP-/- mouse that developed lethal C3G. We tested the effectiveness of these 2 complement inhibitors in triple transgenic mice with established C3G and glomerular disease. No FHm/mP-/-hFDKI/KI mice treated with vehicle survived the 30-d study period. All FHm/mP-/-hFDKI/KI mice treated with the C5 mAb-FH SCR1-5 fusion protein and 50% of mice treated with the anti-C5 mAb survived the 30-d treatment period. Moreover, mice treated with the C5 mAb-FH SCR1-5 fusion protein, but not those treated with the anti-C5 mAb, showed restored plasma alternative pathway complement control. The C5 mAb-FH SCR1-5 fusion protein reversed glomerular disease to a greater degree than the anti-C5 mAb. These data suggest that simultaneously inhibiting the terminal and proximal complement pathways, by anti-C5 mAb and FH SCR1-5, respectively, can reverse established C3G and is more efficacious than inhibiting the terminal pathway alone. A similar approach may be effective in treating human C3G.