Targeting the classical pathway
Potential targets specific for the CP are either the pattern recognition molecule C1q or the serine proteases C1r and C1s. Antibodies against C1q have been generated by Annexon, either as a complete mAb (ANX005) or as a Fab fragment (ANX009) both of which have completed Phase 1b trials for Guillain-Barre Syndrome (GBS) or glaucoma showing full inhibition of the CP activation. The FDA has granted ANX005 Fast Track and Orphan drug designation for the treatment of GBS. Antibodies are also available that are directed against C1s. Based on the mouse antibody TNT003(Shi et al., 2014) the Sanofi subsidiary Bioverativ has developed (a Sanofi company) the humanized antibody sutimlimab (TNT009) that is currently tested in a phase III trial for cold agglutinin disease (CAD), a subtype of autoimmune hemolytic anemia (AIHA) and in a phase I trial for idiopathic thrombocytopenic purpura. In a small cohort of 10 patients suffering from CAD, sutimlimab was found to be safe, well-tolerated and rapidly stopped CP-mediated hemolysis (Jager et al., 2019). In December 2019, Sanofi has reported first results from the phase III trial showing that sutimlimab inhibited hemolysis and improved anemia and fatigue in CAD patients shortly after treatment(Medicine, 2019). Finally, plasma protease C1 inhibitor (C1INH) controls the activity of C1s and has been on the market for more than 20 years for the treatment of hereditary angioedema. The problem with C1INH is that it is not only targeting C1s but also proteases of the coagulation-, kinin- and fibrinolysis-pathways (Levi, Cohn & Zeerleder, 2019). Thus, for selective and tailored targeting of the CP C1INH is not on option.
In summary, antibodies are available that specifically target the LP or the CP and are already in Phase III trials. Given that both virus-driven LP and adaptive immune response-mediated CP activation by virus-specific IgG and IgM antibodies will activate the complement system (Figure 1), it might be insufficient to target the LP only.