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.