Effect of a C1s Inhibitor on the Efficacy of Anti-Capsular Antibodies against Neisseria meningitidis and Streptococcus pneumoniae.

Terminal complement pathway inhibition at the level of C5 alleviates symptoms of several diseases associated with complement overactivation. However, C5 blockade is associated with an increased risk of invasive meningococcal disease despite immunization. Targeting specific complement pathways proximal to C5 provides the theoretical advantage of leaving the other pathways (including the terminal pathway) intact for immune surveillance. We aimed to address the risk of Neisseria meningitidis and Streptococcus pneumoniae infections when inhibiting the classical pathway (CP) using a specific C1s inhibitor (TNT005). Addition of TNT005 to 20% normal human serum that contained anti-meningococcal capsular Ab decreased C4 deposition 8-fold and abrogated killing of N. meningitidis, despite leaving C3 deposition intact. TNT005 impaired killing of N. meningitidis in 78% nonimmune human plasma and 78% whole blood but permitted killing in both when specific anti-capsular Ab was added. Simultaneously inhibiting both the CP and alternative pathway (AP) blocked killing of Ab-coated N. meningitidis in whole blood. Blocking the AP alone abrogated C3 deposition, whereas TNT005 only partially inhibited (∼40% decrease) C3 deposition on S. pneumoniae coated with anti-capsular Ab. Blocking either the CP or AP alone did not impair killing of pneumococci in whole blood containing specific Ab (<10% survival at 3 h); however, blocking both pathways resulted in ∼35% bacterial survival. These data suggest that killing of N. meningitidis or S. pneumoniae in whole blood containing specific anti-capsular Abs is unimpeded by TNT005. Meningococcal and pneumococcal capsular conjugate vaccines may mitigate risk of these infections in patients receiving C1s inhibitors.