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

Abstract

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.

Alternative Complement Pathway Inhibition Abrogates Pneumococcal Opsonophagocytosis in Vaccine-Naïve, but Not in Vaccinated Individuals

“…Current treatment of such diseases includes prevention of the complement membrane attack complex (MAC) with monoclonal antibodies (mAbs) that bind to C5 (41). While MAC formation is involved in uncontrolled lysis of erythrocytes in some of these patients, it is also required for serum bactericidal activity (SBA) and therefore, terminal complement blockage increases the risk of invasive disease by encapsulated bacteria (42)(43)(44)(45). This has led to the concept that compared to C5 inhibition, specific inhibition of the AP may reduce the infection risk.…”

Alternative pathway amplification and infections

“…In the presence of specific anti‐capsule Ab, the amount of C4b deposited on bacteria decreased 8‐fold when C1s was blocked, compared to C4b deposition when complement was intact. Interestingly, C3 deposition in the presence of anti‐capsular Ab was not affected by C1s blockade (Figure 3a, upper graph ), suggesting Ab‐dependent recruitment of the AP 97 . Under the same assay conditions, blocking FB function (leaving the CP intact) also did not impair C3 deposition.…”

“…Pharmacologic blockade of the C1s subunit of C1 with a F(ab') 2 fragment of anti‐C1s abrogated killing of a group C meningococcal strain in 20% Ab (IgG and IgM) depleted human serum that contained specific anti‐group C capsular Ab 97 . In the presence of specific anti‐capsule Ab, the amount of C4b deposited on bacteria decreased 8‐fold when C1s was blocked, compared to C4b deposition when complement was intact.…”

Complement C1s as a diagnostic marker and therapeutic target: Progress and propective

“…Whether they can reduce the microvascular inflammation during AMR and prolong the survival of transplants remain to be further explored. Interestingly, it was found that C1s-specific monoclonal antibody TNT005 did not abolish the therapeutic effects of anti- Neisseria meningitidis and Streptococcus pneumoniae antibodies, whereas simultaneous inhibition of CP and AP blocked the killing function of the anti-bacterial antibodies ( 85 ). Thus, targeting C1s may specifically prevent CP activation without abating the alternative and lectin pathways of complement activation and their associated immunological effector functions, and might also reduce the production of auto-antibodies.…”