The Dual Role of a Polyvalent IgM/IgA-Enriched Immunoglobulin Preparation in Activating and Inhibiting the Complement System

Abstract

Activation of the complement system is important for efficient clearance of a wide variety of pathogens via opsonophagocytosis, or by direct lysis via complement-dependent cytotoxicity (CDC). However, in severe infections dysregulation of the complement system contributes to hyperinflammation. The influence of the novel IgM/IgA-enriched immunoglobulin preparation trimodulin on the complement pathway was investigated in in vitro opsonophagocytosis, binding and CDC assays. Immunoglobulin levels before and after trimodulin treatment were placed in relation to complement assessments in humans. In vitro, trimodulin activates complement and induces opsonophagocytosis, but also interacts with opsonins C3b, C4b and anaphylatoxin C5a in a concentration-dependent manner. This was not observed for standard intravenous IgG preparation (IVIg). Accordingly, trimodulin, but not IVIg, inhibited the downstream CDC pathway and target cell lysis. If applied at a similar concentration range in healthy subjects, trimodulin treatment resulted in C3 and C4 consumption in a concentration-dependent manner, which was extended in patients with severe community-acquired pneumonia. Complement consumption is found to be dependent on underlying immunoglobulin levels, particularly IgM, pinpointing their regulative function in humans. IgM/IgA provide a balancing effect on the complement system. Trimodulin may enhance phagocytosis and opsonophagocytosis in patients with severe infections and prevent excessive pathogen lysis and release of harmful anaphylatoxins.

The Functional Role of IgA in the IgM/IgA-Enriched Immunoglobulin Preparation Trimodulin

“…In a previous work of our team, Schmidt et al [ 111 ] compared assay concentrations with data from trimodulin clinical phase I [ 112 ] and phase II studies [ 21 ]. It became clear that the assay concentrations correspond to immunoglobulin plasma levels of healthy human subjects (~20 g/L immunoglobulin), as well as sCAP patients (~18 g/L immunoglobulin) after trimodulin therapy.…”

Polyvalent Immunoglobulin Preparations Inhibit Pneumolysin-Induced Platelet Destruction

“…When trimodulin was given to patients with sCAP at a dose of 182.6 mg/kg body weight daily on 5 consecutive days, serum concentrations of up to 11.5 mg/mL IgG, 2.0 mg/mL IgM, and 4.1 mg/mL IgA were observed. 23 When IVIG was used in doses of 138.0 to 554.0 mg/kg body weight in patients with primary immunodeficiency, IgG concentrations of up to 16.6 mg/mL were reached 1 hour after infusion and 9 mg/mL IgG 2 weeks after infusion. 24 These pharmacokinetic properties indicate that the concentrations, which had been sufficient in our studies to prevent pneumolysin-induced platelet destruction in vitro, are even below those that can be reached in vivo using standard therapeutic regimens.…”

“… 30 Furthermore, trimodulin but not IVIG was found to interact with the complement system in an either activating or inhibiting way, depending on the concentration. 23 Which of these factors finally contributes to clinical efficacy in acute pneumonia is unresolved.…”

A new hope? Possibilities of therapeutic IgA antibodies in the treatment of inflammatory lung diseases

“…The opsonization and clearance of causal pathogens was shown by a large repertoire of antigen binding activities, as IgM, IgA and IgG antibody titers against relevant bacteria, viruses and fungi were present in trimodulin. It was shown that the antibodies of trimodulin can opsonize and enhance phagocytosis in vitro ( 123 , 191 ). The trimodulin mediated phagocytosis and inflammatory activation of neutrophils was shown to be dependent on IgA-FcαRI and IgG-FcγR binding, highlighting the anti-pathogenic effects of IgA in this therapeutic antibody preparation ( 123 ).…”