# Complement activation in anti-glomerular basement membrane disease before and after treatment with imlifidase

## TL;DR

This study examines how complement activation changes in anti-GBM disease patients before and after treatment with imlifidase, which rapidly depletes IgG.

## Contribution

The study provides new insights into the dynamics of complement pathway activation in anti-GBM disease following IgG depletion therapy.

## Key findings

- The C4d/C4 ratio decreased rapidly after imlifidase treatment, indicating reduced classical pathway activation.
- Terminal complement complexes (sTCC) remained elevated throughout the trial despite IgG depletion.
- Patients with pre-existing anti-drug antibodies showed a more pronounced transient increase in complement activation markers.

## Abstract

The involvement of the complement system in anti-glomerular basement membrane (GBM) disease is well known but incompletely characterized. The ability of autoantibodies to trigger the classical pathway is evident, while the lectin and alternative pathways also seem to be of importance. We studied complement activation in patients treated with imlifidase, which leads to rapid IgG depletion, to elucidate the role of complement in anti-GBM disease.

The GOOD-IDES-01 trial included 15 anti-GBM disease patients treated with one dose of imlifidase in addition to standard therapy with 6 months of follow-up. Plasma samples were analyzed for C3, C4 and complement activation products [C4d, C3bBbP and soluble terminal complement complexes (sTCC)]. Ratios of C4d/C4 and C3bBbP/C3 were calculated to correct for plasmapheresis. Serum samples were analyzed for anti-drug antibodies (ADA) directed against imlifidase.

The C4d/C4 ratio decreased rapidly from its pre-dose level, while sTCC decreased more slowly. sTCC and C3bBbP/C3 were above the reference level throughout the trial. We observed a transient increase in C4d/C4 and C3bBbP/C3, but not sTCC, immediately following treatment with imlifidase, which tended to be more pronounced in patients with more pre-existing ADA.

Classical pathway activation decreased rapidly after autoantibody removal by imlifidase and increased again in most of those that experienced a rebound, but terminal complement activation remained elevated throughout the trial. However, due to the small sample size our results must be interpreted with caution.

GRAPHICAL ABSTRACT