To determine whether active C1s (aC1s) inhibition by claseprubart (DNTH103) suppresses generation of C3a, C3b and membrane attack complex (MAC), and whether its complement inhibition profile is different to that of the C5 inhibitor ravulizumab. 

In generalized myasthenia gravis (gMG), pathogenic antibodies activate the classical complement pathway, culminating in MAC mediated injury at the neuromuscular junction (NMJ). Levels of complement components at the level of C3 have been associated with gMG disease severity in animal models. C5 inhibitors block MAC formation and improve clinical outcomes, but they do not reduce the upstream inflammatory fragments C3a and C3b, which potentially drive NMJ injury and amplify immune responses even without new MAC formation.

We quantified MAC formation using the Wieslab® Complement Classical Pathway assay in 1% normal human serum (NHS). Measured C3a in supernatants by ELISA and assessed C3b deposition on sensitized human red blood cells in 5% NHS by flow cytometry. For each assay, we tested dilution series of claseprubart, ravulizumab, and an isotype control. 

In head-to-head assays, claseprubart to ravulizumab produced comparable inhibition of MAC formation, confirming similar terminal pathway blockade. In contrast, only upstream aC1s inhibition with claseprubart resulted in near complete inhibition of the generation of C3a and C3b under the assay conditions tested, while ravulizumab did not. These findings were reproduced across three independent experiments, supporting a mechanistic distinction between upstream (aC1s) and downstream (C5) blockade. 

Upstream aC1s inhibition with claseprubart prevented MAC formation and reduced C3a and C3b to minimal levels, demonstrating potentially broader inflammatory control than C5 blockade and supporting the possibility for added clinical benefit while sparing the alternative and lectin pathways. These effects may provide immunological advantages by preserving innate defense mechanisms and pathophysiological advantages by limiting complement mediated injury at the neuromuscular junction.