Eculizumab treatment alters the proteometabolome beyond the inhibition of complement

• DOI: 10.1172/jci.insight.169135
• Publication Date: 2023-05-25T16:01:08Z
• Authors: Christopher Nelke; Christina B. Schr...; Frauke Stascheit; Niklas Huntemann; Marc Pawlitzki; Alice Willison; Saskia Räuber; Nico Melzer; Ute Distler; Stefan Tenzer; Kai Stühler; Andreas Roos; Andreas Meisel; Sven G. Meuth; Tobias Ruck
• Keywords: Eculizumab; Complement component 5; Anaphylatoxin

Therapeutic strategies targeting complement have revolutionized the treatment of myasthenia gravis (MG). However, a deeper understanding modulation in human system is required to improve responses and identify "off-target effects" shaping long-term outcomes. For this purpose, we studied cohort MG patients treated with either eculizumab (n = 10) or azathioprine as well treatment-naïve using combined proteomics metabolomics approach. This strategy confirmed known effects on terminal cascade. Beyond that, modulated serum proteometabolome distinct pathways were altered eculizumab-treated including oxidative stress response, mitogen-activated protein kinase signaling lipid metabolism particular emphasis arachidonic acid signaling. We detected reduced levels arachidonate 5-lipoxygenase (ALOX5) leukotriene A4 (LTA4) patients. Mechanistically, ligation C5a receptor (C5aR) needed for ALOX5 generation downstream leukotrienes. As prevents cleavage C5 into C5a, decreased engagement C5aR may inhibit ALOX5-mediated synthesis pro-inflammatory These findings indicate induced by eculizumab, illuminating potential mechanisms action that be harnessed