The mechanism of C5 activation and its impact on the induction of thrombosis

• Applicant: Dr. Christoph Schmidt
• Subject Area: Hematology, Oncology ; Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 495891565

Since the approval of the complement terminal pathway inhibitor Eculizumab as the first in class complement therapeutic in 2007, the initiation of the complement terminal pathway by proteolytic activation of C5 has received continuously increasing interest from basic and clinician scientists alike. Given the remarkable therapeutic success of Eculizumab it is not surprising that complement intervention at the level of C5 is the most sought after strategy in the developmental pipeline for complement inhibition. This may be exemplified by at least ten different C5 inhibiting approaches being currently investigated in clinical trials for at least seven different clinical indications. In contrast to the huge interest in C5 activation and its inhibition our recent findings demonstrate that C5 activation proceeds differently from textbook knowledge. This has an immense impact on our general understanding how the terminal complement effector pathway is activated but also bears important implications for our knowledge on the pathophysiological roles of C5 and its therapeutic inhibition. This includes the role of C5 activation in inducing severe, life-threating thromboembolic conditions: clinical evidence unequivocally shows that C5 inhibition by Eculizumab therapy dramatically reduces fatal thrombotic complications in the diseases paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS) but the detailed pathways underlying this phenomenon remain to be elucidated. Here it is proposed i) to investigate mechanistically on a molecular and cellular level how the complement component C5 is activated, ii) to uncover patient specific factors that drive pharmacodynamics breakthrough of C5 inhibitors (i.e. the phenomenon of residual terminal pathway activation despites excess amounts of divers stoichiometric C5 inhibitors) and iii) to assess the impact of C5 activation on inducing prothrombotic cell activation.

• DFG Programme: Research Grants