Laboratory findings in patients treated with complement factor C3 inhibitor pegcetacoplan

Objectives: Complement inhibitor pegcetacoplan binds to C3 and its activation product C3b. Pegcetacoplan has been approved for the treatment of paroxysmal nocturnal hemoglobinuria. Because pegcetacoplan exerts broad inhibition of the complement cascade its efficacy is also investigated in numerous other diseases caused by complement dysregulation, such as C3 glomerulopathy. Pegcetacoplan causes a number of counterintuitive changes in laboratory results. Methods: In-depth complement analysis in two patients with PNH and three patients with C3 glomerulopathy, all treated with pegcetacoplan. Results: C3 levels increase up to 300 % above reference levels. In vitro testing showed that this is not a turbidimetric artifact in the C3 immunoassay due to pegcetacoplan-C3 complex formation but appears to be caused by increased half-life of C3 bound to pegcetacoplan. Unbiased mass spectrometric plasma proteome analysis confirmed the dramatic pegcetacoplan-induced increase in circulating C3. Surprisingly, also a three-fold increase of properdin was observed during pegcetacoplan treatment. Serum protein electrophoresis showed an additional band in all patients after pegcetacoplan exposure. This C3-band does not migrate at its expected position because of changes in the mass and charge of C3 bound to pegcetacoplan and should therefore not be misinterpreted as an M-protein. Both in vitro experiments and real clinical practice laboratory results demonstrated that pegcetacoplan completely blocked the alternative complement pathway while the classical pathway is affected but remains largely intact. Conclusions: Because of the increasing use of pegcetacoplan in routine clinical practice, it is important that both clinicians and laboratory specialists are aware of these unexpected therapy-induced laboratory findings.