Neutralization of Marinobufagenin Demonstrates Efficacy In Vitro and In Vivo In Models of Preeclampsia

Background/Objectives: Marinobufagenin (MBG), a cardiotonic steroid, is distinctly elevated in preeclampsia (preE) and directly contribute to pathogenesis, possibly through deleterious signaling in cytotrophoblasts (CTBs). In this study, we evaluated the effects of anti-MBG human monoclonal antibody on cellular signaling in CTBs and in a rat model of preE. Methods: CTB cell proliferation, migration, and invasion in response to MBG with and without anti-MBG were evaluated by cell-based studies. Pro-angiogenic and anti-angiogenic factors in response to MBG with and without antibody were measured. Finally, we evaluated the lead anti-MBG antibody in comparison with the parent murine antibody in a rat model of preE. Results: CTB cells exposed to ≥ 1 nM MBG showed decreased (p < 0.05) proliferation, migration and invasion and decreased secretion of VEGF and PIGF, and increased secretion of sFlt-1 and sEng. Pretreatment with anti-MBG significantly (p < 0.05) attenuated the MBG-induced CTBs dysfunction and modulation of VEGF, PIGF, sFlt-1, and sEng expression. In the rat model, anti-MBG treatment normalized blood pressure, reduced proteinuria, and eliminated fetal effects. Conclusions: MBG is a potential causative agent for preE as it causes dysfunction in CTBs due to anti-angiogenic milieu. Our study suggests that anti-MBG antibody binds to MBG, neutralizing it, and preventing downstream signaling in vitro. In a rat model of preE, treatment with anti-MBG antibody was effective at normalizing blood pressure, kidney function, and fetal birth weights. These data suggest that a human monoclonal antibody with high specificity and affinity for MBG has potential as a therapeutic for preE.