Abstract P104: Neutralization Of Marinobufagenin Demonstrates Efficacy In Vitro And In Vivo In Models Of Preeclampsia
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Objective: Marinobufagenin (MBG), a cardiotonic steroid, is distinctly elevated in preeclampsia (preE) and may directly contribute to pathogenesis, possibly through deleterious signaling in cytotrophoblast (CTB) cells. In this study, we evaluate the effects of anti-MBG human monoclonal antibodies on cellular signaling in CTB cells and in a rat model of preE. Methods: CTB cell proliferation in response to MBG with and without anti-MBG was measured using a Cell Titer assay. Pro-angiogenic factors (VEGF and PlGF) and anti-angiogenic factors (sFlt-1 and sEng) 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 previously described rat model of preE which recapitulates the hypertension, proteinuria, and fetal growth effects of human preE. Results: CTB cells exposed to 1 nM MBG showed decreased ( p < 0.05) proliferation, 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 modulation of cell proliferation and expression of VEGF, PIGF, sFlt-1, and sEng. In the rat model, anti-MBG treatment normalized blood pressure, reduced proteinuria, and eliminated fetal effects. Conclusions: MBG has the potential to be a causative agent for preE as it causes dysfunction in CTB cells due to the anti-angiogenic milieu. Our study suggests that anti-MBG antibodies can bind to MBG, neutralizing it, and preventing downstream signaling in vitro. In a saline-induced 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.
