Advancing a novel therapy for preeclampsia

Advancing a novel therapy for preeclampsia Abstract Preeclampsia (PE) is a serious complication of pregnancy manifested by high blood pressure, proteinuria, and edema, sometimes with encephalopathy, seizures, and hepatic failure. PE complicates from 5 to 10% of pregnancies, and is a major cause of maternal and fetal morbidity and mortality worldwide. Nevertheless, no effective therapy exists. There is no known specific treatment, although palliative measures such as antihypertensive drugs, magnesium sulfate, and steroids, and early delivery improve outcomes. Elevation in the circulating level of an endogenous "digoxin-like" factor (EDLF), an unknown substance that cross reacts with anti-digoxin antibodies and inhibits the Na+/K+ ATPase (NKA) was first noted in the 1980s. An extensive literature supports the hypothesis that increased levels of EDLF may be a causative factor in the pathogenesis of hypertension. Recently, marinobufagenin (MBG), an endogenous cardiotonic steroid (CTS), has been identified as the EDLF. Plasma MBG is elevated in pregnancy complicated by PE, suggesting it might play a role in the pathophysiology of PE. Digibind (GlaxoSmithKline) is a commercially available anti-digoxin sheep polyclonal antibody approved for the treatment of digoxin overdose. A clinical trial of Digibind in 51 patients with severe PE showed significant improvement in renal function relative to placebo, with no adverse effects. Digibind cross- reacts modestly with MBG, and also with other CTS. In contrast, an anti-MBG human monoclonal antibody (humAb) is specific for MBG, with minimal cross-reactivity with other CTS. We have identified high-affinity anti- MBG humAbs and evaluated their specificity for MBG over related cardiotonic steroids. We then evaluated the most promising candidate humAbs for their ability to block MBG-mediated signaling. As a result of this work, we identified an anti-MBG humAb with a nanomolar Kd, limited cross-reactivity with related CTS, and the ability to block MBG effects on several pathways. During this Phase 1 project, we will conduct preclinical pharmacology and toxicology studies: teratogenicity testing, plasma half-life, and dose-response studies in an animal model of PE. Demonstration of efficacy without adverse effects will merit submission of a Phase 2 application. Phase 2 work will focus on obtaining additional preclinical data necessary for submission of an IND.