Advancing a novel therapy for preeclampsia 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 thepathophysiology of PE. Digibind (GlaxoSmithKline) is a commercially available anti-digoxin sheep polyclonalantibody 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 themost 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 toblock 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 2work will focus on obtaining additional preclinical data necessary for submission of an IND.
Public Health Relevance Statement: Preeclampsia (PE) is a complication of pregnancy that affects 5-10% of pregnancies and can be life-threatening. PE patients are given supportive therapy, such as anti-hypertensives and steroids. No specific and effective therapy, other than delivery, exists. Recently, a digitalis-like factor, marinobufagenin (MBG) has been implicated as a causative factor in PE. We have identified a novel human monoclonal antibody with high specificity for MBG and have demonstrated its effectiveness in an animal model of PE. This innovative therapeutic humAb will be the first effective treatment of PE.
Project Terms: Achievement, Achievement Attainment, Na(+)-K(+)-Exchanging ATPase, Na pump, Na+ K+ ATPase, Potassium ATPase Sodium, Potassium Adenosine Triphosphatase Sodium, Potassium Adenosinetriphosphatase Sodium, Potassium Pump, Sodium Pump, Sodium-Potassium Pump, sodium potassium exchanging ATPase, Affect, inhibitor, Antibodies, Antihypertensive Agents, Anti-Hypertensive Agents, Anti-Hypertensive Drugs, Anti-Hypertensives, Antihypertensive Drugs, Antihypertensives, Hypotensive Agent, Hypotensive Drugs, Blood Pressure, Blood Vessels, vascular, Cardiac Glycosides, Cardiotonic Steroids, Cardiovascular system, Cardiovascular, Cardiovascular Body System, Cardiovascular Organ System, Heart Vascular, circulatory system, Clinical Trials, Collagen, DOCA, Digoxin, Lanoxin, Edema, Dropsy, Hydrops, Exhibits, Fibrosis, Goals, Half-Life, Human, Modern Man, Hypertension, Vascular Hypertensive Disease, Vascular Hypertensive Disorder, high blood pressure, hyperpiesia, hyperpiesis, hypertensive disease, hypertensive disorder, Kidney, Kidney Urinary System, renal, Light, Photoradiation, Literature, Macaca fascicularis, Cynomolgus Monkey, Cynomolgus macaque, M fascicularis, M. fascicularis, Crab-Eating Macaque, Crab-Eating Monkey, Magnesium Sulfate, Magnesium SO4, Morbidity - disease rate, Morbidity, mortality, Natriuresis, Overdose, Patients, Pharmacokinetics, Drug Kinetics, Sham Treatment, sham therapy, Placebos, Blood Plasma, Plasma Serum, Reticuloendothelial System, Serum, Plasma, Plasma, Play, EPH Gestosis, Preeclampsia, Pregnancy Toxemias, Proteinuria-Edema-Hypertension Gestosis, pregnancy toxemia/hypertension, Pre-Eclampsia, Gestation, Pregnancy, complications during pregnancy, pregnancy-related complications, Pregnancy Complications, Procollagen, ATP-protein phosphotransferase, Kinase Family Gene, glycogen synthase a kinase, hydroxyalkyl protein kinase, phosphorylase b kinase kinase, Protein Kinase, Proteinuria, Common Rat Strains, Rat, Rats Mammals, Rattus, EGF Receptor, EGFR, ERBB Protein, Epidermal Growth Factor Receptor Kinase, Epidermal Growth Factor Receptor Protein-Tyrosine Kinase, Epidermal Growth Factor-Urogastrone Receptors, HER1, TGF-alpha Receptor, Transforming Growth Factor alpha Receptor, Urogastrone Receptor, c-erbB-1, c-erbB-1 Protein, erbB-1, erbB-1 Proto-Oncogene Protein, erbBl, proto-oncogene protein c-erbB-1, Epidermal Growth Factor Receptor, Steroid Receptors, social role, Role, Safety, Seizures, Ovine, Ovis, Sheep, Cell Communication and Signaling, Cell Signaling, Intracellular Communication and Signaling, Signal Transduction Systems, Signaling, biological signal transduction, Signal Transduction, Sodium Nitroprusside, Disodium Salt Nitroprusside, Specificity, Steroid Compound, Steroids, Syndrome, Teratogenic, Teratogenicity, Teratogens, Testing, Time, Tissues, Body Tissues, transcription factor, Basal Transcription Factor, Basal transcription factor genes, General Transcription Factor Gene, General Transcription Factors, Transcription Factor Proto-Oncogene, Transcription factor genes, Structure of umbilical artery, Umbilical Arteries, Vasodilation, Vasodilatation, Vasorelaxation, Work, ATPase inhibitory protein, F1-ATPase epsilon subunit, Na-K ATPase inhibitor, Endothelin-1, EDN1, ET-1, Endothelin Type 1, Measures, Encephalopathies, Liver Failure, Hepatic Failure, Mediating, Site, Area, Phase, protein kinase C-delta, cytotrophoblast, kidney function, Renal function, non-human primate, nonhuman primate, Oxidative Stress, Funding, marinobufogenin, marinobufagenin, Therapeutic Steroid Hormone, steroid hormone, Therapeutic, polyclonal antibody, Supportive Therapy, Supportive care, Life, DLIF factor, DLIS factor, digitalis-like factors, digoxin-immunoreactive factors, digoxin-like immunoreactive factor, digoxin-like immunoreactive substance, digoxin-like factors, Nuclear, fetal, experience, Receptor Protein, receptor, success, Animal Models and Related Studies, model of animal, model organism, Animal Model, Toxicities, Toxic effect, Pharmacology and Toxicology, novel, Digibind, Pathogenesis, Modeling, response, cross reactivity, Adverse effects, Molecular Interaction, Binding, Effectiveness, palliative, Dose, Affinity, Data, Small Business Innovation Research Grant, SBIR, Small Business Innovation Research, Development, developmental, Pathway interactions, pathway, pre-clinical, preclinical, Outcome, human monoclonal antibodies, Hu-mABs, humAbs, human mAbs, human monoclonals, innovation, innovate, innovative, Impairment, novel therapeutics, new drug treatments, new drugs, new therapeutics, new therapy, next generation therapeutics, novel drug treatments, novel drugs, novel therapy, therapeutic target, antibody engineering, pregnant, effective therapy, effective treatment, constriction, potential biomarker, potential biological marker, improved outcome, nanomolar, nano-molar, pathophysiology of preeclampsia, pathophysiology of pre-eclampsia
