Novel Therapy for Preeclampsia
Principal Investigator: James W Larrick
Abstract: DESCRIPTION (provided by applicant): 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, an effective therapy for this disorder does not exist. There is no known specific treatment, although palliative measures such as antihypertensive drugs, magnesium, 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. Digibind cross-reacts with MBG and other CTS. Digibind lowers blood pressure in rodent models of PE. Digibind has been shown to reverse inhibition of the NKA in erythrocytes from patients with PE. In addition to this extensive pre-clinical literature, encouraging results with no adverse effects were obtained in 8 human cases of PE. A clinical trial of Digibind in 51 patients with severe PE showed significant improvement in renal function relative to placebo, with no adverse effects. The overall goal of this project is to develop and characterize a human anti-MBG monoclonal antibody (humAb) as an innovative treatment for PE. A mouse monoclonal antibody (mAb) to digoxin has been extensively studied as a model system and is known to cross-react with all other CTS that have been tested, as well as related steroids. In phase I, we will engineer this murine anti-digoxin mAb into a human mAb with high specificity for MBG. Affinity maturation, in combination with targeted in vitro mutagenesis of specific amino acids known to modify specificity of the binding site for digoxin, will yield multipe clones. Clones will be rank ordered by their affinity and specificity for MBG. Finally, we will evaluate function in an NKA assay. Production of a humAb with a nanomolar Kd, high specificity for MBG, and ability to reverse MBG inhibition of the NKA, will merit submission of a phase 2 application. Phase II work will focus on obtaining the preclinical data necessary for submission of an IND. Pharmacokinetics and toxicity studies, as well as animal studies to demonstrate efficacy, will be performed. PUBLIC HEALTH RELEVANCE: 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. An anti-digoxin sheep polyclonal antibody, Digibind, also reacts with MBG. Digibind was effective for PE in a clinical trial. We will develop a novel human monoclonal antibody with higher specificity than Digibind for MBG. This innovative therapeutic humAb will be the first effective treatment of PE.
Funding Period: 2012-04-15 - 2014-03-14
more information: NIH RePORT