Advancing a novel therapy for preeclampsia

推进先兆子痫的新疗法 摘要 先兆子痫（PE）是一种严重的妊娠并发症，表现为高血压、蛋白尿， 水肿，有时伴有脑病、癫痫和肝功能衰竭。PE并发症占5%至10%， 这是导致怀孕的主要原因，也是全世界孕产妇和胎儿发病和死亡的主要原因。然而， 存在有效的治疗方法。没有已知的具体治疗方法，尽管采取了姑息措施，如 抗高血压药物、硫酸镁和类固醇以及早期分娩可改善预后。抬高 内源性“地高辛样”因子（EDLF）的循环水平，一种与 抗地高辛抗体和抑制Na+/K+ ATP酶（NKA）的作用在20世纪80年代首次被注意到。广泛的文献 支持这一假设，即EDLF水平的增加可能是一个致病因素的发病机制， 高血压近年来，海洋蟾蜍精（marinobufagenin，MBG）被发现是一种内源性强心甾体（CTS） 作为EDLF。妊娠合并PE时血浆MBG升高，提示其可能在妊娠合并PE的发生发展中起作用。 PE的病理生理学Digibind（GlaxoSmithKline）是市售的抗地高辛绵羊多克隆抗体， 批准用于治疗地高辛过量的抗体。Digibind治疗重度肺栓塞51例临床观察 与安慰剂相比，肾功能有显著改善，无不良反应。Digibind交叉- 与MBG以及其他CTS反应温和。相反，抗MBG人单克隆抗体 （humAb）对MBG具有特异性，与其他CTS的交叉反应性最小。我们发现了高亲和力的抗- MBG humAb，并评估其特异性MBG超过相关的强心类固醇。然后我们评估了 最有希望的候选humAb阻断MBG介导的信号传导的能力。由于这项工作，我们 鉴定了具有纳摩尔Kd的抗MBG humAb，与相关CTS的交叉反应性有限，并且能够 阻断MBG对几种途径的影响。在第1阶段项目中，我们将进行临床前药理学研究， 和毒理学研究：致畸性试验，血浆半衰期，和剂量反应研究的动物模型， 体育课证明有效性而无不良反应将值得提交II期申请。2期 工作重点是获得提交IND所需的额外临床前数据。

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.