Novel Therapy for Preeclampsia

先兆子痫的新疗法

• 批准号: 8313827
• 负责人: JAMES W LARRICK
• 金额: $ 22.68万
• 依托单位: PANORAMA RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2014-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313827
• 关键词: A Mouse; ATP phosphohydrolase; Adverse effects; Affect; Affinity; Amino Acids; Animals; Antibodies; Antibody Affinity; Antibody Binding Sites; Antihypertensive Agents; Area; Binding; Binding Sites; Biological Assay; Biological Markers; Biological Models; Blood Pressure; Blood Vessels; Cardiac Glycosides; Characteristics; Clinical Trials; Data; Development; Digibind; Digoxin; Disease; Drug Kinetics; Edema; Encephalopathies; Engineering; Erythrocytes; Functional disorder; Goals; Human; Hypertension; Hypotension; In Vitro; Innovative Therapy; Libraries; Life; Literature; Liver Failure; Magnesium; Measures; Mediating; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; Mutagenesis; Na(+)-K(+)-Exchanging ATPase; Natriuresis; Ouabain; Outcome; Overdose; Pathogenesis; Patients; Phase; Physiological; Placebos; Plasma; Play; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Production; Proteinuria; Pump; Rattus; Regulation; Relative (related person); Renal function; Rodent Model; Role; Screening Result; Seizures; Sheep; Signal Transduction; Specificity; Steroids; Study models; Supportive care; Syndrome; Testing; Therapeutic; Time; Toxic effect; Work; antibody engineering; cross reactivity; digoxin-like factors; effective therapy; experience; fetal; human monoclonal antibodies; improved; inhibiting antibody; innovation; marinobufagenin; mortality; mutant; novel; palliative; polyclonal antibody; pre-clinical; prevent; professor; src-Family Kinases; therapeutic target

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.

描述(申请人提供)：先兆子痫(PE)是一种严重的妊娠并发症，表现为高血压、蛋白尿和水肿，有时还会伴有脑病、癫痫发作和肝功能衰竭。PE导致5%至10%的妊娠并发症，是全世界孕产妇和胎儿发病率和死亡率的主要原因。然而，治疗这种疾病的有效方法并不存在。目前还没有已知的具体治疗方法，尽管缓解措施，如抗高血压药物、镁和类固醇，以及早期分娩可以改善结果。内源性类地高辛因子(EDLF)是一种与抗地高辛抗体交叉反应并抑制Na+/K+ATPase(NKA)的未知物质，在20世纪80年代首次被发现。大量文献支持EDLF水平升高可能是高血压发病机制的一个因素的假说。近年来，一种内源性强心类固醇(CTS)马利诺蟾毒配基(MBG)被确定为EDLF。妊娠合并PE时血浆MBG升高，提示MBG可能参与了PE的病理生理过程。DigiBind(葛兰素史克)是一种商业化的抗地高辛绵羊多克隆抗体，被批准用于治疗地高辛过量。DigiBind与MBG和其他CTS交叉反应。DigiBind可降低PE啮齿动物模型的血压。DigiBind已被证明可以逆转PE患者红细胞中NKA的抑制。除了这些广泛的临床前文献，在8例人类PE病例中也获得了令人鼓舞的结果，没有不良反应。对51名严重PE患者进行的临床试验显示，与安慰剂相比，DigiBind的肾功能有显著改善，没有不良反应。该项目的总体目标是开发和表征一种人源性抗MBG单抗(HumAb)，作为PE的创新治疗方法。一种抗地高辛的鼠单抗(MAb)已被广泛研究为模型系统，并已知与所有其他已测试的CTS以及相关类固醇发生交叉反应。在第一阶段，我们将把这一鼠源性抗地高辛单抗改造成对MBG具有高度特异性的人源性单抗。亲和力成熟，结合已知的改变地高辛结合部位特异性的特定氨基酸的体外定向突变，将产生多个克隆。克隆将根据其对MBG的亲和力和特异性进行排序。最后，我们将在NKA测试中评估功能。生产具有纳米分子KD、MBG高度特异性以及逆转MBG抑制NKA的能力的人源抗体，将值得提交第二阶段申请。第二阶段的工作将集中于获得提交IND所需的临床前数据。将进行药代动力学和毒性研究，以及证明疗效的动物研究。 与公共卫生相关：子痫前期(PE)是一种妊娠并发症，影响5%-10%的怀孕，可能危及生命。PE患者接受支持性治疗，如抗高血压药物和类固醇。除了交付之外，没有任何特定和有效的治疗方法。最近，一种洋地黄样因子--华蟾素(MBG)被认为是PE的致病因素。抗地高辛绵羊多克隆抗体DigiBind也与MBG反应。DigiBind在临床试验中对PE有效。我们将开发一种比DigiBind更具特异性的针对MBG的新型人源单抗。这一创新的治疗性抗体将成为PE的第一个有效治疗方法。