Inotropic Antibodies

正性肌力抗体

• 批准号: 7743594
• 负责人: JAMES W LARRICK
• 金额: $ 19.89万
• 依托单位: PANORAMA RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743594
• 关键词: Active Biological Transport; Active Immunization; Adverse effects; Affinity; Animals; Antibodies; Binding; Biological Assay; Cardiac Glycosides; Cardiac Myocytes; Cell membrane; Goals; Heart failure; Human; Immune Sera; Immunotherapeutic agent; In Vitro; Inbred SHR Rats; Ions; Kinetics; Libraries; Life; Myocardial Contraction; Na(+)-K(+)-Exchanging ATPase; Oryctolagus cuniculus; Patients; Peptides; Phase; Rodent; Site; Work; base; extracellular; human monoclonal antibodies; hypertensive heart disease; in vitro activity; in vivo; novel; pre-clinical; prevent; public health relevance

DESCRIPTION (provided by applicant): An urgent need exists to develop novel therapies for cardiac failure. The Na+/K+ ATPase (NKA) catalyzes active transport of Na+ and K+ ions across the cardiomyocyte plasma membrane. Cardiac glycosides are thought to have a positive inotropic effect by inhibiting NKA. Recent work of Xu et al. (2005, 2006) identified an activation site on NKA. An affinity purified antiserum specific for this extracellular site markedly augments NKA catalytic activity both in vitro and in vivo in rodents. The augmented NKA activity is correlated with a positive inotropic action in vivo. Spontaneously hypertensive rats (SHHF) develop a severe, lethal hypertensive cardiomyopathy. High titer anti-NKA antibodies elicited in SHHF by active immunization completely prevented the lethal CHF of these animals with no noticeable adverse effects over a period of 30 weeks. Based on these initial proof-of principle studies, we have identified several high affinity anti-NKA Fabs from our human Fab phagemid library. The overall goal of phase I will be to characterize a panel of NKA- specific human monoclonal antibodies. The panel will be rank-ordered based on NKA-activating activities in vitro and in vivo. The best "Inotropic Humab" will be selected for preclinical pharmtox and further animal studies to be carried out in Phase II. The preliminary studies of Xu et al., using the rabbit antiserum and active immunization using an NKA-specific peptide, suggest that this approach will provide a novel immunotherapeutic for heart failure. PUBLIC HEALTH RELEVANCE: Narrative: An urgent need exists to develop novel therapies for cardiac failure. We have developed antibodies that may both enhance survival and the qualtiy of life for heart failure patients by increasing the strength of the heart's contractions.

描述（由申请人提供）：迫切需要开发心力衰竭的新疗法。Na+/K+ ATP酶（NKA）催化Na+和K+离子主动转运穿过心肌细胞质膜。强心苷被认为通过抑制NKA而具有正性肌力作用。Xu等人（2005，2006）的近期工作确定了NKA上的激活位点。亲和纯化的抗血清特异性的细胞外位点显着增强NKA催化活性在体外和体内的啮齿动物。增强的NKA活性与体内正性肌力作用相关。自发性高血压大鼠（SHHF）发展为严重的、致命的高血压性心肌病。通过主动免疫在SHHF中引发的高滴度抗NKA抗体完全预防了这些动物的致死性CHF，在30周的时间内没有明显的不良反应。基于这些初步的原理验证研究，我们已经从我们的人Fab噬菌粒文库中鉴定了几种高亲和力抗NKA Fab。I期的总体目标是表征一组NKA特异性人单克隆抗体。将基于体外和体内NKA激活活性对该组进行排序。将选择最佳的“变力性Humab”用于临床前药理学研究，并在II期进行进一步的动物研究。Xu等人的初步研究，使用兔抗血清和使用NKA特异性肽的主动免疫，表明这种方法将为心力衰竭提供新的免疫抑制剂。公共卫生相关性：叙述：迫切需要开发心力衰竭的新疗法。我们已经开发出抗体，通过增加心脏收缩的强度，可以提高心力衰竭患者的生存率和生活质量。