Inotropic Antibodies

描述(由申请人提供)：迫切需要开发治疗心力衰竭的新疗法。Na+/K+ATPase(NKA)催化Na+和K+离子跨心肌细胞质膜的主动转运。心脏糖苷被认为通过抑制NKA而具有正性变力作用。徐等人最近的工作。(2005,2006)确定了NKA上的一个激活位点。一种针对这个胞外部位的亲和纯化抗血清在体外和体内都能显著增强啮齿动物的NKA催化活性。NKA活性的增强与体内的正性变力作用相关。自发性高血压大鼠(SHHF)发展成一种严重的、致命的高血压性心肌病。通过主动免疫在SHHF中诱导的高滴度抗NKA抗体完全阻止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噬菌体文库中鉴定出几个高亲和力的抗NKA Fab。第一阶段的总体目标将是确定一组NKA特异性人类单抗的特征。该小组将根据体外和体内的NKA激活活性进行排序。最佳的“正性肌力HUMB”将被选为临床前药物治疗和在第二阶段进行的进一步动物研究。Xu等人使用兔抗血清和使用NKA特异肽的主动免疫的初步研究表明，这种方法将为心力衰竭提供一种新的免疫疗法。公共卫生相关性：叙述：迫切需要开发治疗心力衰竭的新疗法。我们已经开发出抗体，可以通过增加心脏收缩的强度来提高心力衰竭患者的存活率和生活质量。

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.