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首页> 外文期刊>The Internet Journal of Asthma, Allergy and Immunology >Safety and Pharmacokinetics of a Human IgM anti-Lipid A Monoclonal Antibody in Primary Immune Deficient Patients
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Safety and Pharmacokinetics of a Human IgM anti-Lipid A Monoclonal Antibody in Primary Immune Deficient Patients

机译：人IgM抗脂质A单克隆抗体在原发性免疫缺陷患者中的安全性和药代动力学

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A phase I clinical study of a human IgM anti-lipid A monoclonal antibody was conducted in 24 patients with a primary immunodeficiency syndrome. Six patients each were evaluated at one of four dosage levels: 50 mg, 75 mg, 100 mg or 150 mg. Subjects were observed for both acute adverse events as well as various laboratory parameters over 28 days. In addition, a pharmacokinetic study was done on the single antibody infusion at each dosage level assessing half-life, peak concentration and 24 hr concentration. The results indicated that the infusion may be safely given at all four dosage levels and that the pharmacokinetics of this antibody is probably linear. Corresponding author:Luis M. Salmun, M.D.Children's Hospital Boston300 Longwood AveBoston, MA 02115Telephone # (617) 355-4344Fax # (617) 232-0475We thank Dr. Martin Lee for his statistical support. INTRODUCTION The rate of nosocomial as well as community acquired septicemia has increased over the past decade [1, 2]. Gram negative organisms play a major etiologic role in these infections [3], with Gram negative bacteremia being associated with a mortality rate higher than 20% [4]. For those patients who go on to develop septic shock this mortality rate has been shown to climb over 50% [5, 6].Lipid A, a subunit of the core lipopolysaccharide (LPS) moiety of gram negative bacterial cell walls, is believed to be the trigger in the development of what has come to be known as the sepsis syndrome, which leads to and often culminates in septic shock [7, 8].Over the past two decades, clinical as well as animal and basic data have been accumulating which strongly suggest that antibody to the core LPS structure could be protective against the sequelae of the sepsis syndrome. The first study supporting this theory was published in 1982 by Ziegler and colleagues [7]. Subsequent studies have provided support for this hypothesis [4, 9, 10, 11].The purpose of this study was to determine the safety and pharmacokinetics of a human IgM anti-Lipid A (with a murine J chain) monoclonal antibody in patients with primary immunodeficiencies 24 hours before and 24 hours after they received their intravenous immunoglobulin (IVIG) replacement. METHODS Patient populationTwenty four patients over 13 years of age with a primary immunodeficiency (as defined by the World Health Organization criteria), on maintenance IVIG replacement therapy, were enrolled to participate in the study. At entry, they all signed an informed consent that had been approved by the Committee on Clinical Investigation at Children’s Hospital in Boston. They all had normal renal function and no clinical evidence of active infection for 1 month prior to infusion. Patients with a history of allergy to blood or blood products or to mouse protein, and patients who had been on antibiotic treatment for an active infection over the 2 weeks prior to the monoclonal antibody infusion were not eligible to enter the study.RandomizationPatients were infused with the anti-Lipid A monoclonal antibody in an open label, uncontrolled single infusion fashion. Six patients were randomized to each one of four dosage levels: 50 mg, 75 mg, 100 mg and 150 mg. Within each of the dosage levels, patients were stratified into two categories: half were infused with the anti-Lipid A monoclonal antibody 24 hours prior to their scheduled IVIG infusion, and the other half were infused with it 24 hours after their scheduled infusion of IVIG. Each dosage level, beginning with the lowest, was completed sequentially.Monoclonal antibody preparationThe antibody was originally derived from spleen cells from an individual who had been immunized with Salmonella minnesota (Re595 mutant), whole killed vaccine, prior to undergoing splenectomy for idiopathic thrombocytopenic purpura. This particular antibody was chosen for development based upon its ability to cross-react with the LPS of various Gram negative genera, and it has been shown to react with the Lipid A moiety of LPS i
机译：在24例原发性免疫缺陷综合征患者中进行了人类IgM抗脂质A单克隆抗体的I期临床研究。分别以四种剂量水平之一对六位患者进行了评估：50 mg，75 mg，100 mg或150 mg。在28天内观察对象的急性不良事件以及各种实验室参数。另外，在每个剂量水平对单抗体输注进行了药代动力学研究，评估了半衰期，峰浓度和24小时浓度。结果表明可以在所有四个剂量水平上安全地进行输注，并且该抗体的药代动力学可能是线性的。通讯作者：波士顿医学博士儿童医院Luis M.Salmun马萨诸塞州长伍德大街300号，马萨诸塞州02115电话＃（617）355-4344传真＃（617）232-0475我们感谢Martin Lee博士的统计支持。引言在过去的十年中，医院以及社区获得性败血病的发病率均有所上升[1，2]。革兰氏阴性菌在这些感染中起主要病因作用[3]，其中革兰氏阴性菌血症的死亡率高于20％[4]。对于那些继续发展为败血性休克的患者，该死亡率已显示超过50％[5，6]。脂质A是革兰氏阴性细菌细胞壁核心脂多糖（LPS）部分的亚基，据信导致败血症综合症发展的触发因素，败血症综合症导致并经常导致败血性休克[7，8]。在过去的二十年中，临床以及动物和基础数据不断积累这有力地表明，针对核心LPS结构的抗体可能对败血症综合征的后遗症具有保护作用。 Ziegler及其同事[7]于1982年发表了支持该理论的第一项研究。随后的研究为这一假说提供了支持[4,9,10,11]。本研究的目的是确定人IgM抗脂质A（带有鼠J链）单克隆抗体在患有高脂血症的患者中的安全性和药物动力学。他们在接受静脉免疫球蛋白（IVIG）替代治疗之前和之后的24小时内都患有原发性免疫缺陷。方法患者人群24例接受维持IVIG替代疗法的原发性免疫缺陷（按照世界卫生组织标准定义）的13岁以上患者参加了该研究。进入时，他们都签署了知情同意书，该知情同意书已经波士顿儿童医院临床研究委员会批准。他们都具有正常的肾功能，输液前1个月没有活动性感染的临床证据。对血液，血液制品或小鼠蛋白有过敏史的患者，以及在单克隆抗体输注前2周内接受过抗生素治疗的主动感染患者，均不符合本研究的条件。抗脂质A单克隆抗体以开放标签，不受控制的单输注方式进行。六名患者被随机分配到四个剂量水平中的每个剂量水平：50 mg，75 mg，100 mg和150 mg。在每种剂量水平下，患者分为两类：一半在预定的IVIG输注前24小时输注抗脂质A单克隆抗体，另一半在预定的IVIG输注后24小时输注抗脂质A单克隆抗体。 。从最低的剂量开始，每个剂量水平依次完成。单克隆抗体的制备该抗体最初来源于已被全灭活疫苗的明尼苏达沙门氏菌（Re595突变体）免疫的个体的脾细胞，然后进行脾切除以治疗特发性血小板减少性紫癜。根据其与各种革兰氏阴性菌属的LPS发生交叉反应的能力，选择了该特定抗体进行开发，并且已显示出与LPS i的脂质A部分反应

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