TNF ALPHA/IL1B MONOCLONAL ANTIBODY MICROSPHERE--LETHAL GRAM NEGATIVE PERITONITIS

TNFα/IL1B单克隆抗体微球--致死性革兰氏阴性腹膜炎

• 批准号: 5219873
• 负责人: HAROLD M. MCCLURE
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5219873
• 关键词: Macaca mulatta; chemotherapy; disease /disorder model; interleukin 1; macrophage; microcapsule; model design /development; monoclonal antibody; monocyte; nonhuman therapy evaluation; pathologic process; peritonitis; septic shock; tumor necrosis factor alpha

SPID#: 18 Sepsis due to gram negative and gram positive bacteria is a significant clinical problem despite the advent of antibiotics. Even with effective antibiotic treatment, septic shock continues to be responsible for approximately 400,000 deaths per year in the United States alone. Hallmark complications of septic shock include cardiovascular collapse, increased vascular permeability, pulmonary dysfunction, fever, and alterations in lipoprotein lipase activity characterized by a wasting syndrome. The exact molecular events leading to the progression of sepsis are not clearly understood. However, recent studies have observed that the host response to the invading pathogen contributes to the pathogenesis of sepsis. The cytokines tumor necrosis factor alpha (TNFa) and interleukin-1 beta (1L-1B) have been implicated as principle immune modulators released from activated macrophages during experimental endotoxin shock. To date, the two primary models used in the majority of sepsis studies are either rats/mice or monkeys. The use of monoclonal antibodies (MoAb) against TNFa, given within minutes of an intravenous septic challenge, have been shown to be beneficial in reducing mortality of septic shock in nonhuman primates. However, there is no experimental data in nonhuman primates with septic shock using an infection model such as peritonitis, and clinical trials with monoclonal antibodies in humans with septic shock have been less effective than suggested by studies in the IV animal model. These studies, therefore, were initiated to establish a model of lethal, gram negative sepsis in the rhesus monkey by intraperitoneal inoculation of E. coli. Once established, this model will be used to evaluate the effect of various treatment regimens on blood levels of various cytokines (specifically TNFa and IL-1B), and on their ability to prevent death. The initial treatment to be evaluated will be the use of intravenous microencapsulated monoclonal antibodies to TNFa and IL-1B. Since the microcapsules will be targeted to monocytes/macrophages, a major source of the cytokines, it is believed that microencapsulation of the monoclonal antibodies will result in a much more effective treatment. Specific aims of these initial studies include (1) an assessment of the safety and toxicity of microcapsules administered intravenously; (2) a determination of the minimal effective in vivo dose of microencapsulated cytokine MoAb necessary to sufficiently blunt in vitro endotoxin stimulated cytokine release; (3) an assessment of the ability of microencapsulated cytokine MoAb to blunt in vivo cytokine production; and (4) a determination of the effectiveness of intravenous microencapsulated cytokine MoAb in preventing death following an intraperitoneal E. coli challenge in the rhesus monkey model.

SPID#：18 由革兰氏阴性菌和革兰氏阳性菌引起的败血症是一个重要的 尽管出现了抗生素，但仍存在临床问题。 即使有有效的 抗生素治疗，感染性休克仍然是导致 仅在美国每年就有约 40 万人死亡。 感染性休克的标志性并发症包括心血管衰竭、 血管通透性增加、肺功能障碍、发热等 脂蛋白脂肪酶活性的改变以消耗为特征 综合症。 导致进展的确切分子事件 脓毒症尚不清楚。 然而，最近的研究观察到 宿主对入侵病原体的反应有助于 脓毒症的发病机制。 细胞因子肿瘤坏死因子α (TNFa) 和白细胞介素 1 β (1L-1B) 被认为是主要免疫 实验过程中激活的巨噬细胞释放调节剂 内毒素休克。 迄今为止，大多数使用的两种主要模型 脓毒症研究的对象是大鼠/小鼠或猴子。 单克隆抗体的用途 抗 TNFa 的抗体 (MoAb)，在静脉注射后几分钟内给予 败血症挑战，已被证明有助于降低死亡率 非人灵长类动物败血性休克。 不过目前还没有实验 使用感染模型对患有败血性休克的非人类灵长类动物进行数据分析 作为腹膜炎，以及人类单克隆抗体的临床试验 感染性休克的治疗效果不如研究表明的有效 IV动物模型。 因此，发起这些研究是为了 在恒河猴中建立致命的革兰氏阴性败血症模型 通过腹膜内接种大肠杆菌。 这个模型一旦建立 将用于评估各种治疗方案的效果 各种细胞因子（特别是 TNFa 和 IL-1B）的血液水平，以及 他们预防死亡的能力。 待评估的初始治疗 将使用静脉内微囊单克隆抗体 TNFa 和 IL-1B。由于微胶囊将靶向 据信，单核细胞/巨噬细胞是细胞因子的主要来源 单克隆抗体的微胶囊化将导致 更有效的治疗。这些初步研究的具体目标 包括（1）微胶囊的安全性和毒性评估 静脉注射； (2) 最低有效值的确定 体内剂量的微囊细胞因子MoAb足以充分 钝化体外内毒素刺激的细胞因子释放； (3)评估 微囊细胞因子 MoAb 体内钝化能力的研究 细胞因子的产生； (4) 有效性的确定 静脉注射微囊细胞因子MoAb预防术后死亡 恒河猴模型中的腹膜内大肠杆菌攻击。