Migone Thi-Sau, Subramanian G Mani, Zhong John, Healey Letha M, Corey Al, Devalaraja Matt, Lo Larry, Ullrich Stephen, Zimmerman Janelle, Chen Andrew, Lewis Maggie, Meister Gabriel, Gillum Karen, Sanford Daniel, Mott Jason, Bolmer Sally D
Human Genome Sciences, Rockville, MD 20850, USA.
N Engl J Med. 2009 Jul 9;361(2):135-44. doi: 10.1056/NEJMoa0810603.
Inhalational anthrax caused by Bacillus anthracis is associated with high mortality primarily due to toxin-mediated injury. Raxibacumab is a human IgG1lambda monoclonal antibody directed against protective antigen, a component of the anthrax toxin.
We evaluated the efficacy of raxibacumab as a prophylactic agent and after disease onset in a total of four randomized, placebo-controlled studies conducted in rabbits and monkeys. Animals were exposed to an aerosolized target exposure of B. anthracis spores that was approximately 100 times (in the prophylactic studies) and 200 times (in the therapeutic-intervention studies) the median lethal dose. In the therapeutic-intervention studies, animals were monitored for the onset of symptoms. Animals with detectable protective antigen in serum, a significant increase in temperature, or both received a single intravenous bolus of placebo or raxibacumab at a dose of either 20 mg per kilogram of body weight or 40 mg per kilogram. The primary end point was survival at day 14 (in rabbits) or at day 28 (in monkeys). Safety studies were conducted with intravenous raxibacumab (40 mg per kilogram) in 333 healthy human volunteers.
In both rabbits and monkeys, the time to detection of protective antigen correlated with the time to bacteremia (r=0.9, P<0.001). In the therapeutic-intervention studies, the survival rate was significantly higher among rabbits that received raxibacumab at a dose of 40 mg per kilogram (44% [8 of 18]) than among rabbits that received placebo (0% [0 of 18]; P=0.003). Raxibacumab treatment also significantly increased survival in monkeys (64% [9 of 14], vs. 0% [0 of 12] with placebo; P<0.001). In human subjects, intravenous raxibacumab at a dose of 40 mg per kilogram had a half-life of 20 to 22 days and provided a maximum concentration of the drug in excess of levels that are protective in animals. Concentrations of raxibacumab provide a surrogate end point that should be predictive of clinical benefit.
A single dose of raxibacumab improved survival in rabbits and monkeys with symptomatic inhalational anthrax. (ClinicalTrials.gov number, NCT00639678.)
炭疽芽孢杆菌引起的吸入性炭疽主要因毒素介导的损伤而导致高死亡率。瑞昔单抗是一种针对炭疽毒素成分保护性抗原的人IgG1λ单克隆抗体。
我们在总共四项针对兔和猴的随机、安慰剂对照研究中评估了瑞昔单抗作为预防剂以及在疾病发作后的疗效。动物暴露于雾化的炭疽芽孢杆菌孢子靶暴露剂量，该剂量在预防研究中约为半数致死剂量的100倍，在治疗干预研究中约为200倍。在治疗干预研究中，对动物进行症状发作监测。血清中可检测到保护性抗原、体温显著升高或两者兼有的动物接受单次静脉推注安慰剂或瑞昔单抗，剂量为每千克体重20毫克或40毫克。主要终点是第14天（兔）或第28天（猴）的存活情况。在333名健康人类志愿者中进行了静脉注射瑞昔单抗（每千克体重40毫克）的安全性研究。
在兔和猴中，检测到保护性抗原的时间与发生菌血症的时间相关（r = 0.9，P < 0.001）。在治疗干预研究中，接受每千克体重40毫克瑞昔单抗治疗的兔的存活率（44% [18只中的8只]）显著高于接受安慰剂的兔（0% [十八只中的0只]；P = 0.003）。瑞昔单抗治疗也显著提高了猴的存活率（64% [14只中的9只]，而安慰剂组为0% [12只中的0只]；P < 0.001）。在人类受试者中，每千克体重40毫克的静脉注射瑞昔单抗半衰期为20至22天，药物的最大浓度超过了在动物中具有保护作用的水平。瑞昔单抗的浓度提供了一个替代终点，应能预测临床益处。
单剂量瑞昔单抗提高了有症状吸入性炭疽兔和猴的存活率。（临床试验注册号，NCT00639678。）
