全球首个中东呼吸综合征临床1期试验显示良好安全性

ms003

1月11日，美国临床阶段制药公司SAB Biotherapeutics公布称，公司抗中东呼吸综合征（MERS）免疫治疗候选药物SAB-301在一期临床试验中显示良好安全性。这项由国立卫生研究院（NIH）资助、申办并运行的临床试验的结果已刊登在《The Lancet Infectious Diseases》。



目前，MERS尚无经批准的疫苗或治疗方案，该疾病是一种新发现的、可传染的由一种名为MERS冠状病毒（MERS-CoV）引起的致死性呼吸系统疾病。根据世界卫生组织公布数据，自2012年在沙特阿拉伯第一例确诊病例出现以来，这种疾病已经蔓延到27个国家并有2000多人被感染，死亡率接近40%。


该一期试验主要研究者，Leidos生物医学研究公司医学专家、国立传染病研究院（NIAID）临床研究司的John H. Beigel博士表示：“这是第一次证明在治疗MERS上显示出安全性及治疗潜力的临床研究。SAB-301是一种从牛血浆中发展而来的试验阶段的MERS治疗方法，在健康人群中安全、耐受性良好，并与人类产生的抗体具有相同的半衰期。”
利用从康复病人身上收集的血浆是一种更好和有效的抗体来源，可以被开发用于对抗与近期全球流感、MERS、SARS及Ebola等健康问题相关的病原体。
SAB Biotherapeutics公司CEO兼主席Eddie J. Sullivan博士称：“我们的新型免疫治疗平台是通过使用人类多克隆抗体这种对抗疾病的人自身武器开发而来。使用人类康复血浆作为治疗方案已被证明是有效的，但存在供应不足的问题。相反，我们的大约10只动物可以满足当前的MERS治疗需求。”
SAB公司新型DiversitAb™平台可快速产生大量的靶向性人类多克隆抗体。利用经过基因再设计的转染色体牛(Tc Bovine™)，让其产生人的抗体(免疫球蛋白G)，而不是通过牛对抗原的反应产生。已经在兔子、羊和马中可以产生动物抗体了，而SAB的平台是第一个在大型动物身上产生完全人类抗体的平台。
为了得到SAB-301，转基因牛Tc Bovine会被接种由Novavax提供的MERS抗原，在短时间内，他们便会产生大量的对抗病毒的全人类抗体。通过血浆收集（以与人血浆供体相似的方式），之后纯化后分离出抗体，成为治疗性的抗体制品。
在这次临床研究中，有28名健康志愿者接受SAB-301治疗，10名志愿者接受安慰剂治疗。六组志愿者接受不同的静脉注射剂量，并在90天内接受了6次评估。在治疗组和安慰剂组中常见的不良反应包括轻微头痛和感冒症状。
临床1期530万美元资金是由生物医学高级研究与发展局（BARDA）提供的，包括了临床2期试验款项。随着健康候选人的测试完成，II期临床试验将会在MERS流行地区开展以进一步评估药物的效能与给药。
附文献信息
Title：Safety and tolerability of a novel, polyclonal human anti-MERS coronavirus antibody produced from transchromosomic cattle: a phase 1 randomised, double-blind, single-dose-escalation study
DOI: http://dx.doi.org/10.1016/S1473-3099(18)30002-1
Summary：
Background
Middle East respiratory syndrome (MERS) is a severe respiratory illness with an overall mortality of 35%. There is no licensed or proven treatment. Passive immunotherapy approaches are being developed to prevent and treat several human medical conditions where alternative therapeutic options are absent. We report the safety of a fully human polyclonal IgG antibody (SAB-301) produced from the hyperimmune plasma of transchromosomic cattle immunised with a MERS coronavirus vaccine.

Methods
We did a phase 1 double-blind, placebo-controlled, single-dose escalation trial at the National Institutes of Health Clinical Center. We recruited healthy participants aged 18–60 years who had normal laboratory parameters at enrolment, a body-mass index of 19–32 kg/m2, and a creatinine clearance of 70 mL/min or more, and who did not have any chronic medical problems that required daily oral medications, a positive rheumatoid factor (≥15 IU/mL), IgA deficiency (<7 mg/dL), or history of allergy to intravenous immunoglobulin or human blood products. Participants were randomly assigned by a computer-generated table, made by a masked pharmacist, to one of six cohorts (containing between three and ten participants each). Cohorts 1 and 2 had three participants, randomly assigned 2:1 to receive active drug SAB-301 versus normal saline placebo; cohorts 3 and 4 had six participants randomised 2:1; and cohorts 5 and 6 had ten participants, randomised 4:1. Participants received 1 mg/kg, 2·5 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, or 50 mg/kg of SAB-301, or equivalent volume placebo (saline control), on day 0, and were followed up by clinical, laboratory, and pharmacokinetic assessments on days 1, 3, 7, 21, 42, and 90. The primary outcome was safety, and immunogenicity was a secondary outcome. We analysed the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02788188.

Findings
Between June 2, 2016, and Jan 4, 2017, we screened 43 participants, of whom 38 were eligible and randomly assigned to receive SAB-301 (n=28) or placebo (n=10). 97 adverse events were reported: 64 adverse events occurred in 23 (82%) of 28 participants receiving SAB-301 (mean 2·3 adverse events per participant). 33 adverse events occurred in all ten participants receiving placebo (mean 3·3 adverse events per participant). The most common adverse events were headache (n=6 [21%] in participants who received SAB-301 and n=2 [20%] in those receiving placebo), albuminuria (n=5 [18%] vs n=2 [20%]), myalgia (n=3 [11%] vs n=1 [10%]), increased creatine kinase (n=3 [11%] vs 1 [10%]), and common cold (n=3 [11%] vs n=2 [20%]). There was one serious adverse event (hospital admission for suicide attempt) in one participant who received 50 mg/kg of SAB-301. The area under the concentration–time curve (AUC) in the 50 mg/kg dose (27 498 μg × days per mL) is comparable to the AUC that was associated with efficacy in a preclinical model.
​