First-in-human study of two anti-SARS CoV-2 antibodies in health volunteers

项目摘要 冠状病毒病2019年(新冠肺炎)大流行目前正席卷世界，尚无已知的治愈方法或 预防。除了对健康的影响外，人类活动的必要减少还导致 没有现代先例的经济损失，特别是在卫生保健和卫生设施发达的发展中国家 即使在大流行之前也是不够的。正在进行无数的努力来开发疫苗以 SARS-CoV-2，很可能抗体将是保护措施的关键。 目前正在进行康复患者多克隆血浆形式的新冠肺炎抗体治疗 作为一种治疗选择进行了探索，并已获得FDA的紧急使用授权(EUA)。 在预防人群感染SARS-CoV-2方面，单抗可能被证明特别有用 世卫组织可能不会对疫苗接种产生保护性免疫反应(例如，高龄、免疫损害)和 对于暴露后采取预防措施的高危个体，可发展为严重新冠肺炎。 C135和C144是能与SARS-CoV-2刺突蛋白受体特异性结合的重组全人型单抗 结合结构域(RBD)，并在体外表现出优异的中和SARS-CoV-2活性。两个一氨基 酸突变已被引入以延长半衰期并允许节省剂量。C135-LS和C144-LS 联合用药在预防和治疗实验中显示出显著的活性，在几个相关的 预防和治疗实验中的动物模型。这些临床前数据支持临床评估 并加速SARS-CoV-2感染者的病毒清除和疾病解决。 这项拟议的研究是一项首例人类、开放标签、单剂量、剂量-升级阶段1试验，以评估 C135-LS和C144-LS联合用药在健康志愿者体内的安全性和药代动力学

Project Summary The Coronavirus Disease 2019 (COVID-19) pandemic is currently gripping the world without a known cure or prevention. Aside from the health consequences, the necessary decrease in human activity has resulted in economic losses without modern precedent, especially in the developing world where health care and sanitation were not sufficient even prior to the pandemic. Innumerable efforts are being undertaken to develop vaccines to SARS-CoV-2 and it is likely that antibodies will be essential for protection. COVID-19 antibody therapy in the form of polyclonal plasma from convalescent individuals is currently being explored as a therapeutic option and has been granted an emergency use authorization (EUA) by the FDA. Monoclonal antibodies may prove to be particularly useful in preventing SARS-CoV-2 infection in populations who may not mount protective immune responses to vaccination (e.g. advanced age, immunocompromise) and for post-exposure prophylaxis in individuals at high risk to develop severe COVID-19. C135 and C144 are recombinant, fully human mAbs that specifically bind SARS-CoV-2 spike protein receptor binding domain (RBD) and exhibit exceptional neutralizing activity in vitro against SARS-CoV-2. Two one-amino acid mutations have been introduced to prolong half-life and allow dose sparing. The C135-LS and C144-LS combination has shown remarkable activity in both prophylaxis and therapy experiments in several relevant animal models in both prophylaxis and treatment experiments. These preclinical data support the clinical evahe from SARS-CoV-2 and accelerate viral clearance and disease resolution in SARS-CoV-2-infected individuals. The proposed study is a first-in-human, open label, single dose, dose-escalation phase 1 trial to evaluate the safety and pharmacokinetics of the C135-LS and C144-LS combination in healthy volunteers.