Novel Therapy for SARS-CoV-2 Virus Infection and Pathogenesis by Aerosol Delivery of Monoclonal Antibodies

项目摘要 俄勒冈州国家灵长类动物研究中心（ONPRC）是七个国家灵长类动物研究中心之一 （NPRCs）由国会在1960年代建立。NPRC由NIH主任办公室赞助， 并通过具有成本效益的方式，以独特和必要的方式服务于国家的生物医学研究需求。 向联邦资助的机构提供国家卫生计划和相关的科学专门知识、专门设施和设备， NHPs研究是基础研究和人类应用之间的重要转化环节。的 ONPRC的使命是通过NHP研究项目改善人类健康和生活质量， 提高我们对人类疾病原因的认识，并开发有效的预防，治疗， 和治愈方法 俄勒冈州国家灵长类动物研究中心（ONPRC）P51核心补助金（P51-OD 011092）支持一个殖民地 大约4900只繁殖和研究非人类灵长类动物（NHP），包括恒河猴， 印度起源，日本猕猴，食蟹猴，Hamadrayas和橄榄狒狒，和一个小的 松鼠猴的数量恒河猴和日本猕猴在该中心繁殖。其它物种 从国内进口，以满足项目特定的研究需求。 在这份对父母补助金的补充建议中，我们将测试以下假设：1）当在 激发、吸入、雾化中和单克隆抗体可预防或减轻SARS-CoV-2 恒河猴感染; 2）吸入中和单克隆抗体可减少病毒血症并预防 攻毒后给药时的发病机制。为了验证这些假设，我们将测试人类mAb的混合物， 有效和广泛的SARS-CoV 2中和活性，用于暴露前保护和/或 在雾化和吸入给药后限制病毒脱落， 用SARS-CoV-2鼻内/鼻腔内攻击。将对动物进行病毒学和免疫学随访 使用冠状病毒疫苗和治疗开发的标准方案， 评价网。在尸检时，将收获组织并处理用于病毒定量， 组织学对于暴露后研究，猕猴将感染SARS-CoV-2，并在一天后接受治疗 用同样的人SARS-CoV-2单克隆抗体混合物，比较了不同浓度的气雾剂和静脉注射， 剂量这些原理验证实验将为暴露后气雾剂治疗铺平道路， 抗体和纳米抗体，以实现减少COVID-19疾病的目标。我们的发现将扩大实用性 的非人灵长类动物模型的SARS-CoV-2，并将支持发现新的治疗方法， COVID-19，从而实现P51补助金的主要目的。

PROJECT SUMMARY The Oregon National Primate Research Center (ONPRC) is one of seven National Primate Research Centers (NPRCs) established by Congress in the 1960s. The NPRCs are sponsored by the NIH Office of the Director, and serve the nation's biomedical research needs in a unique and essential fashion through cost-effective provision of NHPs and related scientific expertise, specialized facilities, and equipment to federally funded studies of NHPs that comprise a vital translational link between basic research and human applications. The mission of the ONPRC is to improve human health and the quality of life through NHP research programs that advance our knowledge of the causes of human diseases and that develop effective preventions, treatments, and cures. The Oregon National Primate Research Center (ONPRC) P51 Core Grant (P51-OD011092) supports a colony of approximately 4900 breeding and research nonhuman primates (NHPs), including rhesus macaques of Indian origin, Japanese macaques, cynomolgus macaques, Hamadrayas and olive baboons, and a small number of squirrel monkeys. Rhesus and Japanese macaques are bred at the Center. Other species are imported from domestic sources to fulfill project specific research needs. In this supplement proposal to the parent grant, we will test the hypotheses that: 1) When given prior to challenge, inhaled, aerosolized neutralizing monoclonal antibodies can prevent or mitigate SARS-CoV-2 infection in rhesus macaques; and 2) Inhaled neutralizing monoclonals can reduce viremia and prevent pathogenesis when given after challenge. To test these hypotheses, we will test a cocktail of human mAbs with potent and broad SARS-CoV2-neutralizing activity for their effectiveness in pre-exposure protection and/or limitation of viral shedding following aerosolization and administration by inhalation prior to intranasal/intratracheal challenge with SARS-CoV-2. Animals will be followed for virological and immunological outcomes and pathology using standard protocols developed by the Coronavirus Vaccines and Therapy Evaluation Network. At necropsy, tissues will be harvested and processed for virus quantification and histology. For post-exposure studies, macaques will be infected with SARS-CoV-2, and treated one day later with the same cocktail of human SARS-CoV-2 mAbs, comparing aerosol and intravenous delivery at various doses. These proof-of-principle experiments will pave the way for post-exposure aerosol treatments with potent antibodies and nanobodies toward the goal of reducing COVID-19 disease. Our findings will expand the utility of the nonhuman primate model for SARS-CoV-2 and will support the discovery of novel therapeutics for COVID-19, thereby fulfilling the primary purpose of the P51 grant.