Preclinical evaluation of a potent Lassa fever immunotherapeutic antibody cocktail

有效的拉沙热免疫治疗抗体混合物的临床前评估

• 批准号: 9926211
• 负责人: Robert F Garry
• 金额: $ 110.85万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-26 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926211
• 关键词: Achievement; Address; Africa; African; Animal Model; Animals; Antibodies; Antibody titer measurement; Arenavirus; Biological Products; Cavia; Chemistry; Clinical; Clinical Research; Collaborations; Communicable Diseases; Complex; Convalescence; Data; Disease; Dose; Economics; Epitopes; Evaluation; Formulation; GP2 gene; GTPBP1 gene; Geography; Glycoproteins; Government; Guidelines; Hematology; Human; IgG1; Immunocompromised Host; Immunology; Immunotherapeutic agent; Individual; Industry; Infection; Infection prevention; Intellectual Property; International; Intoxication; Language; Lassa Fever; Lassa virus; Lymphocytic choriomeningitis virus; Macaca fascicularis; Mammalian Cell; Memory B-Lymphocyte; Metabolic; Modeling; Monoclonal Antibodies; Names; National Institute of Allergy and Infectious Disease; Nomenclature; Ownership; Patients; Persons; Pharmacology and Toxicology; Public Health; Readiness; Recommendation; Research; Resolution; Rodent; Scheme; Structure; Survivors; Symptoms; System; Technology; Therapeutic; Therapeutic Monoclonal Antibodies; Time; Universities; Vaccines; Vertebral column; Viral Antigens; Viral Hemorrhagic Fevers; Virus; Virus Diseases; base; design; human monoclonal antibodies; interest; monomer; multidisciplinary; neutralizing monoclonal antibodies; nonhuman primate; pathogen; pre-clinical; preclinical development; preclinical evaluation; programs; prophylactic; protective efficacy; research clinical testing; social; therapeutic candidate; therapeutic evaluation; vector; weapons; working group

“Preclinical evaluation of a potent Lassa fever immunotherapeutic antibody cocktail” ABSTRACT Lassa fever is an often-fatal viral hemorrhagic fever (VHF) that is endemic in West Africa where it causes significant social and economic disruption. The lack of an approved therapeutic or vaccine, potential for geographic expansion of the rodent reservoir, ease of procurement and weaponization of the virus, and the recent emergence of new Lassa virus (LASV) strains support recommendations for enhanced preparedness for Lassa fever (LF). We isolated and characterized over 113 human monoclonal antibodies (MAbs) from memory B cells of Lassa fever survivors, the first large panel of human MAbs against LASV described. We found that the most potent neutralizing hMAbs target quaternary epitopes that require both GP1 and GP2 subunits of each monomer in the trimer. LASV is genetically diverse with four distinct lineages present in West Africa. Some hMAbs neutralized all four LASV lineages. Bicistronic IgG1 backbone vectors for high level stable expression in mammalian cells were used to generate sufficient quantities of the neutralizing hMAbs (BNhMAbs) for therapeutic evaluation using the CHOLCelect system (www.zalgenlabs.com/technology.html). Challenge of outbred guinea pigs (GP) in a model of lethal LF informed the down-selection of BNhMAbs for studies in a nonhuman primate (NHP) model, Cynomolgus macaques. A combination of three BNhMAbs, each with broad neutralizing activity and recognition of distinct epitopes on the LASV glycoprotein complex, rescued 100% of NHPs even after delay in the start of treatment to 8 days post-infection, a time when the animals displayed severe hematological and metabolic dysregulation. Our proposed project meets the strict requirements of RFA-AI-16-034 in that the LASV BNhMAb combo is a previously-identified, well-characterized, candidate therapeutic against an NIAID listed emerging pathogen, LASV. The project will address a particular interest of RFA-AI-16-034 for immunotherapeutics that would “enable prevention of infection or intoxication in the face of an immediate threat, protection of immunocompromised individuals, or post-exposure treatment to suppress infection and disease.” We have named the LASV BNhMAb immunotherapeutic cocktail “Arevirumab” based on guidance from the International Nonproprietary Name (INN) Working Group and the USAN Council (USANC) on monoclonal antibody nomenclature scheme language guidelines. In Milestone 1 we will perform dose finding and dosing interval studies with single LASV BNhMAbs and Arevirumab therapy in guinea pigs and Cynomolgus macaques, both established models of lethal Lassa fever. Chemistry, Manufacturing and Control (CMC) data will be generated in Milestone 2. In Milestone 3 we will perform preclinical pharmacology and toxicology of Arevirumab in appropriate animal models. At the conclusion of the proposed program we will enter clinical evaluation of a first-in-class immunotherapeutic cocktail of human monoclonal antibodies for the prophylactic and post-exposure treatment of Lassa fever. Intellectual property ownership of the antibodies and biopharmaceutical manufacturing technologies, and the capacity to perform therapeutic clinical studies in infected patients from endemic LF regions establishes a commercially feasible path for Arevirumab. This application contains proprietary/priviledged information that Tulane University and its subcontractors request not be released to persons outside the Government, except for the purposes of review and evaluations.

“一种有效的拉沙热免疫治疗性抗体鸡尾酒的临床前评估” 摘要 拉沙热是一种经常致命的病毒性出血热(VHF)，在西非流行，它导致 严重的社会和经济混乱。缺乏批准的治疗方法或疫苗，可能会导致 啮齿动物宿主的地理扩展，病毒的采购和武器化的简便性，以及 最近新出现的拉萨病毒(LASV)毒株支持加强防备的建议 治疗拉沙热(LF)。我们分离并鉴定了113多株人源单抗。 拉沙热幸存者的记忆B细胞，描述了第一组抗LASV的人类单抗。我们 发现最有效的中和hMAb针对同时需要GP1和GP2的四元表位 三聚体中每个单体的亚基。LASV在基因上是多样化的，存在四个不同的谱系 西非。一些hMAb中和了所有四种LASV谱系。高效双顺反子IgG1主干载体 在哺乳动物细胞中的水平稳定表达被用来产生足够数量的中和 用CHOLCelect系统评价疗效的hMAbs(BNhMAbs) (www.zalgenLabs.com/Technology.html)。致死性LF模型对杂交豚鼠(GP)的挑战 向下选择BNhMAb用于非人灵长类动物(NHP)模型的研究 猕猴。三种BNhMAb的组合，每一种都具有广泛的中和活性和识别不同的 LASV糖蛋白复合体上的表位即使在延迟开始治疗后也能100%挽救NHP 到感染后8天，这段时间动物表现出严重的血液学和代谢 监管失调。我们建议的项目符合RFA-AI-16-034的严格要求，因为LASV BNhMAb组合是一种先前确定的、特征良好的针对列出的NIAID的候选治疗方法 新出现的病原体LASV。该项目将解决RFA-AI-16-034对 免疫疗法，将“能够防止感染或中毒，在面对立即 威胁，保护免疫受损的个人，或暴露后治疗，以抑制感染和 疾病。“根据指导，我们将LASV BNhMAb免疫治疗鸡尾酒命名为Arevirumab 来自国际非专利名称(INN)工作组和USAN理事会(USANC)关于 单抗命名方案语言指南。在里程碑1中，我们将执行剂量发现 和单一LASV BNhMAb和Arevirumab治疗豚鼠的剂量间隔研究 食蟹猴和食蟹猴都是致命性拉沙热的模型。化学、制造和 对照(CMC)数据将在里程碑2中生成。在里程碑3中，我们将执行临床前药理学 以及Arevirumab在适当动物模型中的毒理学。在提议的计划结束时，我们 将进入临床评估一流的人类单抗免疫治疗鸡尾酒 拉沙热的预防和暴露后治疗。企业的知识产权所有权 抗体和生物制药制造技术，以及进行治疗的能力 对地方性肝病流行地区感染患者的临床研究建立了一条商业上可行的途径 Arevirumab。 此应用程序包含杜兰大学及其分包商的专有/特权信息 请求不得向政府以外的人发布，除非是为了审查和 评估。