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球蛋白抗体鸡尾酒的临床前评价” 摘要 拉沙热是一种致命的病毒性出血热（VHF），在西非流行， 严重的社会和经济破坏。缺乏批准的治疗或疫苗， 啮齿动物库的地理扩张，易于采购和病毒武器化，以及 最近出现的拉沙病毒新毒株支持加强防范的建议 拉沙热（LF）我们分离并表征了来自于大肠杆菌的超过113种人单克隆抗体（MAbs）。 拉沙热幸存者的记忆B细胞，第一个大的抗LASV的人单克隆抗体。我们 发现最有效的中和hMAbs靶向需要GP 1和GP 2的四元表位 三聚体中每个单体的亚基。LASV具有遗传多样性，其中存在四种不同的谱系， 西非.一些hMAb中和了所有四种LASV谱系。高表达的双顺反子IgG 1骨架载体 在哺乳动物细胞中的水平稳定表达被用于产生足够量的中和抗体。 使用CHOLCelect系统进行治疗评价的hMAb（BNhMAb） （www.zalgenlabs.com/technology.html）。致死性LF模型中远交豚鼠（GP）的攻击 告知BNhMAb的向下选择用于在非人灵长类动物（NHP）模型食蟹猴（Cynomolgus）中的研究。 猕猴三种BNhMAb的组合，每种都具有广泛的中和活性和识别不同的 LASV糖蛋白复合物上的表位，即使在治疗开始延迟后，也能100%挽救NHP 至感染后8天，此时动物表现出严重的血液学和代谢 失调我们提出的项目符合RFA-AI-16-034的严格要求，因为LASV BNhMAb组合是一种先前确定的、充分表征的候选治疗药物，用于治疗NIAID列出的 新兴病原体LASV该项目将解决RFA-AI-16-034的特殊兴趣， 免疫治疗，这将“能够预防感染或中毒，在面对立即 威胁，保护免疫功能低下的个体，或暴露后治疗以抑制感染， 疾病。”我们根据指导原则将LASV BNhMAb免疫抑制剂鸡尾酒命名为“Arevirumab” 国际非专利名称（INN）工作组和USAN理事会（USANC）关于 单克隆抗体命名方案语言指南。在里程碑1中，我们将进行剂量确定 在豚鼠中进行的LASV BNhMAb单次给药和Arevirumab治疗的给药间隔研究， 食蟹猴，两者都建立了致死性拉沙热的模型。化学、制造和 控制（CMC）数据将在里程碑2中生成。在里程碑3中，我们将进行临床前药理学研究 和毒理学。在拟议方案结束时，我们 将进入一流的人单克隆抗体免疫治疗混合物的临床评估， 拉沙热的预防和暴露后治疗。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， 在LF流行地区的感染患者中进行的临床研究建立了商业上可行的途径， 阿瑞鲁单抗。 本申请包含杜兰大学及其分包商的专有/特权信息 不得将请求透露给政府以外的人，除非是为了审查的目的， 评价。