Development of CM-SV1, a monoclonal antibody treatment for Sudan Virus

开发苏丹病毒单克隆抗体疗法 CM-SV1

• 批准号: 10075623
• 负责人: PAUL GUYRE
• 金额: $ 96.28万
• 依托单位: CELDARA MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-16 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10075623
• 关键词: Africa; Amino Acid Sequence; Animals; Antibodies; Antibody Therapy; Bundibugyo virus; Case Fatality Rates; Categories; Cavia; Cessation of life; Chinese Hamster Ovary Cell; Clinical; Communities; Complementarity Determining Regions; Cyclic GMP; Democratic Republic of the Congo; Development; Disease Outbreaks; Dose; Drug Compounding; Drug Kinetics; Ebola Hemorrhagic Fever; Ebola virus; Emergency Situation; Engineering; Epidemic; Event; Family; Fill-It; Filovirus; Frankfurt-Marburg Syndrome Virus; Glycoproteins; Gold; Government; Half-Life; Human; Immunoglobulin G; Immunotherapeutic agent; Industry Standard; Infection; Interferon-alpha; Investigational Drugs; Investigational New Drug Application; Knockout Mice; Letters; Life; Medical Staff; Modality; Modeling; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Nature; Persons; Phase; Population; Preparation; Prevention; Production; Property; Prophylactic treatment; RNA Viruses; Readiness; Research; Risk; Safety; Savings; Standard Model; Sudan Ebola virus; Technology; Therapeutic; Therapeutic Agents; Tobacco; Toxic effect; Uganda; United States Food and Drug Administration; Vaccines; Viral Hemorrhagic Fevers; Virulent; Virus; Virus Diseases; Western Africa; Widespread Disease; Zaire Ebola virus; animal rule; base; biodefense; cell bank; clinical efficacy; commercialization; comparative efficacy; efficacy study; global health emergency; improved; in vivo; manufacturability; meetings; neglected tropical diseases; nonhuman primate; novel; pandemic disease; pathogen; phase 2 study; preclinical development; prevent; programs; prophylactic; success; therapeutic development; therapeutic evaluation

PROJECT SUMMARY The filoviruses (family Filoviridae), comprising five ebolaviruses, a cuevavirus, and two Marburg viruses, are negative-strand RNA viruses that cause severe hemorrhagic fever with up to 90% human case fatality rate. The 2014–2016 epidemic in Western Africa, caused by the Zaire ebolavirus (EBOV) species demonstrated the potential for these viruses to cause dire health emergencies of global scope, and highlighted the need for development of therapeutics and vaccines. Sudan virus (SUDV), Bundibugyo virus (BDBV), and Marburg virus (MARV) have all caused large human outbreaks with high case fatality rates, and thus have similar epidemic potential. In particular, while SUDV, the subject of this proposal caused the 2nd largest filovirus outbreak to date, no therapy or vaccine is currently available. Our product, CM-SV1, is a humanized first-in-class, single dose, monoclonal antibody (mAb) against SUDV for use as both a prophylactic and a therapeutic agent, thus serving the needs of frontline medical staff and infected persons. mAbs represent an attractive therapeutic modality for filoviruses because mAb cocktails or convalescent IgG has been demonstrated to provide post-exposure protection of non-human primates. Furthermore, mAbs are generally well-tolerated and have favorable pharmacokinetic and safety profiles. Given the sporadic and unpredictable nature of outbreaks, it would be highly advantageous to have mAb therapies against each of the filoviruses ready for rapid deployment as emergency therapeutics. To date, we have produced CM-SV1 in both HEK293 and N. bethathasmia (tobacco) and have demonstrated efficacy in lethal challenge models in murine and guinea pig models of SUDV infection. The purpose of this proposal is to first determine developability of CM-SV1 and then to develop CM-SV1 to a technology readiness level (TRL) 5 in preparation for investigational new drug (IND) filing. In Phase I, we will engineer the Fc portion CM-SV1 to have improved prophylactic capabilities, produce CM-SV1 in an industry standard for manufacturing (Chinese Hamster ovary cells), determine developability, demonstrate non-inferior efficacy compared to HEK produced CM-SV1 in a murine challenge model, and determine success in engineering enhanced half-life. In Phase II, we will determine non-inferior efficacy compared to HEK produced CM-SV1 in a guinea pig challenge model, determine toxicity, prepare and file a pre-IND application and conduct a Type B meeting with FDA, and finally demonstrate efficacy of CM-SV1 in a non-human primate SUDV lethal challenge model. At the culmination of this program CM-SV1 will be optimized for cGMP manufacture and IND preparation.

项目概要 丝状病毒（丝状病毒科）由五种埃博拉病毒、一种提示病毒和两种马尔堡病毒组成，是 负链 RNA 病毒，可引起严重出血热，人类病死率高达 90%。 2014-2016 年西非流行病由扎伊尔埃博拉病毒 (EBOV) 物种引起 这些病毒有可能造成全球范围内的严重卫生紧急情况，并强调需要 治疗方法和疫苗的开发。苏丹病毒 (SUDV)、本迪布焦病毒 (BDBV) 和马尔堡病毒 病毒（MARV）都引起了大规模的人类暴发，病死率很高，因此具有类似的特征 流行潜力。特别是，虽然本提案的主题 SUDV 引起了第二大丝状病毒 迄今为止，尚无可用的治疗方法或疫苗。 我们的产品 CM-SV1 是一种针对 SUDV 的人源化单剂量单克隆抗体 (mAb) 既可用作预防剂，又可用作治疗剂，从而满足一线医务人员和 感染者。 mAb 代表了丝状病毒的一种有吸引力的治疗方式，因为 mAb 混合物或 恢复期 IgG 已被证明可为非人类灵长类动物提供暴露后保护。 此外，单克隆抗体通常具有良好的耐受性，并具有良好的药代动力学和安全性。 鉴于疫情的零星和不可预测性，拥有单克隆抗体将非常有利 针对每种丝状病毒的疗法已准备好作为紧急疗法快速部署。 迄今为止，我们已经在 HEK293 和 N. bethathasmia（烟草）中生产了 CM-SV1，并证明了 在 SUDV 感染的小鼠和豚鼠模型中的致死攻击模型中的功效。这样做的目的 建议首先确定CM-SV1的可开发性，然后将CM-SV1开发为技术 准备级别 (TRL) 5 正在准备研究性新药 (IND) 备案。在第一阶段，我们将设计 Fc 部分 CM-SV1 具有改进的预防能力，按照行业标准生产 CM-SV1 用于制造（中国仓鼠卵巢细胞），确定可开发性，证明非劣效 与 HEK 在小鼠挑战模型中生产的 CM-SV1 进行比较，并确定工程的成功 半衰期延长。在 II 期中，我们将确定与 HEK 生产的 CM-SV1 相比的非劣效性 豚鼠挑战模型，确定毒性，准备并提交预 IND 申请并进行类型 B 与 FDA 会面，最终证明 CM-SV1 对非人灵长类 SUDV 致命的功效 挑战模型。在此计划结束时，CM-SV1 将针对 cGMP 生产进行优化， IND 准备。