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

项目总结 丝状病毒(丝状病毒科)由五种埃博拉病毒、一种CuevaVirus和两种Marburg病毒组成，它们是 导致严重出血热的负链RNA病毒，人类病死率高达90%。 2014-2016年西非由扎伊尔埃博拉病毒(EBOV)引起的疫情表明 这些病毒有可能造成全球范围的严重卫生紧急情况，并强调有必要 治疗学和疫苗的发展。苏丹病毒(SUDV)、本迪布乔病毒(BDBV)和马尔堡 病毒(MARV)都引起了大范围的人类暴发，病死率很高，因此有类似的 潜在的流行病。特别是，虽然这项提案的主题SUDV引起了第二大丝状病毒 到目前为止，虽然疫情暴发，但目前还没有可用的治疗方法或疫苗。 我们的产品CM-SV1是一种人源化的一流单剂抗SUDV单抗 可同时用作预防和治疗药物，从而满足前线医务人员和 感染者。单抗是丝状病毒的一种有吸引力的治疗方式，因为单抗鸡尾酒或 恢复期的免疫球蛋白已被证明可以为非人类灵长类动物提供暴露后的保护。 此外，单抗一般耐受性良好，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的性质，拥有mAb将是非常有利的 针对每种丝状病毒的治疗方法准备好作为紧急治疗方法快速部署。 到目前为止，我们已经在HEK293和N.bethathasia(烟草)中生产了CM-SV1，并展示了 小鼠和豚鼠SUDV感染致死攻击模型的有效性。这样做的目的是 建议先确定CM-SV1的可开发性，然后再将CM-SV1发展成一种技术 准备级别(TRL)5，为研究新药(IND)备案做准备。在第一阶段，我们将设计 FC部分CM-SV1具有改进的预防能力，以行业标准生产CM-SV1 为制造(中国仓鼠卵巢细胞)，确定可开发性，展示非劣质功效 在小鼠攻击模型中与HEK生产的CM-SV1进行比较，并决定工程上的成功 增强的半衰期。在第二阶段，我们将确定与HEK生产的CM-SV1相比，在 豚鼠挑战模型，确定毒性，准备和提交预IND申请，并进行类型 B与FDA会面，并最终展示了CM-SV1对一种非人类灵长类SUDV致死病毒的疗效 挑战模型。在这一计划的顶峰，CM-SV1将针对cGMP的制造和 IND准备。

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.