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

项目摘要 丝状病毒（丝状病毒科）包括五种埃博拉病毒、一种库埃病毒和两种马尔堡病毒， 引起严重出血热的负链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，并强调需要 治疗和疫苗的发展。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 流行潜力。特别是，虽然SUDV，该提案的主题引起了第二大丝状病毒 到目前为止，没有任何治疗或疫苗。 我们的产品CM-SV 1是一种抗SUDV的人源化单剂量单克隆抗体（mAb） 用作预防和治疗剂，从而满足前线医务人员的需要， 感染者。mAb代表了丝状病毒的有吸引力的治疗方式，因为mAb混合物或 已经证明恢复期IgG提供非人灵长类动物的暴露后保护。 此外，mAb通常耐受良好，并且具有有利的药代动力学和安全性特征。 考虑到暴发的偶发性和不可预测性， 针对每一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HEK 293和N中生产了CM-SV 1。Bethathasmia（烟草），并已证明 在SUDV感染的鼠和豚鼠模型中的致死攻击模型中的效力。这样做的目的 建议首先确定CM-SV 1的可开发性，然后将CM-SV 1开发为一种技术 准备就绪等级（TRL）5，为研究性新药（IND）备案做准备。在第一阶段，我们将设计 Fc部分CM-SV 1具有改善预防能力，产生符合工业标准的CM-SV 1 用于生产（中国人卵巢细胞），确定可开发性，证明非劣效性 与HEK在鼠攻击模型中产生的CM-SV 1相比，并确定工程化的成功 增强半衰期。在II期，我们将确定与HEK生产的CM-SV 1相比， 豚鼠激发模型，确定毒性，准备并提交IND前申请，并进行类型 B与FDA会面，并最终证明CM-SV 1在非人灵长类动物SUDV致死中的有效性 挑战模式在该计划的高潮，CM-SV 1将针对cGMP生产进行优化， IND制备。

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.