Project I: Discovery and Evaluation of Antibodies and Cocktails

摘要-项目I 普罗米修斯联盟的首要目标是开发基于抗体的药物， 针对三大类A类优先病毒的治疗方法，这些病毒对 国家安全和公共卫生和引起人畜共患病-埃博拉病毒，内罗病毒克里米亚-刚果 出血热病毒（CCHFV）、新大陆汉坦病毒安第斯山脉病毒（ANDV）和Sin Nombre病毒 (SNV)和旧世界汉坦病毒Puumula病毒（PUUV）。没有批准的治疗方法可用于任何 这些病毒。考虑到目前市场上可获得的超过50种基于mAb的疗法的安全性和有效性， 在各种疾病中，mAb是开发针对这些A类病毒的对策的低风险平台。的 快速发现和开发大量病原体特异性人单克隆抗体（mAb） 从康复期和急性感染的捐赠者中获得的捐赠是我们平台的核心力量。来自那些 已经建立了有效的抗体应答，这些天然存在的mAb不太可能引起 组织交叉反应性和人体内的毒性，并且也不需要嵌合或时间- 消费人性化。Prometheus将使用这些单克隆抗体作为原材料， 免疫治疗剂，其（i）对天然病毒基因型变异是稳健的;（ii）利用多表位靶向 和一个创新的功能，我们称之为RAVE（相互拮抗病毒逃逸），以提高效力和抵抗 逃避病毒中和;（iii）利用经调节的Fc效应子特性以延长体内半衰期等 有效消除病毒颗粒和感染细胞;和（iv）可以直接和快速地转变为 先进的临床前开发。项目I将与项目II合作鉴定人类单克隆抗体 和针对CCHFV和汉坦病毒（SNV、ANDV和PUUV）的寡克隆mAb混合物， Prometheus成员已经鉴定出泛埃博拉病毒的人单克隆抗体。我们将 将先导mAb和混合物移交给核心B，作为先进治疗药物开发的候选药物， 项目III：旨在产生用于预防性递送的DNA编码mAb（DMAbs）的研究。在 与SAC协商后，将由核心C评估铅分子在NHP模型中的保护效力 CCHFV和SNV挑战。

Abstract – Project I The overarching goal of the Prometheus consortium is to develop antibody-based prophylactics and therapeutics against three major groups of Category A priority viruses that pose the highest risk to national security and public health and cause zoonotic disease—ebolaviruses, the nairovirus Crimean-Congo hemorrhagic fever virus (CCHFV), the New-World hantaviruses Andes virus (ANDV) and Sin Nombre virus (SNV), and the Old-World hantavirus Puumula virus (PUUV). No approved treatments are available for any of these viruses. Given the safety and efficacy of over 50 mAb-based therapies currently available in market for various diseases, mAbs are a low-risk platform to develop countermeasures for these Category A viruses. The rapid discovery and development of large numbers of pathogen-specific human monoclonal antibodies (mAbs) from convalescent and acutely infected donors is the central strength to our platform. Coming from hosts who have already mounted an effective antibody response, these naturally occurring mAbs are less likely to elicit tissue cross-reactivity and in vivo toxicity in humans and also obviate the need for chimerization or time- consuming humanization. Prometheus will use these mAbs as raw material to produce broadly protective immunotherapeutics that (i) are robust to natural viral genotypic variation; (ii) leverage multi-epitope targeting and an innovative feature we term RAVE (reciprocal antagonism to viral escape) to enhance potency and resist escape of viral neutralization; (iii) exploit tuned Fc effector properties for extended in vivo half-life and more effective elimination of viral particles and infected cells; and (iv) can be directly and rapidly transitioned to advanced pre-clinical development. Project I will work collaboratively with Project II to identify human mAbs and oligoclonal mAb cocktails against CCHFV and hantaviruses (SNV, ANDV, and PUUV) with these properties—pan-ebolavirus lead human mAbs have already been identified by Prometheus members. We will hand off lead mAbs and cocktails to Core B as candidates for advanced development of therapeutics, and to Project III for studies aimed at the generation of DNA-encoded mAbs (DMAbs) for prophylactic delivery. In consultation with the SAC, lead molecules will be evaluated by Core C for protective efficacy in NHP models of CCHFV and SNV challenge.