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预防药物和 针对A类优先病毒的三大组的治疗，这些病毒对 国家安全和公共卫生，并导致人畜共患病--埃博拉病毒，奈罗病毒克里米亚-刚果 出血热病毒(CCHFV)、新世界汉坦病毒(ANDV)和新诺布雷病毒(Sin Norbre Virus) (SNV)和东半球汉坦病毒Puumula病毒(PUUV)。没有批准的治疗方法可用于以下任何一种 这些病毒。鉴于目前市场上可获得的50多种基于单抗的治疗方法的安全性和有效性 各种疾病，单抗是针对这些A类病毒制定对策的低风险平台。这个 大量病原体特异性人类单抗的快速发现和发展 来自恢复期和急性感染的捐赠者是我们平台的核心力量。来自主持人的 已经启动了有效的抗体反应，这些自然产生的单抗不太可能诱导 组织交叉反应和体内毒性，还消除了嵌合化或时间的需要- 消费人性化。普罗米修斯公司将以这些单抗为原料生产具有广泛保护作用的 免疫疗法：(I)对自然病毒的基因变异有很强的抵抗力；(Ii)利用多表位靶向 一种我们称之为RAVE的创新功能(病毒逃逸的互惠拮抗)，以增强效力和抵抗 病毒中和逃逸；(Iii)利用调谐的Fc效应器特性延长体内半衰期和更多 有效消除病毒颗粒和受感染的细胞；以及(4)可以直接和快速地过渡到 先进的临床前开发。项目一将与项目二合作识别人类单抗 和抗CCHFV和汉坦病毒(SNV、ANDV和PUUV)的寡克隆mAb鸡尾酒 特性-普罗米修斯成员已经确定了泛埃博拉病毒导致的人类单抗。我们会 将主要的单抗和鸡尾酒交给核心B，作为治疗学高级开发的候选者，并 项目三，旨在产生用于预防性投放的DNA编码单抗(DMAbs)的研究。在……里面 与SAC协商，Core C将评估铅分子在NHP模型中的保护效果 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.