Project I: Discovery and Evaluation of Antibodies and Cocktails

项目一：抗体和混合物的发现和评估

• 批准号: 10555311
• 负责人: Kartik Chandran
• 金额: $ 101.71万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-14 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555311
• 关键词: Acute; Advanced Development; Affinity; Andes Virus; Animal Model; Antibodies; Antibody Response; Antibody Therapy; Antigens; Antiviral Therapy; B-Lymphocytes; Biological Assay; Biophysics; Blood Screening; Blood specimen; Categories; Cells; Collaborations; Collection; Complex; Consultations; Consumption; Crimean-Congo Hemorrhagic Fever Virus; DNA; Data; Development; Disease; Donor Selection; Dose; Ebola Hemorrhagic Fever; Ebola virus; Epitopes; European; Evaluation; FDA approved; Generations; Genome; Genotype; Glycoproteins; Goals; Half-Life; Hand; Hantavirus; Human; Immunotherapeutic agent; In Vitro; Infection; Lead; Marketing; Medical; Modeling; Monoclonal Antibodies; Nairovirus; National Security; Peripheral Blood Mononuclear Cell; Pharmacotherapy; Plasma; Production; Property; Public Health; Recombinants; Resistance; Risk; Rodent; Safety; Series; Sin Nombre virus; Survivors; Testing; Therapeutic; Time; Tissues; Toxic effect; Triage; Variant; Vesicular stomatitis Indiana virus; Viral; Virus; Virus Diseases; Work; Yeasts; Zoonoses; antagonist; antigen binding; candidate selection; cross reactivity; efficacy testing; experimental study; follow-up; high risk; human monoclonal antibodies; in vivo; innovation; manufacturability; member; nonhuman primate; novel; particle; pathogen; preclinical development; prophylactic; protective efficacy; recruit; response; scale up; synergism; therapeutic development; treatment arm

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.

摘要 - 项目I 普罗米修斯联盟的总体目标是开发基于抗体的预防学和 针对三个主要类别的优先病毒的治疗，这些病毒构成最高风险 国家安全和公共卫生并引起人畜共患病 - 叶虫病毒，奈罗内病毒crimean-congo 出血热病毒（CCHFV），新世界hantaviruses andes病毒（ANDV）和SIN NOMBRE病毒 （SNV）和旧世界的hantavirus puuumula病毒（PUUV）。任何一项都没有批准的治疗 这些病毒。鉴于目前在市场上可用于的50多种基于MAB的疗法的安全性和效率 各种疾病，mab是一个低风险平台，用于为这些类别的A类病毒开发对策。 快速发现和开发大量病原体特异性人单克隆抗体（mAb） 从康复和急性感染的供体中，供体是我们平台的核心力量。来自主持人 已经安装了有效的抗体响应，这些天然发生的mAb不太可能引起 组织交叉反应性和人体的体内毒性，也消除了需要嵌合或时间的需求 消耗人性化。 Prometheus将使用这些mab作为原材料来产生广泛保护的 （i）对天然病毒基因型变异的鲁棒性的免疫治疗剂； （ii）利用多质靶向目标 我们称其为创新的特征，我们称赞（互惠拮抗以逃脱病毒），以提高效力和抵抗力 逃脱病毒神经化； （iii）利用调谐的FC效应特性来扩展体内半衰期和更多 有效消除病毒颗粒和感染细胞； （iv）可以直接和快速过渡到 先进的临床前发展。项目我将与第二个项目合作，以识别人类mAB 与CCHFV和Hantaviruses（SNV，ANDV和PUUV）的寡克隆MAB鸡尾酒与这些鸡尾酒 属性 - 普罗米修斯成员已经识别出pan-ebolavirus铅铅。我们将 将铅mab和鸡尾酒移交给核心B，作为治疗疗法高级开发的候选者，并 针对DNA编码的mAb（DMAB）进行预防性递送的研究III。在 与SAC协商，铅分子将通过核心C评估NHP模型中的受保护效率 CCHFV和SNV挑战。