Project I: Discovery and Evaluation of Antibodies and Cocktails

项目一：抗体和混合物的发现和评估

基本信息

批准号：
10088391
负责人：
Kartik Chandran
金额：
$ 174.54万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-14 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10088391
关键词：
Acute Advanced Development Affinity Andes Virus Animal Model Antibodies Antibody Response Antibody Therapy Antigens Antiviral Agents 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 Dose Ebola virus Epitopes European Evaluation FDA approved Generations Genome Genotype Glycoproteins Goals Half-Life Hand Hantavirus Human Immunotherapeutic agent In Vitro Infection Lead 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 antigen binding base 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

项目摘要

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 普罗米修斯联盟的首要目标是开发基于抗体的预防剂和针对 A 类优先病毒的三大类的治疗方法，这些病毒对人类造成最高风险国家安全和公共卫生并引起人畜共患疾病——埃博拉病毒、内罗病毒克里米亚-刚果出血热病毒 (CCHFV)、新世界汉坦病毒安第斯病毒 (ANDV) 和 Sin Nombre 病毒 (SNV) 和旧世界汉坦病毒 Puumula 病毒 (PUUV) 尚未获得批准的治疗方法。鉴于目前市场上有超过 50 种基于 mAb 的疗法的安全性和有效性。对于各种疾病，单克隆抗体是开发针对这些 A 类病毒的对策的低风险平台。快速发现和开发大量病原体特异性人单克隆抗体 (mAb) 来自康复期和急性感染捐赠者的捐赠是我们平台的核心力量。已经产生了有效的抗体反应，这些天然存在的单克隆抗体不太可能引起组织交叉反应性和人体体内毒性，并且还消除了嵌合或时间-的需要普罗米修斯将使用这些单克隆抗体作为原材料来生产具有广泛保护作用的药物。 (i) 对自然病毒基因型变异具有鲁棒性的免疫治疗；(ii) 利用多表位靶向；我们称之为 RAVE（病毒逃逸的相互拮抗）的创新功能可增强效力并抵抗逃避病毒中和；(iii) 利用调谐的 Fc 效应器特性来延长体内半衰期等有效消除病毒颗粒和受感染的细胞；以及（iv）可以直接快速地转化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。以及针对 CCHFV 和汉坦病毒（SNV、ANDV 和 PUUV）的寡克隆单克隆抗体混合物特性——泛埃博拉病毒主导的人类单克隆抗体已经被普罗米修斯成员识别出来。将先导单克隆抗体和鸡尾酒交给核心 B，作为高级疗法开发的候选药物，并项目 III 旨在生成用于预防性给药的 DNA 编码单克隆抗体 (DMAb)。与 SAC 协商后，Core C 将评估先导分子在 NHP 模型中的保护功效 CCHFV 和 SNV 挑战。