A versatile structure-based therapeutic platform for development of VHH-based antitoxin and antiviral agents

一个多功能的基于结构的治疗平台，用于开发基于 VHH 的抗毒素和抗病毒药物

基本信息

批准号：
10560883
负责人：
Rongsheng Jin
金额：
$ 86.57万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-04 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10560883
关键词：
2019-nCoV 3-Dimensional Affinity Animal Disease Models Animal Model Animals Antibodies Antibody Therapy Antiviral Agents Area Autoimmune Binding Biological Assay Botulinum Toxins Botulism COVID-19 pandemic COVID-19 patient Cell Culture Techniques Characteristics Clinical Clostridium difficile Communicable Diseases Complex Dangerousness Data Development Disease Epitopes Equus caballus Evolution Family Funding Future Goals High Prevalence Human Immune Immune Sera Infection Intoxication Intramuscular Lead Length Life Link Malignant Neoplasms Mediating Messenger RNA Modeling Monoclonal Antibodies Mus Passive Immunotherapy Pathology Poisoning Production Property Prophylactic treatment Proteins RNA Research Route SARS coronavirus SARS-CoV-2 variant Serotyping Specificity Structure Testing Therapeutic Therapeutic Agents Therapeutic Effect Therapeutic Monoclonal Antibodies Therapeutic antibodies Toxin United States National Institutes of Health Vaccinated Variant Viral Virus Virus Diseases Work antitoxin clinically relevant cost design disorder prevention human disease improved in vivo manufacture microbial nanobodies nanoparticle neutralizing antibody next generation novel novel therapeutics pandemic potential pathogen porcine model prevent product development prophylactic public health relevance receptor binding risk minimization standard of care technology platform therapeutic development transmission process vaccine efficacy variants of concern virtual

项目摘要

ABSTRACT In previous NIH sponsored research we successfully tested the hypothesis that integrating structural and mechanistic information into heteromultimeric VHH-based neutralizing agent (VNA) design facilitated development of antitoxins with even greater efficacy and versatility. In this renewal proposal, we will apply these findings to test the hypothesis that our designer VNA platform, which is rapidly responsive to new threats, will permit development of highly practical, next-generation antitoxin and antiviral products that possess excellent potencies in treating intoxications or viral infections and are effective against a broad range of natural pathogen variants. Our research will focus on two pathogens that are major current threats which could benefit from next- generation therapeutics: botulinum neurotoxin (BoNT) and SARS-CoV-2. We propose two Specific Aims which will be underway simultaneously throughout the five years of research. In Aim 1, we will develop a small pool of antitoxin VNAs that protect against all subtypes of the three prevalent BoNT serotypes (A, B and E). BoNTs are CDC Tier 1 select agents. However, the few available antitoxin treatments against BoNTs primarily derive from large animal polyclonal antisera, such as the equine botulism antitoxin HBAT, which suffer from multiple manufacturing and storage challenges. Our goal is to test the platform’s ability to produce highly practical VNAs as a next-generation BoNT antitoxin product, likely delivered as RNA nanoparticles, which improves on the potencies and natural variant specificities of the current HBAT antitoxin product and is rapidly responsive to potential new BoNT threats. In Aim 2 we will develop a single VNA antiviral agent that protects against known variants of SARS-CoV-1 and SARS-CoV-2. SARS-CoV-2 is the viral cause of the ongoing COVID-19 pandemic. A promising strategy for rapid development of a therapy is development of SARS-CoV-2 neutralizing antibodies, especially antibodies targeting the spike protein, for prophylactic or passive immunotherapies. However, novel variants of SARS-CoV-2, which cause enhanced infection and transmission, have emerged, and more dangerous variants are expected to evolve. Of immediate concern are variants that partially escape neutralization by current Ab-based therapies and in vaccinated or previously-infected COVID-19 patients, leading to reduced vaccine efficacy in certain areas with a high prevalence of these variants. We propose an mRNA- based antiviral product that, once administered, elicits expression of a VNA with extremely high virus neutralizing potency. The VNA will contain multiple covalently linked VHHs binding to conserved epitopes of the spike protein. This approach will test the platform’s ability to develop a product that minimizes the risks of immune escape through evolution and selection of clinical strains of SARS-CoV-2 and SARS-CoV-1. If successful, this technology platform could have broad applications in creating practical therapeutics for a wide variety of emerging and potential pandemic viral infections, bioterror threat agents, and other infectious diseases.

抽象的在之前的 NIH 资助的研究中，我们成功地检验了整合结构和促进基于异多聚体 VHH 的中和剂 (VNA) 设计的机械信息开发具有更大功效和多功能性的抗毒素在这个更新提案中，我们将应用这些。我们的设计 VNA 平台能够快速响应新威胁，将验证以下假设：允许开发高度实用的下一代抗毒素和抗病毒产品，这些产品具有优异的性能具有治疗中毒或病毒感染的功效，并且对多种天然病原体有效我们的研究将集中于当前主要威胁的两种病原体，这两种病原体可能会从下一步中受益。新一代疗法：肉毒杆菌神经毒素 (BoNT) 和 SARS-CoV-2 我们提出了两个具体目标。将在五年的研究中同时进行。在目标 1 中，我们将开发一个小型库。抗毒素 VNA 可预防三种常见 BoNT 血清型（A、B 和 E）的所有亚型。 CDC 一级精选药物然而，少数可用的针对 BoNT 的抗毒素治疗主要来自于 BoNT。大型动物多克隆抗血清，例如马肉毒杆菌抗毒素 HBAT，其患有多种疾病我们的目标是测试该平台生产高度实用的 VNA 的能力。作为下一代 BoNT 抗毒素产品，可能以 RNA 纳米粒子的形式提供，这改进了当前 HBAT 抗毒素产品的效力和自然变异特异性，并且能够快速响应在目标 2 中，我们将开发一种单一的 VNA 抗病毒药物，以防御已知的潜在新 BoNT 威胁。 SARS-CoV-1 和 SARS-CoV-2 的变种是当前 COVID-19 大流行的病毒原因。快速开发治疗方法的一个有前景的策略是开发 SARS-CoV-2 中和抗体，尤其是针对刺突蛋白的抗体，用于预防性或被动免疫疗法。 SARS-CoV-2 的变种已出现，可导致感染和传播增强，并且更多预计会出现危险的变体，最令人担忧的是部分逃脱的变体。当前基于抗体的疗法以及在肺炎或既往感染的 COVID-19 患者中的中和作用，导致为了降低这些变异流行率较高的某些地区的疫苗功效，我们提出了一种 mRNA-。基于抗病毒产品，一旦施用，就会引发具有极高病毒中和作用的 VNA 表达 VNA 将包含多个共价连接的 VHH，与刺突蛋白的保守表位结合。这种方法将测试该平台开发将免疫逃逸风险降至最低的产品的能力通过 SARS-CoV-2 和 SARS-CoV-1 临床毒株的进化和选择如果成功的话，技术平台可以在为多种疾病创建实用疗法方面具有广泛的应用新出现和潜在的大流行病毒感染、生物恐怖威胁因子和其他传染病。