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Antibody-based countermeasures against fentanyl and its analogues

基于抗体的芬太尼及其类似物对策

基本信息

批准号：
10598994
负责人：
Marco Pravetoni
金额：
$ 77.44万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10598994
关键词：
Address Adjuvant Administrative Supplement Affinity Alfentanil Antibodies Antigens B-Cell Antigen Receptor B-Lymphocytes Behavior Benchmarking Binding Biological Assay Bradycardia Brain Buprenorphine Canada Chemical Warfare Chemicals Cloning Contractor Development Drug Kinetics Europe Exposure to FDA approved Fab Immunoglobulins Family Fentanyl Formulation Future Generations Goals Half-Life Heroin Hospitalization Human Hybridomas Immunization Immunize Immunoglobulin Fragments In Vitro Industry Industry Standard Intellectual Property Lead Length Lymphocyte Macaca mulatta Magnetism Methadone Military Personnel Modeling Modification Monoclonal Antibodies Mus Naloxone Naltrexone North America Opioid Opioid Antagonist Opioid Receptor Oxycodone Passive Immunization Pharmaceutical Preparations Poisoning Polymers Process Public Health Rattus Risk Risk Assessment Series Site Sufentanil System Technology Testing Toxic effect Transgenic Mice United States Vaccines Ventilatory Depression X-Ray Crystallography analog antagonist base biocompatible polymer biodegradable polymer biophysical properties carfentanil chemical threat commercialization efficacy testing endogenous opioids humanized monoclonal antibodies humanized mouse improved in vivo lead optimization mass casualty medical countermeasure meetings mouse model next generation nonhuman primate opioid overdose polyclonal antibody polymerization preclinical development research clinical testing scale up screening

项目摘要

ABSTRACT. This project will develop monoclonal antibodies (mAb) against toxicity and lethality from accidental or deliberate exposure to fentanyl, carfentanil, acetylfentanil, and alfentanil. The US has seen dramatic increases in fatal opioid poisoning due to the widespread availability of fentanyl and fentanyl-like analogs. Because of the risk for accidental or deliberate mass casualty incidents, the fentanyl chemical family is listed in the DHS Chemical Threat Risk Assessment list. As a complementary adjuvant strategy to current medications for rescue of opioid poisoning (e.g., the opioid receptor antagonist naloxone), our team is developing mAb against fentanyl and its potent analogs to reduce toxicity and lethality in both civilian and defense applications. Our team has shown that antibody-based strategies effectively reduce opioid distribution to the brain as well as opioid-induced respiratory depression and bradycardia in mice and rats. Antibodies selectively target the intended opioid, but do not interfere with endogenous opioids nor with naloxone or other approved medications. Our team has identified lead first-generation mouse anti-fentanyl mAbs using an antigen-based enrichment strategy to isolate opioid-specific B cell lymphocytes from immunized mice to generate hybridomas, and mouse/human chimeric mAb for expression in a suitable mammalian system. The proposed U01 project will further optimize these leads through an iterative developmental plan. AIM1 focuses on optimization of humanized mAb against fentanyl, carfentanil, acetylfentanyl, and alfentanil by integrating humanization of lead mouse mAb and immunization of humanized or transgenic mice. The lead mAb will be used as a benchmark for selection of next-generation candidates. Leads will be identified for their affinity and selectivity in vitro, and for in vivo efficacy in reducing antinociception, respiratory depression and lethality in rats. The humanization process will be guided by biophysical characterization of mAb binding to fentanyl and its analogs by X-ray crystallography. AIM2 focuses on optimization of lead mAb (Fab or F(ab)2 fragments as alternative options) via polymer-based modifications to improve half-life and volume of distribution, and increase efficacy against fentanyl and its analogs. AIM3 will test efficacy of leads co-administered as a multicomponent mAb formulation in combination with opioid antagonists to provide enhanced protection against respiratory depression and lethality in rats challenged with fentanyl and its derivatives. To provide proof of scalability, AIM4 tests the efficacy of the lead humanized mAb in a non-human primate model of opioid-induced respiratory depression. Leads from previous aims will be synthesized at a larger scale at a contractor site. Finally, AIM5 focuses on drafting a regulatory path toward late-stage development and commercialization.

摘要。本项目将开发针对意外感染的毒性和致死性的单克隆抗体（mAb）。或故意暴露于芬太尼、卡芬太尼、乙酰芬太尼和阿芬太尼。在美国，由于芬太尼和芬太尼类似物的广泛可用性，导致致命的阿片类药物中毒。因为风险的意外或故意的大规模伤亡事件，芬太尼化学家庭被列入国土安全部化学威胁风险评估清单。作为当前急救药物的补充辅助策略阿片类药物中毒（例如，阿片受体拮抗剂纳洛酮），我们的团队正在开发抗芬太尼的mAb 以及其有效的类似物，以降低民用和国防应用中的毒性和致命性。我们的团队已被表明基于抗体的策略有效地减少阿片样物质向大脑的分布以及阿片样物质诱导的呼吸抑制和心动过缓。抗体选择性地靶向预期的阿片类药物，但不干扰内源性阿片类药物，也不干扰纳洛酮或其他批准的药物。我们的团队已被使用基于抗原的富集策略鉴定了领先的第一代小鼠抗芬太尼mAb，来自免疫小鼠的阿片样物质特异性B细胞淋巴细胞以产生杂交瘤，以及小鼠/人嵌合用于在合适的哺乳动物系统中表达的mAb。拟议的U01项目将进一步优化这些电极导线通过迭代式发展计划。AIM1专注于针对芬太尼的人源化mAb的优化，卡芬太尼，乙酰芬太尼和阿芬太尼，通过整合小鼠mAb的人源化和人源化或转基因小鼠。先导mAb将用作选择下一代候选人将鉴定先导化合物在体外的亲和力和选择性，以及在体内降低大鼠的抗伤害感受、呼吸抑制和致死率。人性化过程将遵循以下原则：通过X射线晶体学对mAb与芬太尼及其类似物的结合进行生物物理表征。AIM 2重点通过基于聚合物的修饰优化先导mAb（Fab或F（ab）2片段作为替代选项），改善半衰期和分布容积，并增加对芬太尼及其类似物效力。AIM3将测试作为多组分mAb制剂与阿片类拮抗剂联合给药的先导化合物的疗效在用芬太尼激发的大鼠中提供针对呼吸抑制和致死性的增强保护，其衍生物。为了提供可扩展性的证据，AIM4在非人免疫组织化学中测试了先导人源化mAb的功效。阿片类药物诱导的呼吸抑制的灵长类动物模型。来自先前目标的线索将在一个更大的承包商现场的规模。最后，AIM5侧重于起草一条通向后期开发的监管路径，商业化