Antibody-based countermeasures against fentanyl and its analogues

基于抗体的芬太尼及其类似物对策

• 批准号: 10015669
• 负责人: Marco Pravetoni
• 金额: $ 81.38万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10015669
• 关键词: Address; Adjuvant; Administrative Supplement; Affinity; Alfentanil; Antibodies; Antigens; 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; Receptors, Antigen, B-Cell; Risk; Risk Assessment; Series; Site; Structure; Sufentanil; System; Technology; Testing; Toxic effect; Transgenic Mice; United States; Vaccines; Ventilatory Depression; X-Ray Crystallography; analog; 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

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。本项目将开发抗意外毒性和致死率的单克隆抗体（mAb）