The first polymeric opioid conjugate vaccine

第一种聚合阿片结合疫苗

• 批准号: 10287132
• 负责人: David Scott Wilson
• 金额: $ 20.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10287132
• 关键词: Address; Adjuvant; Alanine Transaminase; Animals; Antibodies; Antibody Response; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocytes; Behavior; Bilirubin; Binding; Biocompatible Materials; Biodistribution; Biological Assay; Body Weight; Bone Marrow; Brain; CD4 Positive T Lymphocytes; COVID-19 pandemic; Carrier Proteins; Centers for Disease Control and Prevention (U.S.); Cessation of life; Cleaved cell; Clinical; Cocaine; Communicable Diseases; Complex; Conjugate Vaccines; Development; Diffuse; Dose; Elements; Esthesia; Exposure to; Fentanyl; Formulation; Goals; HIV; Haptens; Helper-Inducer T-Lymphocyte; Human; Immune response; Immunity; Immunoglobulin G; Immunoglobulin-Secreting Cells; In Vitro; Interleukin-12; Ligands; Ligation; Link; Measures; Mediating; Medical; Modality; Monitor; Mus; Nicotine; Opiate Addiction; Opioid; Organ; Overdose; Pain Threshold; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Polymers; Process; Production; Proteins; Rodent; Safety; Saline; Serum; Serum Proteins; Signal Transduction; Structure; Surface; T cell response; T-Cell Activation; T-Lymphocyte; TLR7 gene; TNF gene; Tail; Tetanus Toxin; Time; Toxic effect; Toxin Conjugates; Urea Nitrogen; Vaccinated; Vaccination; Vaccine Design; Vaccines; Water; addiction; base; copolymer; crosslink; cytokine; design; experimental study; flu; immune activation; immunogenic; immunogenicity; improved; lymphoid organ; monomer; novel; novel vaccines; opioid mortality; opioid overdose; opioid therapy; opioid use disorder; pathogen; preclinical efficacy; prevent; response; socioeconomics; treatment strategy

1. Abstract: Opioid addiction is a national medical crisis that is expected to worsen due to the socioeconomic fallout caused by the SARS-CoV-2 pandemic. Opioid vaccines are a promising treatment strategy for preventing opioid overdose and could enhance drug treatment when combined with existing modalities. The aim of vaccination is to generate opioid-specific antibodies (-opioid)s that bind to the drugs and sequester them in the serum, stopping opioids from entering the brain and other organs, and thus preventing overdose and the sensation sought by the user. While monomeric opioid hapten conjugate vaccines composed of opioid monomers conjugated to carrier proteins admixed with experimental adjuvants are efficacious in rodents; the design of current monomeric opioid vaccines is based on monomeric vaccines for cocaine and nicotine that generated relatively weak, short-lived antibody responses in humans. The goal of this proposal is to develop a polymeric opioid conjugate vaccine that induces robust, long-lasting -opioid responses in the absence of toxicity. Durable antibody responses are maintained by long-lived antibody-secreting cells (LLASCs), which are generated upon B cell activation in the presence of B cell receptor (BCR) crosslinking, recognition of pathogen derived immunostimulatory signals, and ligation of co-stimulatory signals from helper T cells. To elicit the signals necessary for opioid-specific B cell activation, our polymeric opioid vaccine against fentanyl—the cause of most opioid overdose deaths—is composed of a water-soluble copolymer that targets and activates fentanyl-specific B cells, termed p(Fent-co-TLR7), conjugated to the immunogenic carrier protein tetanus toxin (TT) via a self-immolative linkage that, when cleaved, releases unmodified TT. We will synthesize p(Fent-co-TLR7) as a random copolymer from a monomer decorated with fentanyl and a second monomer that activates B cells via toll-like receptor 7 (TLR7). Thus, multivalent TT-p(Fent-co-TLR7) conjugates are designed to target and crosslink opioid-specific B cell receptors (BCRs), causing B cell activation and BCR-mediated internalization. Once internalized, TT-p(Fent-co-TLR7) will activate endosomal TLR7, amplifying B cell activation, and release TT. Once released from p(Fent-co-TLR7) polymers, TT can be efficiently processed and its peptides presented on the surface of B cells to TT-specific T cells, resulting in optimal T cell activation and the production of signals that drive B cells to differentiate into LLASCs. In this proposal we will (1) optimize the formulation and demonstrate the mechanisms responsible for the efficacy of TT-p(Fent-co-TLR7), (2) compare the immunogenicity and durability of the immune response generated by TT-p(Fent-co-TLR7) to that of monomeric fentanyl-TT conjugate vaccines, and (3) demonstrate the ability of TT-p(Fent-co-TLR7) to inhibit the behavior effects and lethality of fentanyl. Completion of this proposal will validate the preclinical efficacy of a clinically-viable fentanyl vaccine and deliver a novel vaccine platform that can be modified to treat the illicit use of other drugs as well as infectious diseases.

1。摘要： 阿片类药物成瘾是一种国家医疗危机 SARS-COV-2大流行。阿片类疫苗是预防阿片类药物过量的承诺治疗策略，可以 与现有方式结合使用时，增强药物治疗。疫苗接种的目的是产生特定阿片类药物 结合药物并将其隔离在血清中，阻止阿片类药物进入大脑和 其他器官，从而防止用户过量和感觉。而单体阿片类抗原结合物 由与实验调节器混合的载体蛋白共轭的阿片类单体组成的疫苗是有效的 在啮齿动物中；当前单体阿片类疫苗的设计基于可卡因和尼古丁的单体疫苗， 在人类中产生了相对较弱的短寿命抗体反应。该建议的目的是开发聚合物 阿片类药物结合疫苗在没有毒性的情况下诱导健壮的持久阿片类药物反应。耐用抗体 响应由长寿命的抗体分泌细胞（LLASC）维持，这些细胞是在B细胞激活时生成的 B细胞受体（BCR）的存在，病原体衍生的免疫刺激信号的识别和 来自辅助T细胞的共刺激信号的连接。为了引起阿片类特异性B细胞激活所需的信号， 我们的聚合物阿片类疫苗针对芬太尼（大多数阿片类药物过量死亡的原因）是由水溶性的 靶向和激活芬太尼特异性B细胞的共聚物，称为P（Fent-CO-TLR7），与免疫原性结合 载体蛋白tetanius毒素（TT）通过自适应连接，当切割时，释放出未修饰的TT。我们将 合成P（Fent-CO-TLR7）作为一个随机共聚物，该共聚物从芬太尼装饰的一个月和第二个月 通过Toll样受体7（TLR7）激活B细胞。那是多价TT-P（Fent-CO-TLR7）偶联物的目的 和交联OioID特异性B细胞受体（BCR），导致B细胞激活和BCR介导的内在化。一次 内部化的TT-P（Fent-CO-TLR7）将激活内体TLR7，扩增B细胞激活和释放TT。一次 从P（Fent-CO-TLR7）聚合物释放，可以有效地处理TT，其肽呈现在B表面上 细胞到TT特异性T细胞，从而导致最佳T细胞激活和驱动B细胞的信号产生 分为Llascs。在此提案中，我们将（1）优化公式并演示机制 负责TT-P（Fent-CO-TLR7）的效率，（2）比较免疫原性和耐用性 TT-P（Fent-CO-TLR7）对单体芬太尼-TT偶联物疫苗产生的响应，（3）证明了 TT-P（Fent-CO-TLR7）抑制芬太尼行为效应和致死性的能力。该提议的完成将 验证临床上可行的芬太尼疫苗的临床前效率，并提供一种新型的疫苗平台 修改以治疗其他药物的非法使用和感染疾病。