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场全国性的医疗危机，由于阿片类药物成瘾造成的社会经济影响，预计该危机将进一步恶化。 阿片类药物疫苗是预防阿片类药物过量的一种有前景的治疗策略。 与现有方式结合加强药物治疗 疫苗接种的目的是产生阿片类药物特异性。 抗体（α-阿片类药物）与药物结合并将其隔离在血清中，阻止阿片类药物进入大脑并 其他器官，从而防止过量和使用者所寻求的感觉，而单体阿片半抗原缀合物。 由阿片类单体与载体蛋白缀合并与实验佐剂混合组成的疫苗是有效的 在啮齿类动物中；目前的单体阿片类疫苗的设计基于可卡因和尼古丁的单体疫苗， 在人体中产生相对较弱、短暂的抗体反应。该提案的目标是开发一种聚合物。 阿片类药物结合疫苗，在没有毒性的情况下诱导强烈、持久的 α-阿片类药物反应。 反应由长寿命抗体分泌细胞 (LLASC) 维持，这些细胞是在 B 细胞激活后产生的 B 细胞受体 (BCR) 交联的存在、病原体衍生的免疫刺激信号的识别，以及 连接辅助 T 细胞的共刺激信号以引发阿片类药物特异性 B 细胞激活所需的信号， 我们针对芬太尼（大多数阿片类药物过量死亡的原因）的聚合阿片类疫苗由水溶性 靶向并激活芬太尼特异性 B 细胞的共聚物，称为 p(Fent-co-TLR7)，与免疫原性缀合 载体蛋白破伤风毒素 (TT) 通过自毁连接，在裂解时释放未修饰的 TT。 用芬太尼装饰的单体和第二种单体合成 p(Fent-co-TLR7) 作为无规共聚物 通过 Toll 样受体 7 (TLR7) 激活 B 细胞，因此，多价 TT-p(Fent-co-TLR7) 缀合物旨在靶向作用。 交联阿片类药物特异性 B 细胞受体 (BCR)，导致 B 细胞激活和 BCR 介导的内化。 内化后，TT-p(Fent-co-TLR7) 会激活内体 TLR7，放大 B 细胞活化，并释放 TT。 从 p(Fent-co-TLR7) 聚合物中释放出来的 TT 可以被有效加工，并且其肽呈现在 B 表面 细胞转化为 TT 特异性 T 细胞，从而实现最佳 T 细胞激活并产生驱动 B 细胞的信号 在本提案中，我们将（1）优化配方并演示机制。 负责TT-p(Fent-co-TLR7)的功效，(2)比较免疫原性和免疫持久性 TT-p(Fent-co-TLR7) 对单体芬太尼-TT 结合疫苗产生的反应，以及 (3) 证明 TT-p(Fent-co-TLR7)抑制芬太尼的行为效应和致死性的能力 该提案的完成将。 验证临床上可行的芬太尼疫苗的临床前功效，并提供一种新型疫苗平台 修改用于治疗非法使用其他药物以及传染病。