The first polymeric opioid conjugate vaccine

第一种聚合阿片结合疫苗

基本信息

  • 批准号:
    10441532
  • 负责人:
  • 金额:
    $ 24.56万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-07-01 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

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全国性的医疗危机,由于药物滥用造成的社会经济后果, SARS-CoV-2大流行。阿片类药物疫苗是一种很有前途的治疗策略,可以预防阿片类药物过量, 与现有模式相结合时,加强药物治疗。疫苗接种的目的是产生阿片特异性 抗体(β-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, 其他器官,从而防止过量和用户寻求的感觉。虽然单体阿片样物质半抗原缀合物 由与载体蛋白缀合的阿片样物质单体与实验佐剂混合组成的疫苗是有效的 目前单体阿片类疫苗的设计是基于可卡因和尼古丁的单体疫苗, 在人体内产生了相对较弱的、短暂的抗体反应。该提案的目标是开发一种聚合物 阿片样物质缀合物疫苗,其在没有毒性的情况下诱导稳健的、持久的阿片样物质应答。持久抗体 免疫应答由长寿命的抗体分泌细胞(LLASC)维持,LLASC是由B细胞活化后产生的, 存在B细胞受体(BCR)交联,识别病原体衍生的免疫刺激信号,和 辅助T细胞共刺激信号的连接。为了引出阿片样物质特异性B细胞活化所必需的信号, 我们针对芬太尼的聚合阿片类疫苗-大多数阿片类药物过量死亡的原因-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-TLR 7),与免疫原性 载体蛋白破伤风毒素(TT)通过自分解连接,当切割时,释放未修饰的TT。我们将 由芬太尼修饰单体和第二单体合成作为无规共聚物的p(Fent-co-TLR 7),所述第二单体 通过Toll样受体7(TLR 7)激活B细胞。因此,多价TT-p(Fent-co-TLR 7)缀合物被设计成靶向 并交联阿片类药物特异性B细胞受体(BCR),引起B细胞活化和BCR介导的内化。一旦 内化的TT-p(Fent-co-TLR 7)将激活内体TLR 7,放大B细胞激活,并释放TT。一旦 从p(Fent-co-TLR 7)聚合物中释放,TT可以被有效地加工,并且其肽呈现在B的表面上 细胞转化为TT特异性T细胞,导致最佳T细胞活化和产生驱动B细胞的信号, 分化成LLASC。在本提案中,我们将(1)优化配方并演示机制 负责TT-p(Fent-co-TLR 7)的功效,(2)比较免疫的免疫原性和持久性 由TT-p(Fent-co-TLR 7)产生的对单体芬太尼-TT缀合物疫苗的应答,和(3)证明了 TT-p(Fent-co-TLR 7)抑制芬太尼行为效应和致死性的能力。完成本提案将 验证临床上可行的芬太尼疫苗的临床前有效性,并提供一种新的疫苗平台, 经修改后可用于治疗其他药物的非法使用以及传染病。

项目成果

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David Scott Wilson其他文献

Virgil in the Renaissance
文艺复兴时期的维吉尔
  • DOI:
    10.1017/cbo9780511762581
  • 发表时间:
    2010
  • 期刊:
  • 影响因子:
    0
  • 作者:
    David Scott Wilson
  • 通讯作者:
    David Scott Wilson

David Scott Wilson的其他文献

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{{ truncateString('David Scott Wilson', 18)}}的其他基金

The first polymeric opioid conjugate vaccine
第一种聚合阿片结合疫苗
  • 批准号:
    10287132
  • 财政年份:
    2021
  • 资助金额:
    $ 24.56万
  • 项目类别:
Tolerance-programming biomaterial-based Intranasal ASIT for the treatment of autoimmunity
基于耐受编程生物材料的鼻内 ASIT 用于治疗自身免疫性疾病
  • 批准号:
    10688041
  • 财政年份:
    2021
  • 资助金额:
    $ 24.56万
  • 项目类别:
A muco-penetrating biomaterial-based subunit vaccine for programming protective immune responses to SARS-CoV-2
一种基于粘膜穿透生物材料的亚单位疫苗,用于编程针对 SARS-CoV-2 的保护性免疫反应
  • 批准号:
    10195402
  • 财政年份:
    2021
  • 资助金额:
    $ 24.56万
  • 项目类别:
Tolerance-programming biomaterial-based Intranasal ASIT for the treatment of autoimmunity
基于耐受编程生物材料的鼻内 ASIT 用于治疗自身免疫性疾病
  • 批准号:
    10295511
  • 财政年份:
    2021
  • 资助金额:
    $ 24.56万
  • 项目类别:
A muco-penetrating biomaterial-based subunit vaccine for programming protective immune responses to SARS-CoV-2
一种基于粘膜穿透生物材料的亚单位疫苗,用于编程针对 SARS-CoV-2 的保护性免疫反应
  • 批准号:
    10402927
  • 财政年份:
    2021
  • 资助金额:
    $ 24.56万
  • 项目类别:
A muco-penetrating biomaterial-based subunit vaccine for programming protective immune responses to SARS-CoV-2
一种基于粘膜穿透生物材料的亚单位疫苗,用于编程针对 SARS-CoV-2 的保护性免疫反应
  • 批准号:
    10612436
  • 财政年份:
    2021
  • 资助金额:
    $ 24.56万
  • 项目类别:

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