Vectored delivery of anti-HIV antibodies for mucosal protection

用于粘膜保护的抗 HIV 抗体的载体递送

• 批准号: 10673311
• 负责人: Jose Maria Martinez-Navio
• 金额: $ 78.53万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-14 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673311
• 关键词: Animal Model; Antibodies; Antibody Binding Sites; Avidity; Binding Sites; Biological Availability; Bypass; Characteristics; Circulation; Clinical Trials; Cost efficiency; Dependovirus; Development; Dose; Environment; Future; Gene Delivery; Goals; HIV; HIV Antibodies; HIV Infections; HIV envelope protein; Half-Life; Human; IgG1; Immune system; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Injections; Location; Long-Term Effects; Macaca; Mammals; Mediating; Modeling; Monkeys; Monoclonal Antibodies; Mucous Membrane; Mus; Mutation; Pathogenicity; Periodicals; Peripheral; Persons; Polymeric Immunoglobulin Receptors; Polymers; Property; Prophylactic treatment; Proteins; Recombinant adeno-associated virus (rAAV); Rectum; Route; SIV; Safety; Secretory Component; Serum; Sexual Transmission; Sterility; Surface; Vertebral column; Viral; adeno-associated viral vector; antigen binding; contagion; delivery vehicle; dimer; experimental study; fighting; immunogenicity; in vivo; monomer; neutralizing antibody; prophylactic; rectal; safety and feasibility; simian human immunodeficiency virus; transgene expression; transmission process; vaginal mucosa

Project Summary/Abstract The poor immunogenicity of the HIV envelope spike and its vast variability represent major obstacles for efficient elicitation of protective anti-HIV antibodies. One promising strategy is to bypass the immune system and deliver already known and well-characterized potent and broadly neutralizing antibodies directly to the host. However, periodic administrations of large amounts of protein would be required for long-term effects. Recombinant adeno- associated virus (AAV) vectors have been widely used for gene delivery applications because of their safety and cost-efficiency: one single injection can account for long term expression of the transgene. The use of AAV vectors would bypass the need for periodic administrations of antibody and, as long as the delivered protein is viewed as self, it can result in continuous durable expression. Studies in monkeys and in mice have already shown the extreme promise of AAV for this antibody delivery approach against HIV, and pioneer human trials have demonstrated its safety and feasibility. However, only antibodies in IgG form (monomeric immunoglobulin) have been employed in such AAV-antibody delivery applications, while polymeric immunoglobulins (such as dimeric IgA and pentameric IgM) have been overlooked, despite their desirable characteristics for mucosal protection. In addition, little is known about what proportion of circulating AAV-delivered antibody gets transferred to relevant viral entry points such as the rectal or vaginal mucosae and how that correlates with the level of protection against mucosal exposure that can be achieved. Building up on our previous monkey trials, what we propose here is to evaluate AAV-mediated delivery of a potent and broadly neutralizing antibody as different immunoglobulin types and assess the degree of protection that can be achieved to mucosal viral challenge by each type (Aim 1). We will use the highly relevant macaque model and quantitate in vivo AAV-produced antibody in circulation and in the relevant mucosae. Our goal is to find what immunoglobulin type shows optimal transfer of the AAV-delivered antibody to the viral point of entry in mucosae and/or optimal protection against challenge. Because HIV is mainly transmitted sexually, our findings will be highly relevant in the fight against HIV transmission. Our overall goal is to inform and guide development of the AAV-antibody concept for its use in people.

项目概要/摘要 HIV包膜刺突的免疫原性差及其巨大的变异性是有效治疗的主要障碍。 引发保护性抗 HIV 抗体。一种有前途的策略是绕过免疫系统并传递 已知且已充分表征的直接针对宿主的有效且广泛中和的抗体。然而， 为了获得长期效果，需要定期服用大量蛋白质。重组腺- 相关病毒（AAV）载体因其安全性和有效性而被广泛用于基因递送应用。 成本效益：一次注射即可实现转基因的长期表达。 AAV的使用 载体将绕过定期施用抗体的需要，并且只要传递的蛋白质是 被视为自我，它可以导致持续持久的表达。对猴子和老鼠的研究已经 展示了 AAV 对于这种抗 HIV 抗体递送方法的巨大前景，并开创了人体试验 并论证了其安全性和可行性。然而，只有 IgG 形式的抗体（单体免疫球蛋白） 已被用于此类 AAV 抗体递送应用，而聚合免疫球蛋白（例如 二聚体 IgA 和五聚体 IgM）尽管具有粘膜所需的特性，但仍被忽视。 保护。此外，对于循环 AAV 传递的抗体有多少比例被转移还知之甚少。 相关的病毒进入点，例如直肠或阴道粘膜，以及这与病毒水平的相关性 可以实现的防止粘膜暴露的保护。在我们之前的猴子试验的基础上，我们 这里的建议是评估 AAV 介导的有效且广泛中和的抗体的传递 免疫球蛋白类型并评估对粘膜病毒攻击可以达到的保护程度 每种类型（目标 1）。我们将使用高度相关的猕猴模型来定量体内 AAV 产生的抗体 在循环和相关粘膜中。我们的目标是找到哪种免疫球蛋白类型具有最佳转移效果 AAV 递送的抗体到达粘膜中的病毒进入点和/或针对攻击的最佳保护。 由于艾滋病毒主要通过性传播，因此我们的研究结果对于抗击艾滋病毒具有高度相关性 传播。我们的总体目标是为 AAV 抗体概念的开发提供信息和指导，以用于 人们。