Durable vaginal protection from HIV via mRNA expression of bnAbs

通过 bnAb 的 mRNA 表达持久保护阴道免受 HIV 侵害

• 批准号: 10160529
• 负责人: PHILIP J SANTANGELO
• 金额: $ 72.94万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-16 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160529
• 关键词: AIDS prevention; Adherence; Aerosols; Affect; Anti-HIV Agents; Antibodies; Cells; Cervical; Clinical Data; Developed Countries; Development; Devices; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Epithelial; Epithelium; Explosion; Female; Future; Goals; HIV; HIV Infections; Heterosexuals; Human; Human Herpesvirus 2; Immunity; Immunoglobulin A; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; In Vitro; Individual; Infection; Infection prevention; Inflammation; Interruption; Kinetics; Lesion; Link; Local Microbicides; Longevity; Macaca; Macaca mulatta; Measures; Mediating; Membrane; Messenger RNA; Methods; Modeling; Monoclonal Antibodies; Mucous Membrane; Mus; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Prevention; Prevention Measures; Production; Protocols documentation; Resistance; Resources; Respiratory syncytial virus; Schedule; Sexually Transmitted Diseases; Sheep; Surface; Testing; Therapeutic; Time; Tissues; Topical application; Transfection; Vaccines; Vagina; Viral reservoir; Virus; Water; Woman; antibody engineering; base; cost effective; design; fighting; in vivo; mRNA Expression; microbicide; neutralizing antibody; novel strategies; pathogenic bacteria; pre-clinical; pre-exposure prophylaxis; prevent; protective efficacy; reproductive hormone; reproductive tract; side effect; simian human immunodeficiency virus; social stigma; transmission process; uptake

Project summary In spite of the major advances in the development of effective anti-HIV drugs, currently some 2 million new infections still occur annually worldwide and over 95% via heterosexual contact. While prevention measures have made progress, such as PrEP, these measures are frequently either ignored, misused, or often non- negotiable for the female partner. Thus, providing choices for prevention of infection that are female controlled will be an asset in the fight to curb the rate of new infections worldwide. With the recent explosion of broadly neutralizing antibodies (bnAbs) from HIV infected patients, several have been used to demonstrate prevention of virus acquisition, even when administered post exposure. Unfortunately, vaccines have so far fallen short of inducing bnAbs, and though topically delivered bnAbs have shown protection, such protection has to date shown limited durability. To that end, a novel approach for expressing antibodies, with surprisingly long kinetics, in the female reproductive tract (FRT) via synthetic mRNA was recently demonstrated. Delivery was achieved through direct, rapid, aerosol exposure of the FRT epithelium to naked mRNA in water. Persistence of the antibody was achieved through the incorporation of a GPI-linker into the heavy chain. In rhesus macaques, the ability to protect macaque FRT explants from SHIV infection ex vivo has been shown. The long-term goal is to develop a cost-effective mRNA-based approach for expressing bnAbs in the FRT, providing a new paradigm for generating anti-infection barriers at the mucosal port(s) of entry. The short-term goals are to optimize the delivery, longevity and protective efficacy of bnAbs against SHIV infections of rhesus macaques by: 1) optimizing the delivery approach and protocol such that we have efficient transfection of the vaginal and cervical epithelium, 2) optimization of the antibody linker strategy to promote long-term expression in macaques, and 3) testing of single antibodies and combinations, including bi-specific antibodies. The efficacy of the optimization will be tested in a true challenge study in the macaque model. If successful, design information vital for making a proper device for delivering mRNA to the FRT in humans will be provided, and sufficient pre-clinical data in support of a future FDA IND application.

项目概要 尽管有效抗艾滋病毒药物的开发取得了重大进展，但目前仍有约 200 万新药 全世界每年仍会发生感染，其中 95% 以上是通过异性接触感染。在采取预防措施的同时 虽然已经取得了进展，例如 PrEP，但这些措施经常被忽视、误用或经常被忽视。 女方可以协商。因此，提供由女性控制的预防感染的选择 将成为遏制全球新感染率的斗争中的一项资产。随着最近广泛爆发 来自 HIV 感染者的中和抗体 (bnAb)，其中一些已被用于证明预防 即使是在暴露后施用，也能减少病毒获得的风险。不幸的是，迄今为止疫苗还不够 诱导 bnAb，尽管局部递送的 bnAb 已显示出保护作用，但迄今为止尚未显示出这种保护作用 耐用性有限。为此，一种表达抗体的新方法，具有令人惊讶的长动力学， 最近证明了通过合成 mRNA 实现女性生殖道 (FRT)。交付是通过以下方式实现的 将 FRT 上皮直接、快速、气溶胶暴露于水中裸露的 mRNA。抗体的持久性是 通过将 GPI 连接子并入重链来实现。在恒河猴中，有能力 已证明 FRT 外植体可保护猕猴体外免受 SHIV 感染。长期目标是发展 一种经济有效的基于 mRNA 的方法，用于在 FRT 中表达 bnAb，为 在粘膜入口处产生抗感染屏障。短期目标是优化 通过以下方式优化 bnAb 对恒河猴 SHIV 感染的递送、寿命和保护功效：1) 优化 交付方法和方案，使我们能够有效转染阴道和宫颈上皮， 2) 优化抗体接头策略以促进猕猴中的长期表达，以及 3) 测试 单一抗体和组合，包括双特异性抗体。优化的效果将是 在猕猴模型中进行的真正挑战研究中进行了测试。如果成功，设计信息对于制定适当的方案至关重要 将提供将 mRNA 递送至人体 FRT 的装置，并提供足够的临床前数据支持 未来的 FDA IND 申请。