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

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要尽管开发有效的抗HIV药物方面取得了重大进展，目前约有200万新的新型通过异性恋接触，全世界每年仍会每年发生感染，超过95％。预防措施已经取得了进步，例如准备，这些措施经常被忽略，滥用或通常是非 - 可以对女性伴侣进行谈判。因此，提供预防女性控制感染的选择将是遏制全球新感染率的斗争的资产。随着最近的广泛爆炸来自HIV感染患者的中和抗体（BNAB），有几种被用于证明预防即使在接触后进行治疗，也可以接受病毒。不幸的是，疫苗还没有诱导bnabs，尽管局部交付的bnab已显示出保护，但迄今已显示此类保护有限的耐用性。为此，一种表达抗体的新颖方法，具有令人惊讶的长动力学最近证明了通过合成mRNA的女性生殖道（FRT）。交付是通过 FRT上皮在水中直接，快速，气溶胶暴露于裸mRNA。抗体的持久性是通过将GPI链链接在重链中实现。在恒河猕猴中的能力已经显示了猕猴FRT外植体免受Shiv感染的影响。长期目标是发展一种基于经济有效的mRNA的方法，用于在FRT中表达BNABS，为新的范式提供了在入口的粘膜端口产生抗感染屏障。短期目标是优化 BNABS对Rhesus Macaques的SHIV感染的传递，寿命和保护功效：1）优化递送方法和方案使我们有效地转染阴道和宫颈上皮， 2）优化抗体接头策略以促进猕猴的长期表达，3）测试单抗体和组合，包括双特异性抗体。优化的功效将是在猕猴模型中的真实挑战研究中进行了测试。如果成功，设计信息对于制作适当的信息至关重要将提供用于向人类中FRT传递mRNA的设备，并提供足够的临床前数据以支持未来的FDA IND应用程序。