Vaginal mAB Delivery Systems

阴道 mAB 输送系统

• 批准号: 8706778
• 负责人: Thomas Ray Moench
• 金额: $ 5.66万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8706778
• 关键词: Adherence; Antibodies; Antiviral Agents; Categories; Cervical; Cervix Uteri; Clinical; Coitus; Complex; Data; Development; Devices; Diffusion; Dose; Effectiveness; Environment; Environmental Impact; Epithelium; Failure; Film; HIV; HIV/STD; Human; Immune system; Immunoglobulin G; In Vitro; Infection; Instruction; Mediating; Methods; Modification; Monoclonal Antibodies; Passive Immunization; Performance; Pharmaceutical Preparations; Production; Proteins; Resources; Safety; Simplexvirus; Surface; System; Technology; Tenofovir; Time; Vagina; Vaginal Diaphragm; Vaginal Gel; Vaginal Ring; base; cervicovaginal; cost; flexibility; improved; in vivo; microbicide; novel; pathogen; prevent; small molecule; vaginal microbicide

The recent successful trial of tenofovir vaginal gel provides important proof of concept indicating that a vaginal microbicide can prevent HIV. However, the limited protection observed (39% overall), argues for the development of additional microbicide agents and methods to deliver them. This IPCP application will develop a monoclonal antibody (Mab) based microbicide, distinct from the small molecule antiretrovirals that dominate the current microbicide pipeline. Mabs show promise in providing safe, potent, and specific, yet broad-spectrum microbicide action. Project 4 will attempt to enhance Mab effectiveness by its focus on the means of Mab delivery. Limitations on microbicide effectiveness can be divided into two categories: first, intrinsic failure of the method to provide protection when used ("method failure"); and second, failure to use the method consistently and correctly ("user failure"). We will attempt to reduce this second failure mode by developing three novel non-coital methods of microbicide delivery related by their emphasis on providing non-coital continuous dosing. Because these methods will not require action immediately in advance of coitus, we expect them to improve the proportion of coital acts wherein the microbicide is present. Moreover, we hypothesize an additional benefit: We believe inadequate distribution is responsible for many microbicide failures, and is responsible for the much higher concentrations of microbicide generally needed for in vivo protection compared to that required in vitro. We hypothesize that continuous or repeated dosing will improve microbicide distribution due to generous diffusion time for Mabs to cover the entire folded surface of the vagina. Our three Specific Aims will thus develop athe following three non-coital methods: SA1: Versaring, an intravaginal ring based on technology with proven clinical performance in sustained release of an antiviral, here to be adapted for sustained vaginal release of monoclonal antibodies; SA2: User-recharged Versaring, a modification of Versaring that will allow user replacement of Mab releasing units for production at lowest cost; SAS: Delivery of Mabs using the Duet® cervical barrier device.

最近对替诺福韦阴道凝胶的成功试验提供了重要的概念证明，表明 阴道杀微生物剂可以预防 HIV，但观察到的保护作用有限（总体为 39%）。 该 IPCP 应用将开发更多的杀微生物剂和提供这些杀微生物剂的方法。 开发一种基于单克隆抗体 (Mab) 的杀微生物剂，与小分子抗逆转录病毒药物不同 主导当前杀菌剂管道的单克隆抗体显示出提供安全、有效和特异性的前景。 广谱杀菌剂行动 项目 4 将尝试通过重点关注来提高单克隆抗体的有效性。 单克隆抗体递送方式的局限性可分为两类：第一， 使用该方法时无法提供保护（“方法失败”）；第二，未能使用 一致且正确的方法（“用户失败”）我们将尝试通过以下方式减少第二种失败模式。 开发三种新颖的非性交杀微生物剂递送方法，其重点在于提供 因为这些方法不需要在性交前立即采取行动。 性交时，我们期望它们能够提高性交行为的比例，因此存在杀菌剂。 我们还有一个额外的好处：我们相信分配不充分是造成许多杀菌剂的原因 失败，并导致体内通常需要更高浓度的杀微生物剂 与体外所需的保护相比，我们敢于连续或重复给药。 由于 Mab 有足够的扩散时间来覆盖整个折叠表面，因此改善了杀菌剂的分布 因此，我们的三个具体目标将开发以下三种非性交方法： SA1： Versaring，一种基于技术的阴道内环，其持续释放的临床性能已得到验证 一种抗病毒药物，适用于单克隆抗体的持续阴道释放；SA2：用户充电； Versaring，Versaring 的改进版，允许用户更换用于生产的 Mab 释放单元 以最低的成本；SAS：使用 Duet® 宫颈屏障装置输送单克隆抗体。