Vaginal mAB Delivery Systems

最近替诺福韦阴道凝胶的成功试验提供了重要的概念证据，表明一种 阴道杀微生物剂可以预防艾滋病毒。然而，观察到的有限保护(总体为39%)认为 开发更多的杀微生物剂及其投放方法。此IPCP应用程序将 开发一种基于单抗(Mab)的杀微生物剂，与小分子抗逆转录病毒药物不同 主宰了目前的杀微生物剂管道。单抗在提供安全、有效和特异的 广谱杀微生物剂作用。项目4将试图通过将重点放在 Mab的投放方式。杀微生物剂效力的限制可分为两类：第一， 方法在使用时无法提供保护的固有故障(“方法故障”)；第二，无法使用 方法始终如一且正确无误(“用户故障”)。我们将尝试通过以下方式减少第二种故障模式 发展三种新的非交配给药方法，它们的重点是提供 非性交连续给药。因为这些方法不需要立即在 性交，我们希望他们改善性交行为的比例，其中存在杀菌剂。此外， 我们假设了一个额外的好处：我们认为不充分的分配是许多杀微生物剂的原因 失败，并导致体内通常需要更高浓度的杀微生物剂 与体外所需的保护进行比较。我们假设连续或重复给药将 由于MAb有足够的扩散时间覆盖整个折叠表面，因此改善了杀菌剂的分布 阴道。因此，我们的三个具体目标将发展以下三种非性交方法：SA1： Versling，一种基于技术的阴道内环，临床上证明了其缓释性能 一种抗病毒药物，适用于单抗的阴道持续释放；SA2：用户充电 Versering，对Versering的修改，将允许用户更换Mab释放单元以进行生产 最低成本；SAS：使用Duet®宫颈屏障设备提供单抗。

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.