Vaginal mAB Delivery Systems

最近成功的试验替诺福韦阴道凝胶提供了重要的概念证明表明， 阴道杀菌剂可以预防艾滋病。然而，观察到的保护有限（总体为39%）， 开发另外的杀微生物剂和递送它们的方法。此IPCP应用程序将 开发一种基于单克隆抗体（Mab）的杀微生物剂，不同于小分子抗逆转录病毒药物， 在目前的杀微生物剂生产线中占主导地位。单克隆抗体显示出提供安全，有效和特异性，但 广谱杀微生物剂作用。项目4将努力通过重点关注 Mab的传递方式。杀微生物剂有效性的限制可分为两类：第一， 方法在使用时提供保护的内在故障（“方法故障”）;第二，未能使用 方法一致且正确（“用户失败”）。我们将尝试通过以下方式减少第二种故障模式： 开发了三种新型的非性交的杀微生物剂递送方法， 非性交连续给药。因为这些方法不需要在 性交，我们希望它们能提高杀微生物剂存在的性交行为的比例。此外，委员会认为， 我们假设还有一个额外的好处：我们认为，许多杀微生物剂的分布不充分是原因之一， 失败，并负责高得多的浓度的杀微生物剂通常需要在体内 与体外所需的保护相比。我们假设连续或重复给药将 由于单克隆抗体有充足的扩散时间覆盖整个折叠表面， 阴道因此，我们的三个具体目标将开发以下三种非性交方法：SA 1： Versaring是一种基于技术的阴道环，在缓释方面具有成熟的临床性能 一种抗病毒药物，在此适用于单克隆抗体的持续阴道释放; SA 2： Versaring，Versaring的改良，允许用户更换Mab释放装置用于生产 SAS：使用Duet®宫颈屏障装置输送单克隆抗体。

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.