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，表明阴道杀菌剂可以预防艾滋病毒。然而，观察到的有限保护(总比例为39%)表明，需要开发更多的杀微生物剂和提供这些杀菌剂的方法。IPCP的这一应用将开发一种基于单抗(Mab)的杀微生物剂，有别于目前主导杀微生物剂管道的小分子抗逆转录病毒药物。单抗在提供安全、有效和特异的广谱杀微生物剂作用方面显示出希望。项目4将试图通过侧重于Mab的交付手段来提高Mab的效力。对杀微生物剂效力的限制可分为两类：第一，该方法在使用时未能提供保护(“方法失败”)；第二，未能始终如一地正确使用该方法(“使用者失败”)。我们将试图通过开发三种新的非性交给药方法来减少第二种失败模式，这三种方法与它们强调提供非性交连续给药有关。因为这些方法不需要在性交前立即采取行动，我们希望它们能改善存在杀菌剂的性行为的比例。此外，我们还假设了一个额外的好处：我们认为，不充分的分布是许多杀微生物剂失败的原因，也是体内保护所需的杀微生物剂浓度比体外保护所需浓度高得多的原因。我们假设，连续或重复给药将改善杀菌剂的分布，因为单抗有足够的扩散时间覆盖整个阴道折叠表面。因此，我们的三个具体目标将开发以下三种非交配方法：SA1：Versling，一种基于经临床证明在持续释放抗病毒方面的技术的阴道内环，此处适用于单抗的持续阴道释放；SA2：用户充电的Versling，这是Versling的一种修改，允许用户更换Mab释放单元以最低成本生产；SAS：使用Duet？宫颈屏障装置提供单抗。

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.