Vaginal mAB Delivery Systems

最近成功的替诺福韦阴道凝胶试验提供了重要的概念证据，表明阴道杀微生物剂可以预防艾滋病毒。然而，观察到的保护有限（总体为39%），这表明需要开发额外的杀微生物剂和提供方法。该IPCP应用将开发基于单克隆抗体（Mab）的杀微生物剂，与目前占主导地位的杀微生物剂管道的小分子抗逆转录病毒药物不同。单克隆抗体在提供安全、有效和特异性但广谱的杀微生物剂作用方面显示出希望。项目4将试图通过关注单克隆抗体的输送方式来提高单克隆抗体的有效性。杀微生物剂有效性的局限性可分为两类：第一类，该方法在使用时无法提供保护（“方法失效”）;第二类，未能始终如一地正确使用该方法（“使用者失效”）。我们将尝试通过开发三种新的非性交的杀微生物剂递送方法来减少第二种失败模式，这三种方法强调提供非性交的连续给药。因为这些方法不需要在性交前立即采取行动，我们希望它们能提高杀微生物剂存在的性交行为的比例。此外，我们假设一个额外的好处：我们认为，分配不足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的浓度高得多的原因。我们假设连续或重复给药将改善杀微生物剂的分布，因为单克隆抗体有充裕的扩散时间覆盖阴道的整个折叠表面。因此，我们的三个特定目标将开发以下三种非性交方法：SA 1：Versaring，一种基于在持续释放抗病毒药物方面具有已证实临床性能的技术的阴道环，适用于单克隆抗体的持续阴道释放; SA 2：用户再充电Versaring，Versaring的修改，允许用户以最低成本更换Mab释放单元进行生产; 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.