Vaginal mAB Delivery Systems

最近替诺福韦阴道凝胶试验的成功提供了重要的概念证明，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（总体上为39%）表明，需要开发额外的杀微生物剂和提供它们的方法。该IPCP应用程序将开发一种基于单克隆抗体（Mab）的杀微生物剂，与目前占主导地位的小分子抗逆转录病毒药物不同。单克隆抗体有望提供安全、有效和特异的广谱杀微生物剂作用。项目4将尝试通过关注单抗的交付方式来提高单抗的有效性。杀微生物剂有效性的限制可分为两类：第一，方法在使用时无法提供保护（“方法失效”）；其次，未能始终如一地正确使用方法（“用户失败”）。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这种第二种失效模式，这些方法都强调提供非性交的连续给药。由于这些方法不需要在性交前立即采取行动，我们期望它们能提高使用杀微生物剂的性交行为的比例。此外，我们假设了一个额外的好处：我们认为不充分的分布是导致许多杀微生物剂失败的原因，并且导致体内保护所需的杀微生物剂浓度比体外所需的要高得多。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足的扩散时间覆盖整个阴道折叠表面。因此，我们的三个特定目标将开发以下三种非性交方法：SA1: Versaring，一种基于临床证实的抗病毒药物持续释放技术的阴道内环，适用于单克隆抗体的持续阴道释放；SA2：用户充值Versaring， Versaring的修改版，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.