A practical microbicide based on HIV-1 entry inhibitors

描述(申请人提供)：本IPCP-HTM申请响应RFA Al-07-001，包含三个研究项目，一个是科学核心，一个是行政核心，由首席调查员John P.Moore博士和联席首席调查员Robin A.Shattock博士指导。该计划的目的是进行体外和体内临床前和动物模型研究，旨在促进基于单独和/或联合应用艾滋病毒-1进入抑制剂的阴道杀菌剂的开发。我们的目标是利用我们在病毒学、免疫学、配方化学和哺乳动物生物学方面的集体知识，帮助开发一种基于机制的、针对艾滋病毒-1的杀微生物剂(S)。重点将是开发和评价长效杀微生物剂制剂和给药方法，例如可在使用单一装置后的几周/几个月内在原地提供连续和持续供应活性化合物的控释阴道环，以及可每天使用一次或甚至不频繁使用的半固体制剂。我们将研究的抑制剂包括但不限于：小分子CCRS抑制剂CMPDi67(默克)；小分子附着抑制剂BMS-C(百时美施贵宝)；小分子CXCR4抑制剂AMD3465(AnorMED)；基于GP4i的肽融合抑制剂T-1249(Trimeris)。我们提议：研究项目I：Robin Shattock，人类宫颈和直肠组织模型以及树突状细胞中进入抑制剂的特征；研究项目II：Karl Malcolm，HIV-1进入抑制剂的实用配方；研究项目III：Ronald Veazey，在猕猴中测试实用杀菌剂；病毒学和免疫学核心：John P.Moore；管理核心：John P.Moore。该小组的其他高级成员包括梅丽莎·罗比亚尼和马克·米奇尼克(粒子科学公司)，他们将根据合作协议分别参与研究项目I和III，以及史蒂文·沃林斯基，他们将根据合作协议参加病毒学和免疫学核心。粒子科学的参与满足了拟议研究计划中强制要求的公司要素。如果这项申请成功获得NIH的同行评审和批准，杀菌剂国际伙伴关系将提供支持Shattock、Robbiani和Wolinsky博士领导的研究计划所需的大部分资金，如申请的计划概述部分所述。 项目1：人类宫颈和直肠组织模型以及树突状细胞中进入抑制物的特征(Pi Shattock，Robin J.) 项目1说明(由申请者提供)：已经清楚地确定了杀菌剂在预防艾滋病毒-1粘膜传播方面的潜在作用。然而，对候选杀微生物剂进行严格的临床前评估对于选择用于临床试验的最佳化合物至关重要，因为考虑到正式疗效试验的费用和时间，这最终将节省成本和时间。最近失败或暂停的第三阶段试验(Col-1492、Savvy和纤维素硫酸盐)突显了对未完全优化的候选杀微生物剂进行药效试验的担忧；这些试验表明，开发和配制有效的杀微生物剂可能并不像最初想象的那么容易。虽然单核细胞培养和动物模型可能为杀菌剂的评估提供重要信息，但解剖学、生理学和免疫学问题表明，它们可能不能充分模拟发生在人类粘膜组织中的事件。因此，针对候选杀微生物剂的临床前开发的综合计划需要从几个不同的模型系统中收集信息。因此，Shattock博士和Robbiani博士的团队在体外建立了HIV-1感染人类粘膜组织和树突状细胞驱动的HIV-1传播的最早事件的体外模型。这些模型非常适合于测试旨在阻断HIV-1性传播的药物的有效性，并已被广泛用于评估潜在的杀微生物剂候选。此外，这里描述的实验以及与项目III中描述的实验的交叉验证可能识别潜在的有效性、安全性和依从性的生物标记物，这可能会为未来的临床试验提供信息。在这个项目中，我们将使用这些已建立的模型来评估HIV-1进入抑制剂(单独和联合使用)及其制剂的有效性和配伍。这项研究将受到核心A中开展的工作的影响和指导，并将与领导研究项目II和研究项目III的科学家进行广泛的互动和合作。不同小组之间的互动将导致快速追踪最有希望的抑制剂组合和配方，以便在猕猴模型(研究项目III)中进行评估。

DESCRIPTION (provided by applicant): This IPCP-HTM application made in response to RFA Al-07-001 contains three Research Projects, one Scientific Core and an Administrative Core, under the direction of Principal Investigator, John P. Moore, PhD and co-Principal Investigator, Robin A. Shattock, PhD. The purpose of the program is to conduct in vitro and in vivo pre-clinical and animal model-based research intended to facilitate the development of a vaginal microbicide based on the use of inhibitors of HIV-1 entry, applied alone and/or in combination. Our goal is to use our collective knowledge of virology, immunology, formulation chemistry and mammalian biology to help develop a mechanism-based, HIV-1-specific microbicide(s). An emphasis will be the development and evaluation of long-lasting microbicide formulations and delivery methods, such as controlled release vaginal rings that can provide a continuous and constant supply of active compounds in situ for a period of weeks/months after the application of a single device, and semi-solid formulations that could be applied once-daily or even less frequently. The inhibitors that we will study include, but may not be limited to: the small molecule CCRs inhibitor, CMPDi67 (Merck); the small molecule attachment inhibitor BMS-C (Bristol-Myers Squibb); the small molecule CXCR4 inhibitor AMD3465 (AnorMED); the GP4i-based peptide fusion inhibitor, T-1249 (Trimeris). We propose: Research Project I: Robin Shattock, Characterization of entry inhibitors in human cervical and rectal tissue models, and in dendritic cells; Research Project II: Karl Malcolm, Practical Formulations of HIV-1 Entry Inhibitors; Research Project III: Ronald Veazey, Testing practical microbicides in macaques; Virology and Immunology Core: John P. Moore; Administrative Core: John P. Moore. Other senior members of the team include Melissa Robbiani and Mark Mitchnick (Particle Sciences, Inc) who will participate in Research Projects I and III, respectively, under Cooperative Agreements, and Steven Wolinsky who will take part in the Virology and Immunology Core, also under a Cooperative Agreement. The involvement of Particle Sciences fulfills the mandated corporate element of the proposed research program. If this application is successfully peer reviewed and approved for support by the NIH, the International Partnership for Microbicides will provide the majority of the funding required to support the research programs headed by Drs. Shattock, Robbiani and Wolinsky, as outlined in the Program Overview section of the application. PROJECT 1: Characterization of entry inhibitors in human cervical and rectal tissue models, and dendritic cells (PI Shattock, Robin J.) PROJECT 1 DESCRIPTION (provided by applicant): The potential role of microbicides in preventing the mucosal transmission of HIV-1 has been clearly identified. However, rigorous pre-clinical evaluation of candidate microbicides is essential to the selection of the best compounds for clinical trials, since this will, in the end, provide savings in costs and time, given the expense and length of formal efficacy trials. Concerns with performing efficacy trials with incompletely optimized microbicide candidates have been highlighted by recent failed or halted Phase III trials (COL-1492, SAVVY and Cellulose Sulfate); these trials have suggested that development and formulation of effective microbicides may not be as easy as first thought. While mononuclear cell cultures and animal models may provide important information for the evaluation of microbicides, anatomical, physiological and immunological issues suggest they may not adequately model events that occur in human mucosal tissue. Therefore a comprehensive program for pre-clinical development of microbicide candidates requires that information be accrued from several different model systems. Hence Dr. Shattock's and Robbiani's groups have developed in vitro models of the earliest events in HIV-1 infection of human mucosal tissue and dendritic cell driven HIV-1 spread. These models are ideally suited to test the efficacy of agents designed to block HIV-1 sexual transmission and have been widely used to evaluate potential microbicide candidates. Furthermore, experiments described here and cross validation with experiments described in project III, may identify potential biomarkers of efficacy, safety and compliance that could inform future clinical trials. In this project, we will use these established models to evaluate the efficacy and compatibility of HIV-1 entry inhibitors (alone and in combination) and their formulations. This research will be influenced and guided by work carried out within Core A, and will involve extensive interactions and collaborations with the scientists leading Research Projects II and III. The interactions between the different groups will result in the fast-tracking of the most promising inhibitor combinations and formulations for evaluation in the macaque model (Research Project III).