Pre-Clinical Evaluation of mAb Microbicide Products in Nonhuman Primates

项目总结（见说明）： 在缺乏有效疫苗的情况下，预防艾滋病毒传播仍然是迄今为止可用的主要和经济上可行的感染预防方法。不幸的是，避孕套仍然是迄今为止唯一最有效的方法，这种预防方法在某些社区不一定可用或可接受。因此，耐受性良好和有效的杀微生物剂的基本原理在本提案中得到了强调。不幸的是，以前的临床试验与有前途的杀微生物剂配方不仅未能防止传播，但在某些情况下，甚至有相反的效果，通过促进病毒通过粘膜。这些发现表明需要使用代表人类的动物模型进行彻底的临床前安全性和有效性测试。 非人灵长类动物模型在进入临床竞技场之前完成这些先决条件。 因此，该项目将使用总共55只骑自行车的雌性食蟹猴来评价HEC凝胶与阴道环或粘膜粘附膜的生物分布、药代动力学以及潜在的局部和全身毒性，所述阴道环或粘膜粘附膜被配制成释放能够中和多种HIV分离株和HSV-2gD进入阴道环境的单克隆抗体。将进行初始剂量探索研究，以确定每种HIV MaB对进化枝B SHIV的多次低剂量暴露的保护剂量。该数据将用于配制组合的Mab剂量以通过膜或阴道环递送， 与凝胶相比。完成药代动力学和药效学研究后，将检测通过稳定粘膜粘附膜递送的该组合对重复低剂量SHIV攻击的保护效力。最后，在目标4中，我们将比较通过IVR递送单克隆抗体与薄膜对多次阴道暴露于进化枝B或C SHIV的保护功效，并将最终高剂量激发作为最终保护测试。这些临床前研究的结果将为后续I期和II期人体临床试验的验证和优化提供宝贵的数据。

PROJECT SUMMARY (See Instructions): In the absence of an efficient vaccine, prevention of HIV transmission remains the primary and economically feasible infection prevention method available to date. Unfortunately, condoms have remained the single most effective method available to date, and such prevention method is not necessarily available or acceptable in certain communities. Thus the rationale for well tolerated and efficacious microbicides are a given as highlighted in this proposal. Unfortunately, previous clinical trials with promising microbicide formulations have not only failed to protect from transmission but in certain cases have even had the opposite effect by facilitating viral passage through the mucosa. These findings dictate the need for thorough pre-clinical safety and efficacy testing using an animal model representative of man. This project aims to use the nonhuman primate model to fulfill these pre-requisites before moving to the clinical arena. The project will therefore utilize a total of 55 cycling female cynomolgus macaques to evaluate the biodistribution, pharmacokinetics and potential localized and systemic toxicity of HEC gel versus vaginal rings or mucoadhesive films formulated to release monoclonal antibodies capable of neutralizing a wide variety of HIV isolates and HSV-2gD into the vaginal environment. An initial dose finding study will be performed to identify protective doses for each HIV Mab against multiple low dose esposures to a clade B SHIV. This data will be used to formulate a combined Mab dose to deliver via films or intravaginal rings as compared to gel. After completion of pharmacokinetics and pharmacodynamic studies, this combination delivered via stable mucoadhesive films will be tested for protective efficacy against repeated low dose SHIV challenges. Finally, in aim 4, we will compare delivery of the Mabs via IVR to films for protective efficacy against multiple vaginal exposures to either a clade B or C SHIV with a final high dose challenge as a final test of protection. Outcome of these preclinical studies will provide invaluable data for the validation and optimization of subsequent phase I and II human clinical trials.