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在经济上可行的主要感染预防方法。不幸的是，到目前为止，避孕套仍然是唯一最有效的方法，这种预防方法不一定在某些社区可用或被接受。因此，本提案强调了耐受性良好和有效的杀微生物剂的理由。不幸的是，以前有希望的杀微生物剂配方的临床试验不仅未能防止传播，而且在某些情况下甚至通过促进病毒通过粘膜产生了相反的效果。这些发现要求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。该项目旨在使用 非人灵长类动物模型在进入临床舞台之前满足这些先决条件。 因此，该项目将利用总共55只骑自行车的雌性食蟹猴来评估HEC凝胶与阴道环或粘附膜的生物分布、药代动力学以及潜在的局部和全身毒性。HEC凝胶的配方是为了释放能够中和多种HIV分离株和HSV-2GD的单抗进入阴道环境。将进行一项初始剂量发现研究，以确定每个HIV单抗对B分支Shiv的多个低剂量摄取的保护量。这一数据将被用来制定通过胶片或阴道内环传递的联合单抗剂量，如 与凝胶相比。在完成药代动力学和药效学研究后，将测试通过稳定的粘附膜提供的这种组合对反复低剂量SIV挑战的保护效果。最后，在目标4中，我们将比较通过IVR传递的单抗与胶片对多次暴露于B或C分支Shiv的保护效果，并将最后的高剂量挑战作为保护的最终测试。这些临床前研究的结果将为后续的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.