Monoclonal Antibody-based Multipurpose Microbicides

描述（由申请人提供）： HIV外用杀微生物剂的综合临床前/临床计划（IPCP-HTM）汇集了一个研究人员网络，进行多学科的临床前和探索性临床研究，目的是推进一种安全，新型的多抗体外用杀微生物剂，mapp 66。Mapp 66含有三种单克隆抗体（Mab）的组合，其通过基因工程在本氏烟草（Nicotiana benthamiana）（N）中产生，其被设计为阻断HIV性传播的不同机制：1）游离HIV病毒体的中和（4 E10和VRCO 1 Mab-N）;和2）预防单纯疱疹病毒（HSV）感染，HSV是一种增强HIV感染的性传播病原体（HSV 8 Mab-N）。Mab-Ns将被配制成可生物降解的膜和控释阴道环，并将在体外和体内测试药代动力学/动力学、毒性和抗微生物（HIV、HSV）功效。提出了六个相互关联的科学项目和一个行政核心。项目1（Dr. Whaley，PI）是关键路径项目，将生产用于基础和临床前研究的cGMP Mab-N，进行定量Mab-N抗体检测以支持所有项目进行的研究，并提交IND用于map 66。项目2（安德森博士，PI）将在体外和离体宫颈阴道HIV和HSV感染试验中研究单个Mab-Ns和mapp 66制剂的疗效。项目3（Dr. Lai，PI）将研究Mab-N与生殖器粘蛋白的相互作用，并将在鼠HSV感染模型中使用mapp 66 Mab进行疗效试验。项目4（Moench和Smith博士）将生产具有持续Mab递送的装置（Duet，阴道环），以增强该方法的有效性。项目5（Dr. Villinger，PI）将使用mapp 66-凝胶、薄膜和阴道环进行非人灵长类动物药代动力学/动力学、毒性和SHIV攻毒研究。项目6（Dr. Mayer，PI）包括一项评估map 66-膜在女性中与宫颈屏障（Duet器械）联合使用和不联合使用的药物动力学/动力学和安全性的la期临床试验。管理核心（安德森博士）以及执行和外部咨询委员会将提供科学和行政领导和支持，以协调构成本IPCP-HTM项目的多个研究者和研究中心。

DESCRIPTION (provided by applicant): This Integrated Preclinical/Clinical Program for HIV Topical Microbicides (IPCP-HTM) brings together a network of investigators to perform multidisciplinary preclinical and exploratory clinical studies with the goal of advancing a safe, novel multi-antibody topical microbicide, mapp66. Mapp66 contains a combination of three monoclonal antibodies (Mabs), produced by genetic engineering in Nicotiana benthamiana (N), that are designed to block distinct mechanisms of HIV sexual transmission: 1) neutralization of free HIV virions (4E10 and VRCOl Mab-N); and 2) prevention of herpes simplex virus (HSV) infection, a sexually transmitted pathogen that enhances HIV infection (HSV8 Mab-N). The Mab-Ns will be formulated into a biodegradable film and controlled release vaginal rings, and will be tested in vitro and in vivo for pharmacokinetics/dynamics, toxicity and anti-microbial (HIV, HSV) efficacy. Six interrelated scientific projects and an Administrative Core are proposed. Project 1 (Dr. Whaley, PI) is the critical path project that will produce cGMP Mab-Ns for the basic and preclinical studies, conduct quantitative Mab-N antibody tests to support studies performed by all projects, and submit an IND for mapp66. Project 2 (Dr. Anderson, PI) will investigate the efficacy of individual Mab-Ns and mapp66 formulations in vitro and ex vivo in cervicovaginal HIV and HSV infection assays. Project 3 (Dr. Lai, PI) will study Mab-N interactions with genital mucins, and will conduct efficacy trials with mapp66 Mabs in the murine HSV infection model. Project 4 (Drs. Moench and Smith) will produce devices (Duet, vaginal rings) with sustained Mab delivery to enhance the efficacy of this approach. Project 5 (Dr. Villinger, PI) will conduct nonhuman primate pharmacokinetic/dynamic, toxicity and SHIV-challenge studies with mapp66-gel, film and vaginal rings. Project 6 (Dr. Mayer, PI) consists of a Phase la clinical trial to assess the phamacodynamics/kinetics and safetyof mapp66-film used with and without a cervical barrier (Duet device) in women. An Administrative Core (Dr. Anderson) and executive and external advisory committees will provide scientific and administrative leadership and support in coordinating the multiple investigators and sites that make up this IPCP-HTM program.