Monoclonal Antibody-based Multipurpose Microbicides

描述(由申请人提供)： 这一HIV局部杀菌剂临床前/临床综合计划(IPCP-HTM)汇集了一个研究人员网络，以执行多学科临床前和探索性临床研究，目标是开发一种安全、新型的多抗体局部杀菌剂Mapp66。Mapp66含有三种单抗的组合，这些单抗是通过基因工程在本氏烟草(N)中产生的，旨在阻断HIV性传播的不同机制：1)中和游离的HIV病毒粒子(4E10和VRCO1 Mab-N)；2)预防单纯疱疹病毒(HSV)感染，这是一种可增强HIV感染的性传播病原体(HSV8 Mab-N)。单抗-NS将制成可生物降解的薄膜和控释阴道环，并将在体外和体内进行药代动力学/动力学、毒性和抗微生物(HIV、HSV)疗效测试。提出了六个相互关联的科学项目和一个管理核心。项目1(Whaley博士，Pi)是关键路径项目，该项目将为基础和临床前研究生产cGMP单抗-NS，进行定量单抗-N抗体测试以支持所有项目进行的研究，并为mapp66提交IND。项目2(Anderson博士，Pi)将在体外和体外研究单个单抗-NS和Mapp66制剂在宫颈阴道艾滋病毒和单纯疱疹病毒感染检测中的有效性。项目3(Lai博士，Pi)将研究单抗-N与生殖器粘蛋白的相互作用，并将在小鼠单纯疱疹病毒感染模型中使用mapp66单抗进行疗效试验。项目4(莫奇和史密斯博士)将生产具有持续单抗输送的装置(Duet、阴道环)，以增强这种方法的有效性。项目5将使用Mapp66凝胶、薄膜和阴道环进行非人类灵长类动物的药代动力学/动力学、毒性和SIV挑战研究。项目6(Mayer博士，Pi)包括一项La期临床试验，以评估MAPP66膜在妇女中使用和不使用宫颈屏障(Duet装置)的药物动力学/动力学和安全性。行政核心(安德森博士)以及行政和外部咨询委员会将在协调组成IPCP-HTM计划的多个调查人员和地点方面提供科学和行政领导和支持。

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.