Critical Path Project: Mapp66, a Multi-antibody Prevention Product

项目总结(见说明)： 由于其效力和良好的安全性，人类单抗是产生特异的、但机械上多样化的杀菌剂的主要候选者。该项目的重点是开发Mapp66的关键路径，这是一种人类单抗的组合，用于预防艾滋病毒和单纯疱疹病毒的性传播。Mapp66是在一种适用于大型成本敏感市场的瞬时表达系统(尼古丁)中制造的。Mapp66中的原型单抗具有良好的特性，并与被认为是适当靶点的抗原结合：(A)单纯疱疹病毒上的糖蛋白D；(B)艾滋病毒上的gp41；(C)艾滋病毒上的gpl20。基于Mapp66抗独特型单抗的黏膜和系统疫苗正在独立于该项目开发，但同时通过主动免疫增强抗体介导的保护。 关键路径项目的总体目标是提交一份研究性新药申请(IND)，以支持在人类志愿者中评估MAPP66的阴道膜剂配方。 在特定目的1中，烟草生产的IgG1和lgG2版本的mapp66抗HSV和抗HIV单抗是糖基化的或与均一的哺乳动物多糖一起生产的。对mAbs进行了一系列参数的评估，以最大限度地提高成功工业化的可能性。评估的参数包括：表达、稳定性、中和性、病毒粘液捕获、补体结合和Fcγ受体结合。 在特定目的2中，使用尼古丁制造系统表达选自目的1的Mapp66单抗。纯化的单抗被喷雾干燥，并用于开发阴道膜剂。活动的最终结果是GMP生产喷雾干燥活性药物成分(API)和阴道膜(药物产品)，用于IND-Enabling临床前安全性和有效性研究。 在特定目的中，在体外、动物疗效模型和药理学/毒理学研究中进行了3项使能IND的研究，以表征MAPP66。为了支持人类志愿者的安全测试，Mapp66上的Ind薄膜已经准备好了。 除了进行关键路径研究和满足监管要求外，mapp66 mAbb还被提供给其他项目，用于假说驱动的研究，研究艾滋病毒和HSV mAbb与宫颈阴道环境中的细胞和宿主防御系统的相互作用。

PROJECT SUMMARY (See instructions): Because of their potency and excellent safety profile, human monoclonal antibodies (mAbs) are leading candidates for the generation of specific, but mechanistically diverse microbicides. This Project focuses on the critical path development of mapp66, a combination of human mAbs, to prevent sexual transmission of HIV and HSV. mapp66 is manufactured in a transient expression system (Nicotiana) that is appropriate for large, cost-sensitive markets. The prototype mAbs in mapp66 are well-characterized and bind to antigens recognized as appropriate targets: (a) glycoprotein D on HSV; (b) gp41 on HIV; (c) gpl20 on HIV. Mucosal and systemic vaccines that are based on anti-idiotype mAbs of mapp66 are being developed independent of this project, but in parallel to enhance antibody-mediated protection via active immunization. The overall goal of the Critical Path Project is to submit an Investigational New Drug application (IND) to support evaluation of a vaginal film formulation of mapp66 in human volunteers. In specific aim 1 Nicotiana manufactured IgG1 and lgG2 versions of the mapp66 anti-HSV and anti-HIV mAbs are produced aglycosylated or with homogenous mammalian glycans. The mAbs are evaluated for a range of parameters to maximize the likelihood of successful industrialization. Parameters evaluated are: expression, stability, neutralization, mucus trapping of virus, complement fixation and Fc gamma receptor binding. In specific aim 2 the mapp66 mAbs selected from Aim 1 are expressed using the Nicotiana manufacturing system. Purified mAbs are spray-dried and used for developing a vaginal film formulation. Activities culminate with GMP manufacturing of spray-dried active pharmaceutical ingredient (API) and vaginal film (drug product) for IND-enabling preclinical safety and efficacy studies. In specific aim 3 IND-enabling studies are performed characterizing the mapp66 in vitro, in animal efficacy models and in pharmacology/toxicology studies. An IND on mapp66 film is prepared to support safety testing in human volunteers. In addition to conducting Critical Path studies and addressing regulatory requirements, the mapp66 mAbs are provided to other Projects for hypothesis-driven research into the interactions of HIV and HSV mAbs with the cellular and host defenses in the cervicovaginal environment.