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

项目总结（见说明）： 由于其效力和优异的安全性，人单克隆抗体（mAb）是产生特异性但机制多样的杀微生物剂的主要候选者。该项目的重点是mapp 66的关键路径开发，这是一种人类单克隆抗体的组合，用于预防HIV和HSV的性传播。mapp 66是在瞬时表达系统（Nicotiana）中生产的，该系统适合于大的、对成本敏感的市场。mapp 66中的原型mAb被充分表征并结合被识别为适当靶标的抗原：（a）HSV上的糖蛋白D;（B）HIV上的gp 41;（c）HIV上的gp 120。基于mapp 66抗独特型单克隆抗体的粘液瘤和全身性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价mapp 66的阴道膜剂制剂。 在具体目标1中，Nicotiana生产的IgG 1和IgG 2版本的mapp 66抗HSV和抗HIV mAb是无糖基化的或具有同源哺乳动物聚糖的。对mAb进行一系列参数评价，以最大限度地提高成功工业化的可能性。评价的参数为：表达、稳定性、中和、病毒粘液捕获、补体结合和Fc γ受体结合。 在具体目标2中，使用烟草制造系统表达选自目标1的mapp 66 mAb。将纯化的mAb喷雾干燥并用于开发阴道膜制剂。活动最终以GMP生产喷雾干燥活性药物成分（API）和阴道膜（制剂），用于IND临床前安全性和有效性研究。 在具体目标中，进行了3项IND使能研究，在体外、动物有效性模型和药理学/毒理学研究中表征mapp 66。在mapp 66膜上制备IND以支持人类志愿者中的安全性测试。 除了进行关键路径研究和满足监管要求外，还将mapp 66 mAb提供给其他项目，用于对HIV和HSV mAb与宫颈阴道环境中细胞和宿主防御的相互作用进行假设驱动研究。

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.