Molecular Immunology Unit, Institute for Infection and Immunity, St. George's University of London, London, UK.
Fraunhofer IME, Aachen, Germany.
Plant Biotechnol J. 2015 Oct;13(8):1106-20. doi: 10.1111/pbi.12416. Epub 2015 Jul 3.
Although plant biotechnology has been widely investigated for the production of clinical-grade monoclonal antibodies, no antibody products derived from transgenic plants have yet been approved by pharmaceutical regulators for clinical testing. In the Pharma-Planta project, the HIV-neutralizing human monoclonal antibody 2G12 was expressed in transgenic tobacco (Nicotiana tabacum). The scientific, technical and regulatory demands of good manufacturing practice (GMP) were addressed by comprehensive molecular characterization of the transgene locus, confirmation of genetic and phenotypic stability over several generations of transgenic plants, and by establishing standard operating procedures for the creation of a master seed bank, plant cultivation, harvest, initial processing, downstream processing and purification. The project developed specifications for the plant-derived antibody (P2G12) as an active pharmaceutical ingredient (API) based on (i) the guidelines for the manufacture of monoclonal antibodies in cell culture systems; (ii) the draft European Medicines Agency Points to Consider document on quality requirements for APIs produced in transgenic plants; and (iii) de novo guidelines developed with European national regulators. From the resulting process, a GMP manufacturing authorization was issued by the competent authority in Germany for transgenic plant-derived monoclonal antibodies for use in a phase I clinical evaluation. Following preclinical evaluation and ethical approval, a clinical trial application was accepted by the UK national pharmaceutical regulator. A first-in-human, double-blind, placebo-controlled, randomized, dose-escalation phase I safety study of a single vaginal administration of P2G12 was carried out in healthy female subjects. The successful completion of the clinical trial marks a significant milestone in the commercial development of plant-derived pharmaceutical proteins.
虽然植物生物技术已被广泛用于生产临床级单克隆抗体，但尚未有任何源自转基因植物的抗体产品获得药品监管机构批准进行临床测试。在 Pharma-Planta 项目中，HIV 中和人源单克隆抗体 2G12 在转基因烟草（Nicotiana tabacum）中表达。通过对转基因位点进行全面的分子特征分析、确认遗传和表型稳定性经过几代转基因植物、以及建立主种子库创建、植物栽培、收获、初步加工、下游加工和纯化的标准操作程序，解决了良好生产规范（GMP）的科学、技术和监管要求。该项目根据（i）在细胞培养系统中制造单克隆抗体的指南；（ii）欧洲药品管理局关于在转基因植物中生产的原料药质量要求的草案要点考虑文件；以及（iii）与欧洲国家监管机构共同制定的新指南，为植物来源的抗体（P2G12）制定了原料药规格。根据该工艺，德国主管当局为用于 I 期临床评估的转基因植物来源的单克隆抗体颁发了 GMP 生产许可。经过临床前评估和伦理批准后，英国国家药品监管机构接受了临床试验申请。在健康女性受试者中进行了 P2G12 单次阴道给药的 I 期安全性、双盲、安慰剂对照、随机、剂量递增的首次人体临床试验。临床试验的成功完成标志着植物来源的药物蛋白商业化开发的一个重要里程碑。
