Regulatory approval and a first‐in‐human phase I clinical trial of a monoclonal antibody produced in transgenic tobacco plants

Abstract

SummaryAlthough 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 HIVneutralizing 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.

Recombinant expression of LFchimera antimicrobial peptide in a plant-based expression system and its antimicrobial activity against clinical and phytopathogenic bacteria

“…Several biopharmaceuticals for human use, such as vaccines, antibodies, cytokines and growth factors, have been successfully produced in field-grown tobacco and are in in vitro, animal or human trials, or are approved for sale [29,50]. Recent studies show that tobacco can be used as a suitable expression system for cost-effective production of diagnostic proteins and interleukins and for stable production of recombinant proteins, such as antibodies, across all the plants generations [49,51,52]. The expression of different recombinant proteins in dicot plants, such as tobacco, is generally achieved through the transformation of the transgene using biological methods and utilizing Agrobacterium bacteria [48].…”

A reference genome for Nicotiana tabacum enables map-based cloning of homeologous loci implicated in nitrogen utilization efficiency

“…More recently, potential applications in biopharmaceutical [3, 4] and biofuel [5] production have generated renewed interest in the species. Improved tobacco genomic resources are necessary to facilitate such applications, but genome size and complexity has slowed their development.…”

An Accessory Protease Inhibitor to Increase the Yield and Quality of a Tumour-Targeting mAb in Nicotiana benthamiana Leaves

“…Several proteins of medical interest have been successfully produced in plant systems over the last two decades [2–4], notably including monoclonal antibodies for the diagnosis or treatment of human diseases [5–7]. On the other hand, and although plants have been widely investigated for the production of clinical-grade monoclonal antibodies against human tumours [8], the West Nile virus [9] or the Ebola virus [10], it is only recently that a first plant-made antibody was approved by regulatory bodies for a first-in-human Phase I clinical trial [7]. …”