title: Regulatory approval and a first-in-human phase I clinical trial of a monoclonal antibody produced in transgenic tobacco plants.
abstract: 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.
authors.affiliation: Molecular Immunology Unit, Institute for Infection and Immunity, St. George's University of London, London, UK.
authors.forename: Julian K-C
authors.initials: JK
authors.lastname: Ma
authors.affiliation: Fraunhofer IME, Aachen, Germany.|RWTH Aachen University, Aachen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Drossard
authors.affiliation: Molecular Immunology Unit, Institute for Infection and Immunity, St. George's University of London, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Lewis
authors.affiliation: Department of Chemistry, Universität für Bodenkultur (BOKU), Vienna, Austria.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Altmann
authors.affiliation: Clinical Research Centre, Institute of Biosciences and Medicine, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Boyle
authors.affiliation: Department of Plant Production and Forestry Science, ETSEA, University of Lleida-Agrotecnio Center, Lleida, Spain.|Institució Catalana de Recerca i Estudis Avançats, Passeig Lluís Companys 23, Barcelona, Spain.
authors.forename: Paul
authors.initials: P
authors.lastname: Christou
authors.affiliation: Molecular Immunology Unit, Institute for Infection and Immunity, St. George's University of London, London, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Cole
authors.affiliation: John Innes Centre, Norwich Research Park, Norwich, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Dale
authors.affiliation: Molecular Immunology Unit, Institute for Infection and Immunity, St. George's University of London, London, UK.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: van Dolleweerd
authors.affiliation: Molecular Immunology Unit, Institute for Infection and Immunity, St. George's University of London, London, UK.
authors.forename: Valerie
authors.initials: V
authors.lastname: Isitt
authors.affiliation: Polymun Scientific Immunbiologische Forschung GmbH, Klosterneuburg, Austria.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Katinger
authors.affiliation: Fraunhofer IME, Aachen, Germany.|RWTH Aachen University, Aachen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Lobedan
authors.affiliation: Fraunhofer IME, Aachen, Germany.|RWTH Aachen University, Aachen, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Mertens
authors.affiliation: Molecular Immunology Unit, Institute for Infection and Immunity, St. George's University of London, London, UK.
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Paul
authors.affiliation: Fraunhofer IME, Aachen, Germany.|RWTH Aachen University, Aachen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rademacher
authors.affiliation: Fraunhofer IME, Aachen, Germany.|RWTH Aachen University, Aachen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Sack
authors.affiliation: John Innes Centre, Norwich Research Park, Norwich, UK.
authors.forename: Penelope A C
authors.initials: PA
authors.lastname: Hundleby
authors.affiliation: Polymun Scientific Immunbiologische Forschung GmbH, Klosterneuburg, Austria.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Stiegler
authors.affiliation: Fraunhofer IME, Aachen, Germany.|RWTH Aachen University, Aachen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Stoger
authors.affiliation: TRM Ltd, York, UK.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Twyman
authors.affiliation: Polymun Scientific Immunbiologische Forschung GmbH, Klosterneuburg, Austria.
authors.forename: Brigitta
authors.initials: B
authors.lastname: Vcelar
authors.affiliation: Fraunhofer IME, Aachen, Germany.|RWTH Aachen University, Aachen, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Fischer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis* / Q000627:therapeutic use*; D000080908:Broadly Neutralizing Antibodies; D017277:Drug Approval; D005260:Female; D054794:Glycomics; D015483:HIV Antibodies; D006801:Humans; D008969:Molecular Sequence Data; D010641:Phenotype; D030821:Plants, Genetically Modified; D055550:Protein Stability; D040901:Proteomics; D011817:Rabbits; D012926:Social Control, Formal; D014026:Nicotiana / Q000235:genetics*; D014170:Transformation, Genetic
chemical_list: C529157:2G12 monoclonal antibody; D000911:Antibodies, Monoclonal; D000080908:Broadly Neutralizing Antibodies; D015483:HIV Antibodies
keywords: good manufacturing practice; human trial; monoclonal antibody; phase I; tobacco; transgenic plants