Molecular Pharming in Plants and Plant Cell Cultures: a Great Future Ahead?
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Commentary RITALA, HÄKKINEN & SCHILLBERG Molecular pharming in plants & plant cell cultures: a great future ahead? 2 Commentary Molecular pharming in plants and plant cell cultures: a great future ahead? Pharm. Bioprocess. Keywords: biobetter • biopharmaceutical • bioreactor • emergency vaccine • molecular farming • plant biotechnology • plant cell culture • recombinant protein • transgenic • transient expression Plant biotechnology may not be a famil- tion and genetic improvements. Both the Anneli Ritala*,1, Suvi iar concept to the general public, but it is US FDA and European Medicines Agency T Häkkinen1 & Stefan 2 a rapidly developing field of research that are familiar with these systems, and stan- Schillberg 1 involves the use of plants, plant tissues and dard protocols can be followed to ensure VTT Technical Research Centre of Finland, P.O.Box 1000, Tietotie 2, FI- plant cell cultures to make or modify prod- the approval of new products. However, 02044 VTT, Espoo, Finland ucts and processes. The versatility of plants equivalent protocols are only just emerg- 2Fraunhofer Institute for Molecular and plant cells can be harnessed to produce ing for plant-based production systems, and Biology and Applied Ecology IME, diverse products, including valuable pro- only one plant-derived biopharmaceutical Forckenbeckstrasse 6, 52074 Aachen, teins. This is often described as ‘molecular protein is currently on the market. With Germany * Author for correspondence: anneli. farming’ and it requires the introduction of their established production infrastructure [email protected] foreign DNA into plants or plant cells, turn- and regulatory framework, microbial and ing them into factories for the production mammalian production systems have raced of specific recombinant protein products. far ahead of their plant-based counterparts. The term ‘molecular pharming’ is often No company will change their production 10.4155/PBP.14.21 used instead to highlight the production of host without a clear economic benefit, nor protein-based biopharmaceuticals, which will they consider plants and plant cells for contributes to the sustainable production new products if there is no advantage over of drugs that promote human and animal their incumbent technology. Furthermore, wellbeing. Both terms also apply to the pro- new companies will not base their manufac- duction of valuable secondary metabolites turing on a second-best option. Therefore, 3 such as the anticancer drugs paclitaxel, vin- plant-based systems must begin to com- cristine and vinblastine, but we will focus pete head-to-head with the established sys- on recombinant proteins and their use as tems and, on a technological basis, we can biopharmaceuticals in this article. already identify the areas where plant-based 2014 The biopharmaceutical markets have systems have the advantage, namely in terms expanded rapidly over the last 20 years, and of speed, improved product quality and scal- are projected to more than double in volume ability. over the next decade from US$200 billion The international success story of molec- in 2013 to at least US$500 billion in 2020. ular pharming began in 2006 with the US The two major biopharmaceutical produc- Department of Agriculture approval of a tion systems are microbes (mainly Esch- poultry vaccine against Newcastle disease erichia coli and yeast) and mammalian cells developed by Dow AgroSciences (IN, USA) such as the Chinese hamster ovary platform. [1,2]. The vaccine was manufactured in trans- In both cases, productivity has increased genic tobacco cell suspension cultures and substantially over the last decade due to was a benchmark for the regulatory accep- process optimization, platform standardiza- tance of plants as a manufacturing platform, part of 10.4155/PBP.14.21 © 2014 Future Science Ltd Pharm. Bioprocess. (2014) 2(3), 00–00 ISSN 2048-9145 1 Commentary Ritala, Häkkinen & Schillberg although ultimately, the product was not marketed floodgates for the clinical development of additional because the company withdrew from animal vaccine products in the future. research. Currently, the brightest star in the molecu- There are many different plant-based production lar pharming sky is Elelyso™ (taliglucerase alfa) pro- systems in development and one can evaluate and duced in carrot cells by the Israeli company Protalix select the most suitable system for a given target prod- Biotherapeutics (Carmiel, Israel) [2] and licensed to uct to achieve the optimal characteristics. However, Pfizer Inc. (NY, USA). This is a recombinant form this has diluted efforts to establish a standardized reg- of the human enzyme glucocerebrosidase, which is ulatory process and may delay overall progress in the used for the treatment of the lysosomal storage dis- field and fulfilment of industrial standards. Neverthe- order Gaucher disease. The recombinant product met less, none of the plant-based systems under develop- the primary end points in successful Phase III clinical ment are ideal for all target molecules, so the parallel trials in September 2009 and gained FDA approval development of different platforms is advantageous in 2012. The product is currently on the US and for the progress of molecular pharming. The poten- Israeli markets, but the European Medicines Agency tial of different plant-based production platforms is granted 10-year European marketing exclusivity discussed in more detail below. to another product in 2010 and thus Elelyso can- The greatest advantage of intact plants that are sta- not receive approval for Gaucher disease until 2020. bly transformed to produce a target protein is their Elelyso has a longer serum half-life than its Chinese unparalleled scalability. For biopharmaceutical prod- hamster ovary-derived counterpart Cerezyme® (Gen- ucts, manufacturing will probably be restricted to zyme, MA, USA) [3,4] and is produced by targeting greenhouses and other closed environments to ensure the protein to the plant vacuole, which exposes ter- product safety and batch-to-batch consistency when minal mannose residues on the glycan chains that are production is carried out under controlled condi- required for receptor binding. This avoids the need tions. For example, ORF Genetics (Kopavogur, Ice- to trim the terminal sugars in vitro, which is part of land) [8] uses barley plants grown in greenhouses to the production process for Cerezyme. The long serum produce recombinant growth factors, cytokines and half-life has a strong impact on patient compliance interleukins in the cereal seeds for research purposes. because fewer doses are required. In addition, the Similarly, the Canadian company SemBioSys (AB, disposable bioreactor production platform ProCel- Canada) developed a safflower-based production lEx® (Protalix Biotherapeutics) can easily be scaled system for insulin and completed Phase I/II clinical up to address market needs, and thousands of liters trials in 2009 before filing for bankruptcy in 2012. of cell suspension culture can be harvested weekly. The SemBioSys platform was so efficient that theo- From the traceability and cross-contamination point retically 16 mid-sized Canadian farms could have of view, disposable bioreactors are the best option for produced enough insulin to meet the entire global biopharmaceutical production. demand. Although the current E. coli platform also Several plant-derived biopharmaceutical products meets this capacity, it is more expensive to establish in are currently undergoing clinical trials. The EU FP6- developing countries, which would therefore benefit funded academic consortium Pharma-Planta [5] pio- most from the production of inexpensive medicines neered the regulatory process for the entire European in plants. molecular pharming community by taking a tobacco- The use of plant cell suspension cultures for derived HIV-neutralizing monoclonal antibody from molecular pharming is advantageous owing to the initial vector construction and gene transfer through high product quality and scalability. Since the with- all phases of development and manufacturing to drawal of Dow AgroSciences from the animal vaccine launch a Phase I clinical trials, which concluded in market, Fraunhofer Institute for Molecular Biology 2011. The consortium worked closely with EU and and Applied Ecology [9] has continued to develop national regulatory authorities to ensure the safety of the tobacco BY-2 cell platform in the context of the the antibody and promote the acceptance of plant- EU-FP7-funded project CoMoFarm [10] combined based production platforms. In January 2014, a col- with orbitally shaken bioreactor technology from laboration between Icon Genetics GmbH (Halle, Ger- Kühner (Basel, Switzerland) [11] . The 200 l OrbShake many) [6] and Bayer Innovation GmbH (Düsseldorf, device was used for the large-scale cultivation of 100- Germany) [7] resulted in the completion of a Phase liter BY-2 cell suspension cultures, resulting in cell I clinical trial for a personalized plant-derived vac- growth and target protein yield comparable to stan- cine for the treatment of non-Hodgkin’s lymphoma. dard cultivation using shake flasks, thus achieving a These examples represent important milestones in the several 100-fold scale up without loss of productivity history of plant molecular pharming and open the [12] . VTT Technical Research Centre of Finland used 2 Pharm. Bioprocess. (2014) 2(3) future science group Molecular pharming in plants & plant cell cultures: a great future ahead? Commentary traditional microbial bioreactors to cultivate