Molecular pharming’s foot in the FDA’s door: Protalix’s trailblazing story

Abstract

Objectives This short commentary examines the factors that led to Food and Drug Administration’s approval of the first plant-derived biologic. Results In 2012, the first plant-derived protein pharmaceutical (biologic) was approved for commercial use in humans. The product, a recombinant form of human β-glucocerebrosidase marketed as ELELYSO, was developed by Protalix Biotherapeutics (Carmiel, Israel). The foresight to select this particular therapeutic product for development, flawless production pipeline, and serendipity seem to provide the key in explaining how ELELYSO became the first plant-derived biologic to achieve approval by Food and Drug Administration. Conclusions While the circumstances that enabled Protalix and its scientists to become the first to arrive at this historic milestone are perhaps unique, it is anticipated that more biologics will follow suit in winning regulatory endorsement.

CRISPR/Cas9‐mediated knockout of six glycosyltransferase genes in Nicotiana benthamiana for the production of recombinant proteins lacking β‐1,2‐xylose and core α‐1,3‐fucose

“…Furthermore, the first plant-made pharmaceutical protein to be approved by the FDA for human parenteral administration (taliglucerase alfa, proprietary name Elelyso, produced by Protalix Biotherapeutics as a replacement therapy of Gaucher's disease) benefits from terminal mannose residues on the a-1,3-fucoseand b-1,2-xylose-containing Nglycan structures generated in plant cell vacuoles (Tekoah et al, 2013). Exposed mannose residues are required for the efficient uptake of the enzyme into macrophages but terminal sialic acid residues are added when the equivalent product is made in mammalian cells, and these residues must be trimmed off in vitro before formulation (Grabowski et al, 2014;Mor, 2015). These examples demonstrate the ambiguity of N-glycosylation in plantmade pharmaceutical proteins: in some cases, the plant N-glycans are beneficial and in other cases they are detrimental.…”

Will plant-made biopharmaceuticals play a role in the fight against COVID-19?

“…Other platforms are based on plant biomass propagation using bioreactors with suspensions of cell cultures (e.g. carrot or rice cells) [9,10].…”

“…Today, plant-made biopharmaceuticals have become a reality. At least one product has entered the market, namely taliglucerase alfa, a carrot-made enzyme obtained in bioreactors that is prescribed as replacement therapy for Gaucher´s disease [10]. Other products are close to be approved, for instance, clinical trials are ongoing to evaluate influenza vaccines produced by Medicago Inc [13].…”

Development of Systems for the Production of Plant-Derived Biopharmaceuticals

“…The approval by the USFDA of a recombinant vaccine against Newcastle disease virus produced in non-nicotinic transgenic tobacco cell cultures was a monumental event in the development of plant cell culture as a bioproduction platform [63]. Since then, the commercial success of Elelyso, the first recombinant pharmaceutical protein for human use produced in plant cells, has proven the value of this approach [64]. D. carota, the original species used by Protalix Biotherapeutics, is now the most famous plant species for production of pharmaceuticals, with ten vaccines, against measles, hepatitis B virus (HBV), human immunodeficiency virus, Y. pestis, Chlamydia trachomatis, M. tuberculosis, enterotoxigenic E. coli, Corynebacterium diphtheria/Clostridium tetani/Bordetella pertussis, and Helicobacter pylori, awaiting completion of development [65].…”