“Some of the therapeutic antibodies are required now in tens of thousands of grams per year,” says John Birch, chief scientific officer of the Lonza Group, based in Basel, Switzerland, which is planning three new 20,000-litre mammalian cell-culture reactors in the United States for monoclonal antibody production, in addition to its present capacity. Antibody harvests from cultured mammalian cells are around a gram per litre of culture.
But the cost of scaling-up production using mammalian cells can be prohibitive, particularly for a clinical trial of an antibody that may not turn out to be worth it. Looking to fill a gap in the market are alternatives such as the transgenic goats of GTC Biotherapeutics in Framingham, Massachusetts, and the transgenic rabbits produced under a GTC Biotherapeutics licence by BioProtein Technologies of Paris, France. “If I need it, I breed it — the walls of my bioreactor are expandable,” says Thomas Newberry, vice-president of GTC Biotherapeutics. He estimates that the cost of producing a founder goat is about US$10 million. Although pricey, this is a fraction of the estimated $200 million–500 million that is needed to build a large-scale mammalian cell-culture bioreactor. The company estimates that a single goat can produce up to a kilogram of pure antibody per year. Goat-produced antibodies are in clinical trials to determine whether they match the safety, efficacy and pharmacokinetics of more traditionally produced counterparts.
“There's a whole category of antibodies that have not been effectively explored for therapeutic or preventive use, and for facing down viruses in the mouth, genito-urinary and respiratory tract,” says Elliott Fineman, president and chief executive of Planet Biotechnology in Hayward, California. These are the secretory IgA antibodies, which cannot be produced from mammalian cell culture in significant amounts. Instead, his company is using transgenic tobacco plants to produce CaroRx, a monoclonal secretory IgA against the bacterium Streptococcus mutans, a leading cause of tooth decay. Originally created as 'Guys 13' by Thomas Lehner and Julian Ma at Guy's Hospital in London, CaroRx has shown its ability to block colonization by S. mutans in phase II clinical trials, and Planet Biotechnology is hoping to apply shortly for a licence to market the antibody in Europe for topical application by dentists and patients following antiseptic cleansing of teeth. If the company succeeds, it will be the first 'plantibody' to reach the market.
Fineman estimates that building, equipping and validating a facility to produce 100 kilograms of antibody from plants would cost between $30 million and $50 million. Keeping cost down is particularly important for antibodies intended for non-therapeutic use against diseases that are not life-threatening. “Nobody's going to take a £2 hike in the cost of toothpaste,” says Ma.
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Clayton, J. Going into production. Nature 426, 727 (2003). https://doi.org/10.1038/426727a