The Applications - - BioPharm International


The Applications

BioPharm International

Insect Cells

Advantages: Posttranslational modifications; properly folded protein; product is secreted; fairly high expression levels; expresses within about four weeks; baculoviruses are harmless to humans.

Disadvantages: Minimal regulatory track record and short history of use; slow growth, expensive media; baculovirus infection is an extra step in the process; contain immunogenic host cell proteins; some incorrect glycosylation; mammalian viruses can infect the cells in warm culture.

Products made by insect cells. BEVS insect cell expression is the least frequently used expression system for fermentation or cell culture in the biopharmaceutical industry. It is a relatively new technology that some companies are beginning to put into use. Those include Pfizer, Wyeth-Ayerst, Bayer, and Human Genome Sciences, which is working to remove certain genes from the 100 or so that make up the baculovirus genome in hopes of easing purification of insect-cell sourced products.

Novavax is using insect cell culture to produce virus-like particles (the protein shells of viruses without the genetic material inside) for use as vaccines, therapeutics, and in diagnostics, viral structure crystallography, and viral drug-delivery systems.

Mammalian Cells

Advantages: Usually fold proteins correctly; usually make correct posttranslational modifications; can secrete protein; good regulatory track record; only choice (except for transgenics) for the largest, most complicated proteins.

Disadvantages: Expensive media; slow growth; may contain allergens and contaminants from bovine sources; require extensive characterization (many adventitious agents are harmful to humans and mammalian cells alike); complicated purification; expensive, $500–5,000/gram of final product.

Products made by mammalian cell culture. Mammalian cell lines and hybridomas usually can be counted on to fold human proteins properly and to perform the correct posttranslational modifications that make proteins work. As an expression system used by the biopharmaceutical industry, mammalian cell culture is second only to bacterial cell culture in frequency of use. The first drug to be produced commercially by mammalian cell culture was tissue plasminogen activator (tPA), used to dissolve blood clots. Another recombinant protein produced by mammalian cells is a glycoprotein called factor VIII, which induces blood clotting. Hemophiliacs used to be treated with factor VIII purified from human blood, which led to the infection of thousands of people with HIV. Now the protein comes from a much safer source: genetically engineered CHO cells.

The molecular weight of tPA is about 70,000 daltons, and factor VIII is much larger, almost a million! So are some of the monoclonal antibodies (like Genentech's Herceptin and Ortho Biotech's OKT-3) being produced by hybridoma cells in culture. These are all complex proteins that can be produced only by the cells of higher animals. Genentech's CHO facility in Vacaville, CA, can produce over 1,000 kg of MAb per year in fermentors totaling about 150,000 liters of capacity. That's considered one of the most efficient mammalian cell culture facilities in the world.

Transgenic Animals

Advantages: Capable of complex protein processing and of very large proteins; very high expression levels; correctly fold proteins; easy scaleup; low-cost production ($20–50/gram of final product).

Disadvantages: Little regulatory experience; unknown potential for viral contamination; variable expression levels; long time scales; unanswered purification questions; continuous production complicates definition of batches and lots; questions regarding observance of cGMPs on the farm; unresolved public image problems.

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