Agricultural Policy Analysis Center - University of Tennessee - 310 Morgan Hall - Knoxville, TN 37996-4519

www.agpolicy.org - phone: (865) 974-7407 - fax: (865) 974-7298

Biotech Biotech Tobacco:Tobacco:

Assessing Assessing Commercialization Commercialization

PotentialPotential

42nd Tobacco Workers Conference

Charleston, South CarolinaJanuary 18, 2006

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Kelly Tiller & Marie WalshThe University of Tennessee

This project was supported by Initiative for Future Agriculture and Food Systems Grant no. 2001-52100-11250 from the USDA Cooperative State Research, Education, and Extension Service.

Biotech Tobacco: Advantages

• Tobacco is not in the food/feed chain

• Tobacco is easily manipulated using biotechnology tools– Fully mapped genome

• Tobacco produces a lot of biomass, quickly

• Tobacco grows well in a variety of locations and conditions

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Genetic Modification

• Expression of novel compounds in tobacco– The vast majority of the research identified to

date involves expression of novel compounds

• Hyper-expression of existing compounds in tobacco– Secondary metabolites, corrosion inhibitors

• Modification of existing tobacco compounds to have new characteristics

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Biotech Tobacco Applications

• Biopharmaceuticals– The vast majority of activities

– The fastest growing segment of pharmaceuticals

• Bioterrorist vaccines and countermeasures

• Miscellaneous other compounds– Food safety

– Biomaterials

– Industrial enzyme production AAPP CCAA

Biopharmaceuticals

• Biopharmaceuticals (biologicals) include:– Protein and enzyme therapeutic compounds– Monoclonal antibodies– Subunit vaccines

• Revenues $40b in 2003, $65b by 2008

• 600 biologicals currently under development and/or in clinical trials

• Potential for follow-on biologicals (biogenerics)

• Most either derived from animal tissue or produced in mammalian cell culture systems– Usually Chinese Hamster Ovary (CHO) system

PMP: Potential Positives

• Upstream costs of plant based production systems may be 70-80% lower than mammalian cell culture – Lower capital costs and operating costs

• Nearing capacity for mammalian cell culture systems?? Expensive to expand

• High initial estimates of plant based system productivity

• Easy scale-up of production to kg quantities

• Potential to address illnesses of little interest to large pharmaceutical companies

• PMPs may be safer than mammalian systems because they don’t contain mammalian viruses

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Mammalian Cell Culture Capacity

• Conventional wisdom that production capacity is strained

• Growth in demand for giant bioreactors due to growth in monoclonal antibody drugs– As opposed to recombinant proteins

• New facility construction costly and lengthy

• May not be as bleak as thought– Expansion occurring– Mammalian cell line productivity increasing– Alternative production platforms still

commercially unproven

PMP: Advantages?

• Productivity of plant systems

• Cost of producing biopharmaceuticals in plant systems– Upstream vs. downstream costs

• Time to market of PMPs– Time needed to develop and scale-up

– Time needed for regulatory approval

• Embrace of Big Pharma

Status of Biotech Tobacco Pharmaceutical Production

• Erythropoietein

• Human Growth Factor

• β-Interferon

• Malaria epitopes

• Streptococcus Surface Antigen IgA (Dental Caries)

• Carcinoembryonic Antigen

• Colon Cancer Antigens

• Interleukin 10 (Chrohn’s Disease; Inflammatory Bowel Syndrome)

• Glucocerebrosidase (Gaucher’s Disease)

• Interleukin 4

• Urokinase (Breaks Blood Clots)

• Human Serum Albumin

• Rabies Antigens

• Hepatitis B Surface Antigen

• Rotavirus VP6

• Labile Eneterotoxin (Botulism)

• Zonna pellucida ZB3 Protein (Contraceptive)

• Gastric Lipase (Cystic Fibrosis)

• Creatine Kinase

• Protein C (Anticoagulant)

• Neutropenia (Granulocyte Macrophage Colony Stimulating Factor)

• Epidermal Growth Factor

• α and β Hemoglobin

• Angiotensin Converting Enzyme (Hypertension)

• Insulin Like Growth Factor (Diabetes)

• Tissue Necrosis Factor (Rheumatoid Arthritis)

• HIV-1 Peptide

• Lactoferrin

• Substance P (Neuropeptide)

• Animal Pharmaceuticals (Vaccines)

• Feline Parvovirus (Panleukopenia)

• Canine Parvovirus

• Bovine Foot and Mouth

• Measles

• Aprotinin (Protease Inhibitor)

• α-Galactosidase (Fabry’s Disease)

• Interferon α 2a and 2b

• Personalized Non-Hodgkin’s Lymphoma Vaccines

• Papilloma Virus Vaccines

• Lysosomal Acid Lipase (Woman’s Disease; Atherosclerotic Plaques)

• Personalized Vaccines for Follicular Lymphoma

• α Trichosanthin (HIV)

• Diagnostics for Ovarian Cancer

• Diagnostics for Ecclampsia

• Biomarkers for Alzheimers Disease

Status of Biotech Tobacco Pharmaceutical Production

• Expression does not equal commercialization

• Clinical trials precede commercialization– Require several years to complete (7.8 years)

• Average cost of bringing a new drug to market is $897 million

• Costs for manufacturing the products only about 10-20% of total cost– Downstream costs similar for plant and animal

systems

Tobacco PMP Clinical Trials

• CaroRxTM – topical preventative intervention to prevent tooth decay– Planet Biotechnology– Phase II/III

• Personalized non-Hodgkin’s Lymphoma cancer vaccines– Large Scale Biology Corporation– Phase I/II

• RhinoRxTM – treatment of colds– Planet Biotechnology– Phase I

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Commercially Available PMPs

• Prodigene, produced in corn– Avidin – Glycoprotein used as a diagnostic– B-Glucuronidase – hydrolase used as visual

marker in transgenic plants– Trypsin (TrypZean) – Protease enzyme used in

processing pharmaceuticals– Aprotinin (Aprolizean) – Protease inhibitor used

in cell culture

• Large Scale Biology Corporation, produced in tobacco– Aprotinin – Protease inhibitor used in cell

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Tobacco Demand Potential

• Wide range of market potential

• CaroRx: 55 acres to provide one treatment per year for every child in the U.S. and U.K.

• Human blood serum albumin: 16,000 acres to displace world production

• Most human therapeutic proteins have small markets, high value – < 10 kg/yr, > $10,000/gram AAPP CCAA

Field Production Challenges

• Farms producing biopharmaceuticals are “manufacturing facilities” and have same FDA requirements

• FDA says, “important to dispel notions that pharma crops are a value-added opportunity for a significant number of farmers.”

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Bioterrorist Vaccines & Countermeasures

• FY2004 Biodefense Research Budget: $41.3 billion

• NIH-NIAID bildefense funding increased from $0 in 2000 to $1.7 billion proposed in 2006

• Tobacco transformed to produce potential bioterrorism vaccines or countermeasures including:– Heat labile enterotoxin (botulism), ricin

(neurotoxin), anthrax, small pox, the plague

• Fraunhofer USA, University of Maryland, Thomas Jefferson Medical Center particularly active

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Other Novel Compounds

• GM tobacco used produce antibodies to detect foodborne pathogens– Listeria, salmonella, E. coli, cryptosporidium

– Toxin Alert developing food wrapping containing antibodies to several food poisoning bacteria and some pesticides

– Working with University of Guelph and Mississippi State

• Several biomaterial expressed in GM tobacco– Elastin, collagen, spider silk, polyhydroxyalkonates,

polyaspartate, modified pectin

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Cautions

• Very expensive to develop and approve ANY of these products

• Estimates of cost adventages are very preliminary

• Very stringent FDA regulation and oversight, even at the farm level

• The plant platform is still commercially unproven

• Time to market is very long

• Big Pharma vs. Little Pharma

• So far, applications would not require significant field-grown quantity of tobacco AAPP CCAA

What’s Driving R&D?

• Not mammalian cell culture capacity

• Generally not upstream cost reductions

• Potential for scale-up– Products with very large market potential– Marginal cost savings add up

• Potential for individualized applications– Products with very high market value

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Major Players (today)

• U.S. firms:– Chlorogen / University of Central Florida– Large Scale Biology Corporation– Panorama Research– Planet Biotechnology– Phytomedica– SomaGenics

• Non-U.S. firms:– Center for Genetic Engineering aned

Biotechnology, ERA Plantech, Farmacule Bioindustries, Guardian Biotechnologies/Nexgen Biotechnologies, Icon Genetics AG, Meristem Therapeutics, Plantechno, Plantigen AAPP CCAA