Transcript 05.Selected Products.Farmaceuticals.web

Selected Products of
Bioprocessing
digging a bit deeper
Farmaceuticals
• genetic modification of
animals
• production of therapeutic
proteins in milk, eggs or
blood
Demand?
• >100 protein based drugs
are in advanced phases of
clinical trials
• production facilities cost
$200m-400m
• goats and cows most
promising alternative
Goat’a be kid’in
• animals as bioreactors
• milk loaded with proteins
• GTC Biotherapeutics, Massachusetts
engineered (transgenic) goats, producing
14 varieties of therapeutic proteins
• 18 months/goat
• $100m/herd
Goat versus Cow
• 18 months to make
transgenic goat
• 3 years/cow
• 2 L/day milk/goat
• 20 L/day/cow
Cost?
• mammalian cell culture: $150/gram
• transgenic animals: $2/gram
• don’t believe everything you read
GTC goals
• recombinant human anti-thrombin III
(rhATIII), anti-coagulation protein found in
blood
• $250m worldwide market
• presently $10m/year sold in US
• treat hereditary difficiency
GTC goals
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recombinant human serus albumin (rHSA)
demand 400 tons/year
presently isolated from plasma
supply and safety concerns
bioreactors unrealistic given demand
Third product?
• malaria vaccine MSP-1 from goat milk
• 8 goats produce enough vaccine to
inoculate 20 million people
• Pharming Group, Leiden,
Netherlands
• C1 inhibitor (C1 INH) for
hereditary angioendema (lack
inhibitor protein)
• C1 is “proenzyme” in serum
complement pathway, which is
controlled by inhibitor
• being produced from wabbits
Other Pharming products
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fibrinogen and collagen produced in cows
used in wound healing and cosmetics
lactoferrin, an anti-infective
20 cows can produce world fibrinogen
supply (150 kg)
• cow producing 10,000L milk/year
generates 100 kg protein (10 g/L)
• fermentation process, 200-300 kg/year
Transgenics versus bioprocess
• capital cost advantage
• $40 – 200m/production
facility
• capital costs in farming are
considerably less
• relatively homogeneous
medium
BioProtein Technologies, Paris
• proteins from rabbit milk
• 4-5 months to sexual maturity
• gestation 1 month
• rather prolific breeders
Rabbit versus CHO cells
• line of transgenic rabbits in 6
months
• product within year
• similar time frame to CHO
cells
• 250 mL milk/day compared to
20L/cow
• 1-10 g/L recombinant protein
Potential products
• antibodies, plasma
proteins, hormones
• some success with
human growth
hormone and cellularsuperoxide dismutase
transgenic embryo
microinject transgene
into fertilized oocyte
recipient female
breeding
selection of
transgenic wabbit
milk extraction and purification
• Gala Design, Middleton, WI
• focus on gene insertion using retrovirus
vectors
• transfection rate 50-100% in cows, pigs,
monkeys
• genes inserted into eggs before
fertilization (transgametic), followed by
in vitro culture... many transgenic
embryos result, are fertilized and the
rest is up to nature
Consider the chicken!
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eggs are sealed and sterile
protein loaded
chickens grow fast and easier than cows
occupies 1 ft2
Transgenic chickens
• chimeric chickens produce 1 human
antibody and 1 mouse antibody in egg
albumen
• low yields
• working on insulin and human serum
albumen
• express proteins in eggs at 1 mg/egg
• 20 mg/kg chicken (similar productivity to cow)
• laying at 5 months
• produces 600-700 eggs/chicken
• 100m chickens/rooster in 2 years
• sterile packaging
• storage without need for stabilization
• 88% protein in egg white
• 11 proteins make up 95% of egg white
• crack and separate 200,000 eggs/h/machine
• widely used in vaccine manufacture, so
acceptable as transgenic medium
• AviGenics is expressing interferons, antibodies
and cytokines
Regulatory approval
• challenge
• fears of bovine spongiform encephalitis
(mad cow) as example
• also fears of prions
• some argue that milk producing animals
do not harbour human viral pathogens
Other cost considerations
• raising animals costs 30-80% less than
cell culture
• $300,000/transgenic cow
• $30,000/transgenic pig
• cloning costs $100-200K/animal
• related facilities $5-7m
• but lifetime or production, plus offspring