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CHAPTER 1 - BIOTECHNOLOGY INTRODUCTION AND DEFINITIONS
Summary
This chapter defines what is meant by ‘biotechnology’ and gives a brief historical overview of the first animal health drug, bovine somatotrophin, produced using biotechnology. A description of the four protein therapeutics (growth hormones for cattle, pigs and horses, and a feline interferon) for veterinary applications produced by recombinant technology is given, followed by an overview of how recombinant technology has been used to produce new vaccines for animal health.
1.1 Biotechnology introduction
Biotechnology products have historically been defined as therapeutic proteins that are produced by inserting a foreign gene into bacteria or cells, and culturing them in such a way that they produce large quantities of the biologically active protein coded for by the inserted gene. These proteins are then harvested and purified to yield the active drug.
In the last ten years, the concept of biotechnology has been greatly expanded, and now includes a wide array of technologies such as therapies based on DNA or anti-sense RNA administration, DNA vaccines, recombinant vaccines, cloning of animals and plants to produce therapeutic proteins, creation of transgenic animals that have exogenous genes inserted or particular genes deleted, and other technologies based on our rapidly expanding understanding of genomics.
Biotechnology has resulted in a number of important breakthroughs in human health, including monoclonal antibodies to treat cancer, and therapeutic proteins for a variety of diseases, including anaemia, diabetes and arthritis. In 2002, according to a report produced by Ernst and Young (Beyond Borders: The Global Biotechnology Report, 2003), there were more than 300 biotechnology products listed as being in late-state human clinical testing, and this was a 50% increase compared to 2001. Research and development spending rose 34% to $22 billion. From 2000–2003, there were a total of 64 biotechnology products approved for sale in North American and Europe, including hormones, blood factors, thrombolytics, vaccines, interferons, monoclonal antibodies and therapeutic enzymes (Walsh, 2003).
1.2 History of development of animal health products
What about applications for animal health? There are nowhere near as many products either approved or in development for veterinary compared to human health use. The biotechnology industry in general is not focused on opportunities in animal health, with a few notable exceptions. Company founders and investors are, for the most part, interested in developing human health products, and feel compelled to focus their company on this market. Cash is usually limited, and exploration of animal health applications is often considered a dilution of the primary effort of the company’s mission. Researchers may feel that there is some regulatory risk to testing their human health drug or technology in species other than rodents and dogs, the traditional toxicology species. If an unexpected result is seen when their lead molecule is tested in, for example, a pig, will this affect the regulatory approval or perceived risk of the molecule for humans?
Some biotechnology CEOs worry that their company will not be taken as seriously by the human pharmaceutical industry if they develop a veterinary application or make a deal with an animal health company. Many small companies are unaware of the animal health market, and surprised to learn that animals receive sophisticated health care. Few venture capital companies invest in agriculture and animal health, and are therefore not knowledgeable regarding the opportunities, so little private capital is available for research and development.
In spite of these hurdles, a number of biotechnology companies have successfully developed their technologies for animal health applications. Some companies are exclusively focused on agriculture and animal health, while others are working in both human and animal health. These companies are aware of the risks and perceptions and have developed strategies to deal with them, and are reaping the rewards of expanding their licensing revenues.
1.3 Biotechnology products on the market
Below is a brief overview of the products that are used in veterinary medicine that have been produced using biotechnology. This brief overview makes it clear that there are significantly fewer products for animals than for humans. Whole classes of biotech drugs available for humans are not seen in animal health, for example, monoclonal antibodies. In general, this is related to the size of the market, the production cost and profit margin, and the fact that research for animal applications has lagged behind that for human health.
1.3.1 Recombinant proteins
The first biotechnology product to reach the human market was insulin produced by recombinant DNA technology in 1982, which replaced the insulin previously obtained from cow and pig slaughterhouse material. The extremely successful protein therapeutic, erythropoietin (Epogen) originally produced by Amgen, is another example of the early application of recombinant technology. This protein is a recombinant form of the natural human hormone produced by the kidneys, which causes stimulation of red blood cell production and is used to treat anaemia in chronic kidney disease and has become a multi-billion dollar drug. In the animal health market, the first product produced using biotechnology methods was bovine somatotrophin (bST), a recombinant form of bovine growth hormone that is used to increase milk production and is the largest selling pharmaceutical product for dairy cattle (Posilac, Monsanto). The commercial form of bST presently used in the United States is a prolonged release formulation (500mg methionyl-bST) that is administered to lactating dairy cattle every two weeks.
Even as biotechnology has provided a number of new therapies to human medicine, animal health products have been few, and far between. Some of this can be explained by the battle necessary to bring bST through the regulatory approval process, with approval finally achieved November 1993 and marketing starting early 1994 after many years of struggle. In fact, the companies originally developing bST, including Elanco, Monsanto, UpJohn and American Cyanamid, banded together with the Animal Health Institute to work on public relations, governmental relations, both state and national, regulatory studies and negotiations needed to bring the product to market, knowing that no one company alone had the resources to complete the task. Eventually, only Monsanto was able to complete the project, and today markets the product. The extent and cost of this process have had a chilling effect on attempts to bring other recombinant products to the market.
Public acceptance has been slow and difficult, with some consumers refusing the product entirely and buying bST-free milk. In 2003, Monsanto brought suit against various companies marketing their milk labelled as hormone-free; stating that this was misleading labelling, as all milk contains natural hormones. Monsanto asserts that this type of labelling implies that hormone treated milk is somehow unsafe, and this contradicts the FDA review of the product, which has found milk from treated animals to have no human food safety issues. Consumers, however, feel that they have a right to know if bST is used in the production of the milk that they purchase, so they may choose to avoid it if they like.
After many years of controversy with worries over everything from human health effects of drinking milk from bST treated cows, to the effects on the cow (claims of increased incidence of mastitis and metabolic stress) to worries about the impact on the family farm, the product is now widely used.
According to the Council for Agricultural Science and Technology, bST is used commercially in over 20 countries (Etherton et al, 2003). It is estimated that bST has achieved over $200 million annual sales, and represents the animal health drug with the highest dollar sales (Fountain & Thurman, 2002). In 2003, Monsanto announced its intention to build a new $180 million state of the art manufacturing plant for bST. Why has bST achieved such market success? The answer is simple – the product increases milk production in a safe and cost effective way, with a net profit for the producer. According to the Monsanto website (www.monsantodairy.com/updates/bovine.html) ‘of the nearly 9 million dairy cows in the United States, approximately 35% are in herds supplemented with Posilac and approximately 13,000 dairy producers are currently taking advantage of the benefits offered by Posilac’ with ‘users report productivity increases of 8 to 12 pounds per day per cow’.
One of the major concerns regarding the use of this first ever biotechnology product for use in animals were related to the safety of the animals treated – would the growth hormone somehow harm the cows? In an unusual move, the Veterinary Medicine Advisory Committee of the Food and Drug Administration (FDA) in the US in 1996 asked Monsanto to put in place the most extensive post-approval monitoring program ever conducted for an animal pharmaceutical. Data was collected on the use of Posilac to help determine if the product had an impact on the safety of the treated cattle or quality of milk. This study was conducted over two years in 28 commercial dairy farms in four regions across the US. Over a thousand cows were monitored, in both large and small dairies. There was no indication from the study that use of bST caused animal welfare or human food safety concerns. (The full report is available at www.monsantodairy.com/about/animal_health/2001_pamp_report.html.)
The Joint Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives (JECFA) of the United Nations released a report in 1998, concluding that milk from cows supplemented with Posilac is safe. Agreeing with the results of the post-approval studies in the US, they stated ‘there are no food safety or health concerns related to bST residues in products such as meat and milk from treated animals’.
In spite of these encouraging findings, Posilac is barred for sale in both the EU and in Canada. Canadian regulators agree that there is no significant risk for humans in drinking milk from Posilac treated cows, but they claim that cattle treated with Posilac have higher risks of mastitis, infertility and lameness.
A Korean company, LG Life Sciences Animal Health (Seoul, Korea) has a version of bST called Boostin, which they claim has the top market share for bST in Mexico, Brazil, Venezuela, Columbia, South Africa, Pakistan and Korea. They are conducting clinical trials in the US and ‘expect to be approved by the FDA/CVM by 2006’, according to a company brochure (2003). They also have developed a unique product – Eltosil, which is recombinant bST for oral administration to fish. Presumably the administration of growth hormone stimulates the rate of growth for fish under aquaculture conditions.
Another biotechnology product that has been developed for animals is porcine recombinant growth hormone (pST) for pigs, although as yet it is not available in a number of important markets, including the US. Alpharma (Fort Lee, New Jersey) has acquired the exclusive worldwide licence for Reporcin (pST) and simultaneously purchased the product’s manufacturer and marketer, Southern Cross Biotech (Toorak, Victoria, Australia). Porcine somatotrophin was originally developed in collaboration with researchers at the Melbourne University Veterinary Science Centre for Animal Biotechnology.
Porcine recombinant growth hormone controls growth by directing nutrients toward production of lean muscle rather than fat, and increasing feed efficiency. Reporcin is administered by daily injection over a 21–45 day period using a proprietary low penetration gas-powered gun. Reporcin is licensed in Australia, New Zealand, Malaysia the Philippines, Vietnam, South Africa, Mexico and Brazil. According to a news article from five years ago, licences were to be pursued in the US and 13 other countries (Animal Pharm 430, 8 October 1999, p.21) but as of 2003, no FDA approval has been announced. A recent report (Etherton, 2003) stated, ‘porcine somatotrophin is undergoing testing required for FDA approval.’
Alpharma in the fall of 2002 stated in a press release that, ‘the company had commissioned an independent study of the US swine market to evaluate the future potential for the animal health product, Reporcin. This study, which was completed in the third quarter, concluded that market acceptance would be lower than expected. As a result, the company’s future revenue expectations for Reporcin have been reduced. The company wrote down property, plant and equipment and intangible assets relating to Reporcin to recognise the reduction in value. The company sells Reporcin in five countries and intends to continue to market this product in all countries where registrations are held.’
The Joint FAO/WHO Expert Committee on Food Additives 52nd meeting, in February of 1999 concluded that an acceptable daily intake (ADI) nor a maximum residue limit (MRL) for pST need not be specified, because ‘available data on the toxicity and intake of the veterinary drug indicate a large margin of safety for consumption of residues in food when the drug is used according to good practice.’ Additional information on Reporcin is available at the Alpharma website (www.reporcin.com/index.htm) For a comprehensive review of the biology and use of bST and pST, see Etherton & Baumann, 1998.
Equine somatotrophin (eST) was developed by BresaGen (Thebarton, SA, Australia) for use in horses and launched in Australia in 1998, followed by registration in New Zealand in 2000. The label claim is as ‘an aid in the improvement of nitrogen balance in horses aged over 15 years when fed at a plane of nutrition of at least 120% of daily requirements’, but the company describes on its website (www.bresagen.com) a number of possible off-label indications as diverse as wound healing, improved reproduction, and improvement in conditioning. EquiGen Injection is a freeze-dried form of methionyl equine somatotrophin produced by recombinant DNA technology. It is essentially identical to the naturally occurring eST produced in the pituitary gland of horses, with the addition of a methionine residue to facilitate protein expression. Bresagen is pursuing registration in additional markets. They also have developed canine somatotrophin, but it is not approved by regulatory authorities, and the company says that project is currently ‘on hold’ (Dr Edwina Lamkin, Veterinary Product Manager, personal communication, November 2003).
In human medicine, various human interferons have been proven effective for the treatment of hepatitis B and C, hairy cell leukaemia and multiple sclerosis, among others. Until recently, interferon was not available for use in animals. In November of 2001, the European Commission issued a marketing authorisation to Virbac valid throughout the EU for interferon omega, called Virbagen Omega. The product is indicated for immunostimulation and treatment of viral infections such as parvovirus in dogs. It is approved for use in Australia but not yet in the US. It is a feline recombinant interferon – type omega. In a study conducted by scientists at Virbac, dogs experimentally infected with parvovirus were successfully treated with recombinant feline interferon – type omega (Martin et al, 2002) and this study was followed by a multi-site field trial using 94 dogs naturally infected with parvo, where the treatment also was successful (de Mari et al, 2003).
According to a 2002 press release from Virbac, ‘Virbagen Omega is the first veterinary interferon to be registered in Australia’ and this treatment is ‘now available world-wide’. The Virbac protein is produced from a baculovirus system grown in silkworms. The product is labelled for use in dogs infected with parvovirus, but apparently is also effective in cats. Virbagen Omega treatment results in ‘a significant reduction in the duration of the disease in cats with infected with calicivirus infection, with 86 percent of severe cases and 97 percent of mild cases responding favourably to treatment’ according to the company. Virbagen Omega is available through veterinarians only and is relatively expensive (www.virbagenomega.com).
1.3.2 Recombinant vaccines
Vaccines for animals made using biotechnology are widely available, and the technology is relatively mature and accepted, with the exception of DNA vaccines, which are still in the research stage. This is in sharp contrast to recombinant proteins for use in animal health, where only four products are marketed and only one, bST, can be truly considered a commercial success.
Until recently, vaccines were limited to live or killed antigens from pathogens. Although very effective for many years, these vaccines are difficult to manufacture in a defined manner, and have the potential for various problems including reversion to virulence, contamination with unwanted pathogens, and allergic reactions to impure preparations.
More than a dozen veterinary vaccines are available that use recombinant and sub-unit antigens (Animal Pharm 473, 11 July 2001, p23). Microbial genomics has made innovations in vaccine antigen creation possible. Pathogen genes can be identified and deleted, while leaving the key antigens related to immunity intact. This allows the creation of live, but non-pathogenic vaccines. To create purified antigens, genes can be inserted into in vitro expression systems to create antigens that are highly immunogenic, but are only fractions of the pathogenic organism, assuring against revision to virulence or infectivity. Another advantage to this approach is that, if designed properly, tests may be developed that can distinguish infected from vaccinated animals, by looking for antibodies to pathogen antigens not contained in the vaccine. Animals can be both vaccinated, and tested for disease control purposes, where previously, any test could not distinguish between vaccinated and infected animals. These types of vaccines are called marker vaccines.
Antigen identification and production using recombinant methods has also been applied to vaccines against parasites. For example, the TickGard vaccine from Australia, developed by the Commonwealth Scientific and Industrial Research Organization (CSIRO) and Biotech Australia, and launched in 1994, was created using a well-characterised tick antigen produced in a recombinant system. The tick ingests the induced antibody from the host, and the antibody is absorbed via the tick’s digestive system, disrupting the normal physiology of the tick. The original antigen, Bm86, not only protects against the Boophilus microplus tick, from which it was first isolated, but shows some cross-protection to other tick species.
Researchers have been experimenting with direct in vivo administration of DNA coding for antigens instead of the antigen proteins themselves, and have been able to elicit immune responses. This work has been promising, but generally, DNA vaccines elicit a relatively weak response. New research is ongoing to develop methods to increase this response and no DNA vaccine is yet approved for marketing (see Chapter 5).
New approaches to adjuvants have been developed that influence the antibody or cell mediated immune response. Technologies include using a non-replicative, recombinant viral vector restricted to avian replication (canarypox), which increases the immune response to the primary antigen. Canarypox containing vaccines have been shown to be effective in protection against rabies virus challenge in cats and dogs, against canine distemper virus, feline leukaemia virus and equine influenza virus (Paoletti, 1996). One example of this approach is the development of Merial’s Eurifel FeLV, the first vaccine against feline leukaemia using the canarypox vector. This vaccine is being rolled out for sale across Europe. Canarypox is under development for use in human health by Aventis for new HIV vaccines, and further veterinary use of this type of approach is expected.
Recombinant, or genetically engineered vaccines for food-borne pathogens have been developed and are available commercially (Etherton, 2003). No DNA vaccines, however, are approved for market, and regulators are concerned with the effects of possible human ingestion of plasmid DNA.
More details are given in Chapter 5 on the use of biotechnology to develop improved vaccines for animal health.
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