|The waiting game
When selecting a transgenic manufacturing platform, one of the most important considerations for a biopharmaceutical company is SPEED, particularly if the product is already in clinical trials. Due to the high “cost of entry” inherent in both traditional biologic manufacturing and first generation transgenic technologies, many companies, not wanting to commit large sums of money to an unproven product, wait until they have some efficacy data before investing in manufacturing capacity for the product. Unfortunately, the lead time to acquire/build manufacturing capacity often delays the product market launch date.
TranXenoGen has addressed this critical issue by selecting what it considers to be the optimum production species: chickens. Chickens have the great advantage of short development cycles (21 days to hatch) and short maturation cycles (5 to 6 months). This means that from the receipt of the partner’s gene sequences, TranXenoGen anticipates generating first generation chimeric transgenic chickens in 6 to 9 months and full germline birds in 12 to 18 months. These timelines are highly competitive in meeting the needs of companies with products as advanced in development as Phase III clinical trials.
|COST OF ENTRY
The first “cost of entry” to a transgenic production system that a biopharmaceutical company is faced with is the establishment of a small number of “founder” transgenic animals, expressing the specific product of interest. Since these founder animals may ultimately be used to generate the animals that produce the therapeutic protein administered as a drug to human patients, the animals used to generate “transgenic founders” must meet significant health criteria. In milk-producing ruminants, such as cows, BSE (often known as mad cow disease) is of critical concern. In sheep and goats, “scrapie” (the ovine and caprine equivalents of BSE) are of equal concern. In addition, the technology most commonly used to generate transgenic mammals is pronuclear microinjecting. This approach involves injecting the transgene individually into hundreds of single cell embryos, which is both costly and inefficient.
TranXenoGen has the significant advantage of being able to source SPF (specific pathogen free) eggs and chickens, generated primarily for the “egg-derived” vaccine industry, from U.S. vendors. Consequently, TranXenoGen is assured of the health status of its founder birds. In addition to their availability, chickens are inherently faster and much less expensive to develop than large ruminant mammals. As a result, TranXenoGen believes that it will reduce the cost of entry of transgenic production.
Yield up to 500kg or more per year
COST OF GOODS
|Large Volume Logistics
While in theory any transgenic manufacturing system should be capable of producing large volumes of product, from several kilograms up to several tons, there are logistical issues with some transgenic technologies. For example, large ruminant animals breed very slowly (cows produce one offspring per year; sheep and goats, two to four) and this makes the generation of a large herd (anything from tens to thousands of animals) a very slow process. Transgenic plants require large areas for planting and containment. Small volumes of product can be produced from plants grown in greenhouses where these genetically modified organisms can be contained. However, when the volumes of product required begin to escalate up into the tens of kilograms, reaching perhaps 100 kilograms or more, these plants will most likely have to be grown out in the open on huge multiple acre sites.
More is definitely better
|Folding and Structure
The issue of correct processing of the therapeutic protein, often ignored in the initial decision-making process by companies selecting a transgenic manufacturing technology, is now becoming recognized as being of critical importance. This realization is the result of various companies experimenting with transgenic expression systems. Companies have typically focused on high-level expression when selecting a transgenic technology, but the vast majority of therapeutic proteins are not simple linear protein sequences. Most are folded into secondary and tertiary structures and over half have post-translational modifications, including glycosylation structures, disulfide bonds, gamma carboxylation and amidation. These modifications usually have to be correctly completed to confer the required activity and/or plasma circulating half-life of the protein. Endogenous plasma proteins in particular tend to need a full complement of sialic acid to complete their glycosylation structures; otherwise, the half-life of the protein in plasma is often greatly reduced.
|A controlled environment
Transgenic chickens have the advantage over other transgenic animals that they can be housed in a contained/barrier facility from the moment they hatch from their shell. Chickens have been reared and housed this way for the egg production industry for decades. TranXenoGen can add the element of controlled, filtered air flow to its chicken production facility to provide a barrier to adventitious agents which could contaminate the production flock. The result is a totally enclosed, contained and controlled environment.
The egg white is contained in the sterile environment of the eggshell, and the therapeutic protein is maintained in a sterile state until the shell is broken as it enters the purification process.
|Familiar regulatory territory
Chicken eggs have been used for many years in the production of certain vaccines. As a result, the manufacturing infrastructure has been well established (including clean facilities, SPF birds and fully automated equipment), and the regulatory authorities are experienced in examining products derived from eggs and approving the facilities used to produce such products. The endogenous proteins contained in eggs are well characterized and extensively studied and purification technologies have been established to remove them.
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