Drugs from Chimeric Chickens
Origen Therapeutics, which raises chickens to lay human antibodies, isn't the only firm scouring the barnyard.
January 16, 2006 Print Issue
Monoclonal antibodies are used in drugs like Avastin and Herceptin that treat colorectal, and breast—and make piles of money for manufacturer Genentech. That company’s market cap doubled in the past year, much of the rise coming on the back of news that the drugs were proving successful in battling still other cancers.
Odd then that, back in the 1980s, Britain’s National Research Development Corporation evaluated the technology as "difficult for us to identify any immediate practical application." British entrepreneurs still bite their lips recalling that premature judgment.
The business case for producing cheaper monoclonal antibodies turns out to be pretty solid, so it's no surprise that several companies are trying to do just that. Burlingame, California-based Origen Therapeutics is one of the companies leading the pack. It claims it can dramatically cut the cost of monoclonal antibody production by creating nothing less than chimeric chickens.
The idea: rear hens which deposit human antibodies in the whites of their eggs—by creating birds that aren't 100 percent bird, at least in terms of their genetics. Origen scientists have created circles of DNA, called vectors, which are capable of inserting genes encoding human antibodies into chicken embryonic stem cells. The stem cells are extracted from an embryo, genetically modified using the vectors, and then reinserted to divide many times over as the bird develops. The result is a grown hen with lots of cells containing some human DNA.
The inserted human genes are flanked by genetic code which controls the production of ovalbumin, a protein that makes up 54 percent of the egg white. Result: the same hormonal cues which induce a hen's normal ovarian cells to make ovalbumin also launch therapeutic antibody production in the cells with human DNA.
This is how Origen chickens deposit expensive medicines in the neat sterile packages we commonly break open to scramble, poach, and fry.
Betting the Farm
Antibodies are important and profitable because they are precision instruments. The body makes these Y-shaped instruments. The body makes these Y-shaped proteins in many variations to home in on, for instance, cancerous cells.
Scientists realized the potential of using antibodies like missile guidance systems for therapeutic molecules well before Cesar Milestein and Georges Kohler developed their Nobel-prize winning formula for producing them in bulk.
Being precision instruments, antibodies with payloads of medicine leave few side effects. Today they can be made to bind to any substance, and there is growing demand for anyone who can make them quickly and cheaply. So far, 17 antibody-based therapeutics have received approval from the U.S. Food and Drug Administration. Well over a hundred more are floating in the development pipelines of various biotech companies.
Milestein and Kohler’s first cell line to pump out large quantities of identical antibodies (hence the name, monoclonal) came from the fusion of a healthy antibody-producing cell with a cancerous one, called a myeloma. Probably the most widely established method today involves using Chinese hamster ovary (CHO) cells, which can also be tweaked to proliferate indefinitely. These cells make antibodies in their millions in stainless steel fermentation vats up to 10,000 liters in volume.
A CHO cell production facility costs several hundred million dollars to build. Genentech, for example, paid $408 million in cash for Biogen Idec’s facility in June. It’s this sort of spending that leads to manufacturing costs of about $100-$150 per gram of antibodies, and the same amount again to put antibodies through the follow-on purification process.
By comparison, Origen CEO Robert M. Kay claims his company can create monoclonal antibodies at prices that should get investors taking chimeric chickens seriously. The chicken method costs just a couple of dollars per gram of antibodies—with the same purification costs—at CHO cell production speeds.
Cheaper and More Powerful
What’s more, Origen recently reported in the journal Nature Biotechnology that its antibodies killed prostate tumor cells at 10 to 100 the rate achieved by the same antibody made from conventional CHO techniques. The egg-derived antibodies also performed better in some toxicity assays, a feat that could augur well for Genentech’s Rituxan and Herceptin antibody drugs, Nature Biotechnology says.
For sure, other investigators are hunting for profits from other cheaper and unconventional production techniques. Some are working on plants. Others have inserted human genes into just about every mammal in a farmyard, including goats, cows, sheep, pigs, and rabbits—all in aid of collecting human antibodies in animal milk.
One example is Framingham, Massachusetts-based GTC Biotherapeutics, a company with a penchant for goats. “They’re an interesting mixture between the speed of a mouse and the volume of a cow,” says Thomas E. Newberry, GTC’s VP of corporate communications.
In other words, goats have agreeably short reproduction cycles and produce masses of milk. Right now, GTC makes a recombinant form of antithrombin, called ATryn, which is actually not an antibody but an anticoagulant and anti-inflammatory protein normally manufactured by separating the protein from human plasma.
In theory at least, goats could help manufacturers meet potential projected U.S. annual demand for 600kg of the protein a lot easier than by exercising other options. Mr. Newberry says that if antithrombin could be extracted from all donated human blood in the U.S., the exercise would yield only 100kg—an amount just 150 goats could generate. GTC has already filed for the product’s approval with European regulators, and says it could get a decision as early as April.
Goats vs. Chickens
As with chicken eggs, the cost of milking for drugs is comparably lower than current production methods, leaving GTC with handsome margins since it plans to market the protein “near the upper end of the price scale.”
Although goat milk extract may be further along the approval path than chicken egg white components, there are a number of reasons chickens make particularly good drug factories. For one, the bioscience industry is familiar and comfortable with using eggs to make vaccines. Chicken husbandry is also highly developed and widely streamlined. A rooster, for instance, can father 15,000 eggs in six months. And if Origen knows what a rooster can do, it’s because it has devoted considerable biotech know-how to making the egg and chicken industries more efficient.
So far Origen has raised a total of $15 million over three rounds of financing, up to $6 million of that from 16 grants from the National Institutes of Health. It is not alone in its attempt to get chickens to lay golden drugs. Athens, Georgia-based Avigenics in is also reportedly working on the problem. The company did not respond to repeated calls for details. Origen’s Mr. Kay contends that, while other companies may be working on chicken transgenics, they are focusing on methods of introducing DNA into chicken cells that can accommodate only strands of DNA too small potentially to code for the production of monoclonal antibodies, he says.
Cancer patients are still many regulatory trials away off from being treated with products derived from bird eggs. For one thing, Origen VP of research Robert Etches says the company plans to have chickens lay polyclonal antibodies and to create fully transgenic hens so that all their cells contain human antibody genes—increasing the concentration of human antibodies in egg white. Among other things, it means human genes could be passed on to the progeny of Origen chickens.
Talk about plucky.
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