“Understandably, introducing a new animal system to the biopharmaceutical arena garners some skepticism, and we are challenged to get private sector investors to appreciate the advantages and overcome the perceived risks.”
Once upon a time, chickens were known mainly for their contribution to Sunday dinners or, to the younger set, as the main ingredient in a nugget. But if one California biotech succeeds, chickens may soon be just as well known for their biopharmaceutical production capabilities.
Origen Therapeutics, founded in 1997 and based in Burlingame, is developing genetically modified chickens to not only discover new human therapeutics but produce them as well—and in a way that is cheaper and faster than more conventional drug fermentation processes. Or so hopes the company. Its chances of success improved in early October when it was awarded a $2-million, three-year grant by the U.S. National Institute of Standards and Technology (NIST).
Analysts say Origen’s work could have significant commercial as well as scientific implications. “This work addresses a major biomedical issue—how to produce antibody-based medicines in an easy, cost-effective way,” says Matthew E. Portnoy, program director of the division of genetics and developmental biology at the National Institute of General Medical Sciences (National Institutes of Health). “Beyond that, it will help researchers understand stem cell biology and development—something that holds great value for all sorts of basic studies.”
While therapies today are based on monoclonal antibodies, or antibodies produced by one type of immune cell, Origen is focusing on polyclonal antibodies, which are derived from different B cells, or immune cells. The company believes polyclonal antibodies will be more useful because they can recognize more than one epitope while monoclonal antibodies can recognize only one. An epitope is the smallest part of the antigen—an invader such as a virus or bacteria which triggers the body’s immune system—that is recognized by an antibody.
Origen is not yet revealing its therapeutic focus, but polyclonals are likely to have potential in allergic diseases, autoimmune disease, infection, and cancers. The company expects to have a lead polyclonal antibody product in early clinical trials around 2012, which is likely to be the first genetically engineered polyclonal antibody created from a fully human DNA sequence to enter the clinic.
Financing is one of the company’s greatest challenges. “It will take several years (in part due to the breeding cycle of the birds) before we can take a product into the clinic,” says Robert M. Kay, Origen’s President and CEO. “While the costs of doing this with transgenic chickens is somewhat less than conventional approaches to development of immunotherapeutics, it is still substantial. Understandably, introducing a new animal system to the biopharmaceutical arena garners some skepticism, and we are challenged to get private sector investors to appreciate the advantages and overcome the perceived risks.”
Producing a transgenic chicken was no easy task. To ensure that the genetic modifications are passed on to offspring, they must be incorporated in the germline. A chicken’s embryonic stem cells do not contribute to the germ line, as they do with animals such as mice, and their primordial germ cells, which can differentiate into sperm and egg cells, were known to be notoriously difficult to grow in culture.
However, researchers at Origen developed new techniques and were able to grow the cells in the laboratory. The next step, funded by the NIST grant, will be to genetically engineer the primordial germ cells to create birds in which the chicken antibody genes will be replaced with human counterparts. These chickens, when exposed to antigens, will produce human polyclonal antibodies, in contrast to non-transgenic chickens, which would produce avian antibodies that would trigger an immune response in humans.
So why go to all the effort of developing transgenic chickens, rather than mammals? Because chickens have their own built-in production technology. As part of the normal process, chickens pass antibodies on to their chicks in the yolk to protect the young bird. Once the chicken’s immune system has been modified, the immunized chicken will produce eggs with yolks rich in human monoclonal antibodies, and will pass this ability on to its offspring.
Compared with the high-cost fermentation process required to produce monoclonal antibodies, the expense of housing the chickens and extracting the antibodies should be relatively low. Once the polyclonal antibody-laden eggs are produced by the chickens, the method of extraction is relatively quick and simple. The food industry has already developed high-speed machinery to separate the whites from the yolks. The yolks are then mixed with cold water and allowed to settle, and the polyclonal antibodies remain in the aqueous supernatant in a high concentration. The antibodies can be extracted using standard protein purification processes.
These high-tech chickens have come a long way since the time of the ancient Egyptians, who used chicken soup as a cure for the common cold, and Avicenna, a 10th century Persian physician, who wrote about its curative powers. In some ways, by using chickens as little mobile antibody factories, Origen Therapeutics is just carrying on the tradition.