Origen Therapeutics today announced the first published scientific report of fully functional, human sequence monoclonal antibodies (mAbs) produced in chickens. The antibodies were expressed solely in the chicken oviduct and deposited into egg white in concentrations of 1-3 milligrams per egg. Moreover, antibodies produced in this manner demonstrated 10-100 fold greater cell-killing ability (ADCC) compared to therapeutic antibodies produced by conventional cell culture methods.
The new report was published in the September issue of Nature Biotechnology by researchers from Origen Therapeutics and their collaborators at Medarex, Texas A&M University and the University of California, Los Angeles. A research brief commenting on the potential impact of this development for the production of human therapeutic proteins was also published in the September issue of Nature Medicine.
"This work demonstrates the potential for producing therapeutic proteins with enhanced properties in the eggs of chickens as an alternative to established mammalian cell culture systems," said Robert J. Etches, Ph.D., D. Sc., Origen Therapeutics vice president, research. "Antibodies produced by this method had very similar physical and biological characteristics to those produced in CHO cells, including nearly identical binding curves, similar affinities, and an equal ability to be internalized by antigen on prostate cancer cells. At the same time, chicken-produced antibodies lacked the sugar residue, fucose, which greatly increases their cell-killing activity compared to CHO-produced antibodies."
To create the antibody-producing chickens, the researchers first inserted into chicken embryonic stem cells the genes encoding the antibody and the regulatory sequences restricting its deposition to egg white. The stem cells were then introduced into chick embryos. At this stage of development, the embryonic stem cells can make significant contributions to the developing chicken. Resulting chimeras with large contributions from the stem cells lay eggs containing milligram amounts of antibody, which is then separated from the egg white proteins generating the purified product.
"This work represents a considerable advance over past efforts to develop avian transgenes, which were limited to the insertion of only small pieces of DNA," commented Dr. Etches. "The technology described here is a general method for inserting DNA encoding proteins of essentially any size and complexity while achieving high levels of protein expression. Moreover, it is the only technology to date that restricts deposition of the therapeutic protein to egg white."
"Monoclonal antibodies have demonstrated great success as human therapeutics, with over 25 approved for human therapeutic use and an increasing number of these proteins in clinical development," continued Dr. Etches. "We expect the demand for more potent anti-cancer monoclonal antibodies and for lower production costs to increase at a rate that will tax existing cell culture production systems. The introduction of this new chicken-based production technology will be of considerable interest to an industry coping with the commercial supply of an ever increasing number of therapeutic antibodies."
"We believe the chicken system is an attractive one for therapeutic protein production compared to either plant systems or to other transgenic animal systems," said Robert Kay, Ph.D., Origen Therapeutics president and chief executive officer. "The fact that the chicken-produced anti-cancer antibodies show dramatically enhanced cell killing activity elevates the chicken system considerably relative to other non-traditional production technologies and some traditional cell culture methods as well."
"Furthermore," Dr. Kay continued, "unlike other transgenic an imal systems, the time from antibody identification to production in eggs can be as short as 8 months versus 18 months to 3 years for goats or cattle. The egg is sterile and stable, providing a good starting material for isolation and purification of the protein of interest. Moreover, conditions for good manufacturing practices have been long-established for vaccine production in chicken eggs."
"This work really exemplifies the spirit of our Small Business Innovation Research grant program," said Matthew E. Portnoy, Ph.D., program director at the National Institute of General Medical Sciences at the National Institutes of Health. "This new technology has the potential to drive down drug manufacturing costs, which could make medicines and health insurance plans less expensive for all of us."