Cangene Poised For New Foray Into Recombinant Protein Market

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By Vincent Wright

A long-standing research partnership with the University of Manitoba (U of M) (Winnipeg, MB) appears to be paying handsome dividends to Cangene Corp. (Winnipeg, MB), a world leader in specialty hyperimmune plasma products, and bacterial expression system bioprocess technologies.

The relationship with Mike Butler, PhD, a professor in the department of microbiology, is providing Cangene with an important new window on mammalian cell bioprocessing techniques — a capability that could significantly enhance the company’s stature in the burgeoning market for recombinant protein biopharmaceuticals.

A December 2003 summary report from the Canadian Bioprocessing Initiative states that the market for recombinant proteins is expected to reach $53 billion by 2010. These next-generation therapies, together with other biologicals, now account for more than 50 per cent of all new submissions to the United States Food and Drug Administration.

At the same, however, it’s widely acknowledged that there’s a severe worldwide shortage of bioprocessing capacity, one that could delay or threaten the market introduction of dozens of biological therapies. The situation is compounded by an acute lack of highly qualified personnel trained in bioprocess technologies.

“Our process-development research is aimed at eliminating a critical bottleneck in the production of biopharmaceuticals. And we’re doing our part to alleviate the chronic shortage of skilled professionals in this area,” Butler explains.

“Process-development research,” he adds, “does not always get the same recognition as discovery research, even though it’s of comparable importance to the biotechnology industry.”

Fortunately, the accomplishments of Butler’s lab, in collaboration with Cangene, have not gone unnoticed. In late October, Butler and Cangene were jointly honoured with a coveted Synergy Award for Innovation. Presented by the Natural Sciences and Engineering Council of Canada (NSERC) (Ottawa, ON), which promotes higher education-business collaboration under its Research Partnerships Program, the Synergy Awards celebrate outstanding achievements in university-industry interaction.

Butler’s collaboration with Cangene began in 1990 when he left Manchester Metropolitan University (Manchester, U.K.) to assume a new Industrial Research Chair at the U of M. Sponsored by generic drug giant Apotex Inc. (Weston, ON), parts of which were acquired by Cangene in a 1995 reverse takeover, the chair involved the study of mammalian cell systems for the production of monoclonal antibodies by hybridomas, and the production of anchorage-dependent cells on microcarriers.

The success of the chair led to two follow-on, NSERC-funded collaborative research and development (CRDs) projects in laboratory-scale bioreactor processes. The first dealt with developing a mammalian cell culture process for the production of erythropoietin, currently the biggest selling recombinant protein. The second, for which research is ongoing, entails the development of a mammalian cell culture process for producing beta-interferon used in various cancer treatments.

In both projects, the key challenge for Butler and his fellow researchers is to develop mammalian cell processes that enable “consistent glycosylation” of recombinant proteins, according to Cangene president and CEO John Langstaff, PhD.

“This is all about consistency,” Langstaff suggests. “You have to be able to consistently produce therapeutic proteins that are safe and efficacious, and that’s why we’re enthused about Mike Butler’s work on consistent glycosylation.”

Glycosylation refers to a process in which sugars are secreted from the cell, forming a protective coating around the protein. In theory, without this protective sugar coating, Langstaff says, most recombinant protein therapies would not survive in the human bloodstream. Sugars also permit recombinant protein therapies to target specific cells.

Butler says his group has managed to “significantly enhance the yield” from mammalian cell bioprocesses, while “defining control parameters for ensuring that glycosylation is appropriately and consistently added to the protein.”

Butler’s research, Langstaff says, “has helped us gain important new insights into the function of sugars in mammalian cell processes. His understanding of the relationship between process conditions and the degree and type of glycosylation is particularly relevant because the bioactivity and half-life of glycoprotein therapeutics are dependent on glycosylation patterns.”

Another important achievement for Butler’s group is the development of serum-free media for the growth of mammalian cells. These formulations, which are being commercialized by a spin-off company, Biogro Technologies Inc. (Winnipeg, MB), eliminate the need for bovine serum, which is a potential source of contamination (particularly viruses and prions) in mammalian cell bioprocesses.

Although Cangene has yet to formally announce products out of the relationship with Butler, Langstaff says the collaborative work in mammalian cell bioprocesses will allow his company to diversify both its product and manufacturing technology base. Virtually all of the products in Cangene’s current biotechnology R&D pipeline are generated using bacterial (microbial) expression systems.

“Traditionally, mammalian cell fermentation is far more difficult and challenging than bacterial fermentation,” Langstaff maintains. Part of the difference is that, because they don’t glycosylate, bacterial fermentation systems are less complex. But that also means they are unsuitable for the production of most recombinant proteins, particularly the more complex varieties.

In addition to recombinant proteins, mammalian cell bioprocesses can also be applied to the production of monoclonal antibodies and vaccines. Langstaff says the next generation of Cangene’s hyperimmune products will likely be based on monoclonal antibodies manufactured by mammalian cell bioprocesses.

“From a commercial standpoint, we are just beginning to realize the value of our relationship with Mike Butler. And we expect to continue to realize value for many years to come,” he says.

Langstaff also praises Butler for maintaining strong ties with other disciplines at the U of M and other schools across Canada. In particular, he says Cangene is enthused about the collaboration between Butler’s group in microbiology and the internationally renowned time-of-flight mass spectrometry research group in the departments of physics and chemistry. The latter group, which partners with the Manitoba Centre for Proteomics (Winnipeg, MB), maintains unique expertise in the study of protein structures.

Outside of Manitoba, both Butler and Cangene are among the principal investigators and industrial sponsors of Cell-Net, the Cell-Factory Bioprocessing Research Network funded by a $2-million NSERC grant. Within Cell-Net, Butler is heading up one of three thematic areas: cell strain selection, development and characterization, including cell lines metabolically competent for glycosylation.

Beyond the research, Butler says Cell-Net’s emphasis is on advanced training of highly qualified personnel. “It’s all about building critical mass in Canada in this all-important area of bioprocessing,” he says.

Butler’s lab has already been building critical mass for Cangene. The company has hired six former students with postgraduate and post-doctoral training, including two senior scientists responsible for bio-manufacturing technology development.

“Mike Butler has managed to bring experts into his lab from outside the Winnipeg community,” Langstaff notes. “It seems it’s easier for him to do that than it is for us. As a result, we tend to hire people out of his lab, rather than trying to recruit from outside the community.”

As Butler observes, “Cangene provides an important employment outlet that helps motivate people trained in my lab. At the end of the day, any company that invests its time and resources in a university becomes more favourably placed to find new recruits as the need arises.”

Vincent Wright is an Ottawa, Ont.-based freelance writer with over 20 years of experience in science and technology communications.