Issue Date: March 10, 2008
CLEVELAND BIOLABS (CBL) is a typical virtual biopharmaceutical firm. With a cancer therapy in Phase II clinical trials, and a radiation protection and mitigation drug currently before the Department of Defense, it employs a network of contract service firms around the world. That a company started in Cleveland does basic research at a cancer institute near its headquarters in Buffalo, while managing development in Chicago indicates that geography is flexible in the virtual pharma world.
Another indication of that flexibility is CBL's contract with SynCo Bio Partners, based in Amsterdam. SynCo is conducting process development and manufacturing to current Good Manufacturing Practice (cGMP) standards on Protectan CBLB502, CBL's recombinant protein treatment for radiation. CBL selected SynCo, a small bioprocessing specialist, over two major contractors with U.S. operations: Cambrex's biopharma division, now a part of Lonza, and Diosynth.
The choice was made by CBL's development team of three independent consultants and Ed Venkat, director of drug development. Venkat has a fairly standard set of criteria for selecting partners. It includes commercial experience, technical expertise, management track record, and financial strength. Another consideration, according to Venkat, is speed of response, and it is there that SynCo particularly impressed CBL.
SYNCO WOULD have to be fast to keep up with CBL. Venkat describes a series of weekly teleconferences and regular trips to Amsterdam with his three consultants to meet with SynCo. Among matters addressed at these meetings was coordination of early development work between SynCo and the laboratory of one of Venkat's consultants, Andrei Osterman, an associate professor of bioinformatics and systems biology at Burnham Institute for Medical Research, in La Jolla, Calif. Teamwork between CBL and SynCo resulted in complete technology transfer and commercial-scale production—going from 10 L in the U.S. to 1,200 L in Amsterdam—in one year.
Susan Dana Jones, vice president and senior consultant at BioProcess Technology Consultants in Boston, worked with Venkat on vendor selection. She says SynCo appeared to line up perfectly with CBL's needs. "When we got their proposal and went over the program, the cost, the timeline, the technology, SynCo just seemed like a very good fit," she says. "And the cost would be competitive despite the euro being so strong." The total payment to SynCo under the contract will be between $4 million and $5 million.
The current state of the project, according to Jones, proves that fit. "To get to that size batch with a reliable cGMP process in that amount of time was quite an incredible feat," she says. "We generally tell clients to expect something like that to take 18 to 24 months."
Speed was important for CBL because it is attempting to come back in round two after losing a bid on the Defense Department project to Osiris Therapeutics, which has a cell-based radiation therapy. Approximately $10 million in funding for development is at stake, Venkat says.
Unlike Osiris cell therapy, CBL's protein-based drug has not been tested on humans. But Venkat claims his company's approach has a major practical advantage.
"Our drug would be carried by the soldiers," he says. "When the command center tells them they are exposed to radiation, they inject themselves. Cell-based systems use special stem cells, and when soldiers are exposed, they would have to be air lifted and treated with an infusion."
Venkat says CBL has submitted an Investigational New Drug Application to the Food & Drug Administration. He expects to get a green light for trials in humans in a matter of weeks. In tests of CBLB502 in mice and monkeys carried out in Brazil and China, 70% of animals exposed to radiation lived after treatment, whereas 70% without treatment died.
CBLB502 is a truncated version of flagellin, a protein found in the flagella of bacteria. Flagellin modulates nuclear factor kappa B (NF-kB), which controls cell death, or apoptosis, Venkat explains. CBL engineered a short sequence of the molecule, including the key amino acids, to elicit the desirable reaction in humans at a higher potency.
"When animals are exposed to radiation, NF-kB is modulated negatively," Venkat says. "Tissues and cells commit suicide, causing destruction of blood and bone. This drug modulates NF-kB positively and prevents apoptosis. If you prevent it for 10 days or so, cells will restore themselves naturally to their original state, even when exposed to lethal doses of radiation."
CBL produces the truncated flagellin from an engineered gene that is inserted in a plasmid expression system carried by Escherichia coli, Venkat says. E. coli growth generates the product.
CBL contracted with Ohio State University to produce 10 L of CBLB502 through a lab-scale process developed by Venkat's group. "I must confess," Venkat says, "it was a rudimentary process. It was not optimized." SynCo would have to design a completely new process for large-scale production and protein extraction that would involve two chromatographic purification steps: ion exchange followed by hydrophobic-interaction chromatography with a polishing filtration step to remove trace endotoxins.
Sandra Verhaagh, project manager at SynCo, says the general bacterial expression and bioprocessing aspects of the project were not new to the company. Still, all projects run into unforeseen problems. For example, transferring production from a research-scale cell bank to a large-scale bank required adjustments, as did fermentation methods. These were solved expeditiously in collaboration with CBL's development group, she says.
"Their process knowledge is very strong," Verhaagh says, crediting Osterman's protein expression and purification know-how as aiding the process. "But also what helped is our flexibility," she says. "We are not a huge company. This helped us along the road when we saw that additional work needed to be done. It helps that we are two small companies."
Joanne McCudden, director of sales and marketing for SynCo, agrees that collaboration has been the key to success so far. "The technology was not the unique part of this project. "We do a lot of process development with E. coli and bacterial systems," she says. "The unique part was that the project team was such a diverse group of people. It would seem like a recipe for disaster."
Although SynCo is a relatively new company, its roots go back to Cetus, a biotech firm established in the 1970s and acquired by Chiron in 1991. When Chiron spun off its European operation in 2000, the Amsterdam operation became SynCo. "When we started we had very few contracts," McCudden recalls. "The main one was with Novartis for a commercial vaccine." That kept the business stable for a year or two, but the company was looking to expand.
Jones at BioProcess Technology Consultants, the matchmaker for SynCo and CBL, continues to consult on the project. "I've never seen it go so smoothly," she says. Among other things, she credits Osterman's enthusiasm. "He is an academic researcher, and he had never moved anything from the laboratory into a more-regulated cGMP environment," she says. "His attitude made a real contribution."
For his part, Osterman observes that industry has "a completely different notion of time." When time is added as a factor, he says, what would be a suboptimal route in an academic lab becomes the optimal route in production. "One of the first things I learned on this project as an academic researcher," Osterman says, a graduate of Moscow State University in 1993 with a Ph.D. in microbiology, "is that it is humbling and exciting to contribute to something with a bottom line."
This is the kind of attitude Venkat likes because the clock is ticking. "We have to present the proposal for development work ASAP," he says. "We are on the verge of taking it to the next level. Winning government funding would fuel work on the final formulation, the development of an optimized delivery system, and validation," he says. "We will again be on a very aggressive timeline—one more year to do all that."
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