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Volume 85 Issue 14 | pp. 24-25
Issue Date: April 2, 2007

Cover Stories: Pharma Outsourcing

Canadian Chemistry

Case Study #3: A query about a basic supply relationship evolves into a complex manufacturing pact
Department: Business
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The Right Mix
BioVectra's unique toolkit allows it to assemble all of Helix' immunoconjugate.
Credit: BioVectra
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The Right Mix
BioVectra's unique toolkit allows it to assemble all of Helix' immunoconjugate.
Credit: BioVectra

SOMETIMES IT PAYS to be a little nosy. By probing the pipeline of a customer buying research supplies, Canadian custom manufacturer BioVectra opened the door to a project that ties together a range of its technologies. The resulting manufacturing agreement with Helix BioPharma, a small Canadian biotech firm developing novel cancer therapeutics, could be the first chapter in a long-lasting relationship.

BioVectra, which has its headquarters in Prince Edward Island, had been supplying Ontario-based Helix with urease, an enzyme isolated from jack beans, and with IPTG (isopropyl-β-D-thiogalactopyranoside), which is often added to a fermenter to trigger the expression of certain genes. "One of our salespeople got inquisitive and called to ask what they were using the compounds for," says Dale Zajicek, BioVectra's chief operating officer.

Helix explained that it was doing preclinical work on L-DOS47, a compound in which the anticancer enzyme urease is tethered to an antibody targeting lung cancer cells. The resulting immunoconjugate enables the direct delivery of urease, a highly potent agent that would be too toxic if delivered systemically like other chemotherapeutics.

Sensium Technologies, the research arm of Helix, had discovered and developed DOS47, the urease-containing component of L-DOS47; Helix, however, licensed the antibody from Canada's National Research Council.

John Docherty, Helix' vice president of corporate development, explains that the strategy behind L-DOS47 is to change the microenvironmental pH of cancer cells, which generally need acidic surroundings to survive. The antibody delivers urease to a tumor, where the enzyme then metabolizes urea, a by-product of amino acid degradation that is abundant in the interstitial space that separates cells.

Urea forms two metabolites that Helix believes stimulate cancer cell death. These metabolites are hydroxide ions, which raise the pH around the cell, and ammonium ions, which are reputedly cytotoxic and can readily diffuse into cancer cells.

Several biotechnology firms practice immunoconjugation, or the use of an antibody to deliver a drug payload to a target, but Helix does it differently, according to Docherty.

Companies such as Seattle Genetics and ImmunoGen unload powerful chemotherapeutics internally; their conjugates penetrate the cancerous cell, where the antibody then releases the cytotoxic payload (C&EN, Sept. 25, 2006, page 51). With Helix' immunoconjugate, on the other hand, the payload—urease—stays bound to the antibody and does its work outside the cell. "By remaining intact, the urease is essentially free to act over and over on endogenous urea while staying bound to the surface of the cancer cells," Docherty says.

If the model proves successful, Helix expects to create a platform of immunoconjugates that link cancer-specific antibodies to urease. The company has an agreement with Canada's National Research Council to discover and develop other antibodies that could be paired with DOS47 to target a range of cancers.

Clued in to the complexity of the L-DOS47 project, BioVectra pointed out to Helix that it had been building up some unique and relevant experience. BioVectra boasts the ability to extract and purify natural products from plant biomass, a skill Helix was already tapping with its urease purchases. In addition, BioVectra has 25,000 L of fermentation capacity that has been inspected by the Food & Drug Administration, and it is one of just a few companies able to use bacterial fermentation to make highly potent biologic compounds.

Furthermore, BioVectra had in recent years added drug conjugation capabilities as an extension of its business in polyethylene glycol reagents. "We have manufactured PEGs and done conjugation with both small and large molecules," Zajicek says. "The chemistry of getting the right linkers and the proper sites is well within our technical skill base."

TAKEN TOGETHER, BioVectra's tools clearly match what Helix needs to assemble its cancer drug. "It's a really exciting project for us," Zajicek notes, "because it combines a number of capabilities we've been developing over the past few years."

At the same time, Helix had to begin considering scale-up partners. Sensium could make L-DOS47 at the bench scale, but it didn't have the capacity to produce clinical-trial quantities. "As we saw success through the preclinical program, we wanted to ramp up and move aggressively toward the clinic," Docherty says.

The two companies began discussing the possibility of a contract manufacturing relationship late last spring. Helix then conducted an initial audit of BioVectra's facilities in Prince Edward Island. Next came technical discussions, and by early January, the companies had signed a deal.

Today, Helix is focused on finishing the preclinical studies for L-DOS47, while BioVectra works in parallel to optimize and scale up the manufacturing process. BioVectra expects to be supplying clinical-trial quantities within the next four to six months. Helix' goal is to file an Investigational New Drug Application with FDA by the end of the year.

If all goes well in early-stage trials, Helix would look for licensing partners to bring the drug to market. "We don't aspire to launch and commercialize it ourselves," Docherty notes.

Though it is early, a strong potential exists for an expanded collaboration between the two firms. Should Helix go forward with other immunoconjugates that use urease as the payload, BioVectra would be a likely manufacturing partner, Docherty notes, adding that no commitments to that effect are yet in place.

"We are working on what we hope to be a strong Canadian success story," he says.

 
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