Anticancer CRUSADER

DR. DAVID YOUNG OF ARIUS RESEARCH INC. IS DETERMINED TO SUCCEED IN PERSONALIZED CANCER THERAPY

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By Amber Lepage-Monette

With a medical degree and a career practising cardiac surgery, how does one decide to switch into the business end of biotech?

“Being rather simplistic, I thought I’d rather affect more people than less, because that was the initial goal of getting into medicine in the first place,” says Dr. David Young, president and CSO of Arius Research Inc. (Toronto, ON).

“So I made what was a very difficult choice, which was, leave the familiar world of academic surgery — where you train, you know most of the people, it was a very comfortable environment, you knew what was going to happen next — to this very unfamiliar territory that is Canadian biotech.”

Collaboration to Commercialization
Young’s introduction to the business world initially came about through his research work in xenotransplantation — transplantation of animal organs into humans.

Conducting his master’s research at the University of Toronto (Toronto, ON), Young collaborated with Spectral Diagnostics Inc. (Toronto, ON) to develop antirejection antibodies to prevent necrosis — or cell death — which occurs because humans have pre-formed antibodies that cause necrosis of pig cells.

Though Young and a scientist at Spectral received patents for their collaborative work, a company was never formed. The experience did, however, give Young a new outlook toward scientific research.

“I think that was my first inkling that there was a different way of doing science: a very practical type of research that really had real-world impact,” Young says.

He also left with an understanding of how difficult commercialization can be, and with a plan for how he would approach future commercialization opportunities.

“It was very hard to get all the pieces together to get a biotech company started from academia, and so, I made a very conscious decision,” Young says. “The lesson I learned was to do it outside of the University of Toronto.”

Young had also started his PhD studies in xenotransplantation, working on isolating human blood lectins that cause pig-cell apoptosis, another form of cell death. Young found that the lectins were binding to sugar forms, or glycoforms, found on pig cells.

Through his research work with Spectral, Young was collaborating with biochemist Inka Brockhausen, PhD, who was then with the Hospital for Sick Children (Toronto, ON) working on human leukemia. For Young’s research team, Brockhausen was analysing chemical pathways that put glycoforms on the cell surfaces, and noticed that enzyme pathways for pig cells were similar to those of leukemia cells that she was working with.

The researchers began questioning if the lectins could kill cancer cells and not normal cells, and the research that would later lead to the development of Arius was born.

“This was one of the first realizations that, yes, you can make compounds that can bind to cancer cells and selectively kill them and not kill the normal cells, because they have two different biochemical pathways that put these sugars on the cell surface,” Young says.

Young approached George Jackowski, PhD, CEO and CSO of SynX Pharma Inc. (Toronto, ON), who had previously worked at Spectral, to ask for lab space and the help of SynX’s then director of research Miyoko Takahashi, PhD.

Using his own money, Young leased space from SynX, and paid for reagents, technicians and anything else he needed to try to develop targeted anticancer antibodies.

“Our proposition was, let us — instead of looking at whether these antibodies bind to cancer cells and not normal cells — let us ask what we think is a more important and more relevant question: do these antibodies kill the cancer cells and not the normal cells?” Young says.

Young explains that a “gentlemen’s handshake” agreement was formed with SynX Pharma, whereby if the experiments worked, and patents were obtained, SynX would be a partial owner of the company that would be formed. In the early days of Arius, he says, SynX owned one-fifth of the company.

Young says Jackowski and Takahashi’s help was instrumental in starting a new company.

“George and Miyoko have always been very supportive of things I’ve done, to the extent that they would provide their guidance, and in the case of SynX, space and the willingness to, in essence, risk their opportunity costs for this venture,” Young says.

Targeting Cancer
When it comes to Arius’s work in monoclonal antibodies, personalized therapy is the name of the game.

“Our mission is to come up with as many of these new target therapies as we can, because we think that this next stage in cancer treatment is going to be a very personalized method of picking the right drugs, the right patients,” he says.

Young explains that in personalized medicine, drugs are designed specifically for the targets that the patient expresses, providing therapy geared toward the individual’s cancer that will prove to be less toxic in terms of side-effects and more effective in treating the patient.

In working with monoclonal antibodies, Young says the company tries to identify the innate function of these antibodies.

“The antibody can bind to its target and do something to help kill the cell, or it can just bind to its target and you have to attach a payload to the antibody for that payload to kill the cell,” Young explains. “And we take the view that if the antibody, as a naked antibody, has an effect, you can always attach more things . . . but you can’t really engineer in that innate function.”

Monoclonal antibodies are generated when a mouse is immunized with human cancer cells that have targets on their surface, which cause the mouse’s immune system to produce antibodies against all targets that are on the cell, Young says. The trick is sorting through the billions of antibodies for the desired ones.

The company uses its FunctionFirst™ technology platform to assist in selecting those antibodies that have anticancer abilities.

Arius currently has three antibodies that are within two years of the clinic, Young says. The company’s lead antibody, ARH416-16-2, recognizes CD44 — an antigen that researchers are now starting to think may be a cancer stem cell marker.

“The reason why this is exciting is that we have, over the last 30 years or so, a lot of drugs that can shrink tumours. But what happens is, even as we use these drugs in clinical trials, we don’t get tremendous survival benefits,” Young explains.

“So you may get an extra four months, or six months of survival, but . . . for the most part, you don’t get cures.”

The theory behind cancer stem cells is that, in tumours, there are fast-growing cells that are affected by chemotherapy, but there are also slow-growing, pluripotent cells that aren’t affected by chemotherapy, Young explains. These slow-growing cells can eventually give rise to other cancer cells and repopulate the tumours.

Young says that other researchers have identified slow-growing cells from patient tumours that are CD44 positive. This is welcome news to the company, as its ARH416-16-2 antibody not only targets CD44 but also triggers apoptosis.

“For us, this discovery is very serendipitous,” Young says. “When we make these antibodies ahead of time, you don’t know what the targets are. We have to go back and discover what the targets are. And so as it turns out, CD44 was the target for this antibody.”

The company’s second antibody, AR7BD-33-11A, is the first drug against a target in the class of cell surface molecules called tetrospanins, Young says.

“This antibody is tremendously potent because you can dose down to very small amounts, such as 0.2 milligrams per kilogram, and have survival benefits and tumour-suppression benefits,” he says.

AR7BD-33-11A is currently designed to be a second-line therapy for use in combination with traditional cancer treatments — such as surgery, chemotherapy or radiation — to prevent tumour regrowth, Young says.

Stepping Up
When first starting Arius, Young had to juggle his management role at the company with surgical work at St. Michael’s Hospital (Toronto, ON).

“Initially, I was associate staff there, and then when Arius started, I would work at St. Michael’s maybe two, three days a week,” he says. “But obviously, in the beginning of a startup’s life, things are not as all-consuming. But now, in the last two or three years, it got much, much busier.”

Young hasn’t operated at St. Michael’s in several years, he says, but is gracious when it comes to the question of whether he prefers the scientific or business role.

“To me it is changing, and whatever I do, I find I’m the most interested and fascinated by that thing at that point in time. So when we’re, in some senses, in a science cycle, I’m absorbed by it. And then when we’re in a business cycle, then I feel driven by that too,” he says. “In biotech, they’re so intertwined that you really can’t do one without the other.”

Initially, Arius had a separate president and CSO. But when that situation didn’t work out for the company, Young stepped in, and says he had no reservations about taking on the role of president at Arius.

“It had to be done, and I thought, well, you know what, there’s no reason why I can’t do it as well as anybody else,” he says. “I understand the business, I understand the technology. It would just be more work. But that’s OK.”

All in all, taking on a business role has been a very educational, learn-as-you-go process for Young.

“It’s fascinating,” he says. “And, I think, looking back on it, if I had known how much I didn’t know, I probably wouldn’t have done it.”

Determination, Young says, is what makes it all possible.

“If you’re passionate about something, and you’re willing to work hard at it, there’s no reason you shouldn’t succeed,” he says. “There may be a lot of obstacles, but generally, I think hard work and passion will overcome those.”