Unlocking the potential of biologics to put a bulls-eye on cancer
January 30, 2019
It's been called the emperor of all maladies – the one no one wants to hear about, especially when talking to their doctor: cancer. In part due to an aging population, the Canadian Cancer Society recently estimated that nearly half of all Canadians will be diagnosed with cancer at some point in their lifetimes.
But it's not all bad news. Through a combination of innovative industry partnership and groundbreaking research, scientists are finding new ways to battle against this longstanding adversary. Chief among them is Dr. Ali Tehrani – when he began pursuing his vision of intelligent, computer-assisted modelling of protein molecules, he didn't fully grasp the potential impact his work might have. The company he founded in British Columbia in 2003, Zymeworks Inc., is now a global leader in the field of biotherapeutics, the science of treating disease with medicine made from or using living cells. Through the development of a range of technology platforms and resulting therapeutics, the company is now a growing source of hope for the future treatment of a range of cancers – starting with breast, stomach, and ovarian cancer.
"Targeted drug therapies hold enormous potential for the future treatment of a range of cancers," says Tehrani. "Biologics enable the targeting of cancerous cells in ways that are more effective and efficient, often without the side effects normally associated with traditional chemotherapies. Our mission at Zymeworks is to create novel therapies that allow patients worldwide to return home to their loved ones, disease free."
A global success story, made in Canada
Today, Zymeworks is a shooting star in the world of biotechnology. In May 2017, the company raised approximately $58.5 million (USD) as part of its launch on the Toronto and New York stock exchanges and became one of the top health technology firms in the world in terms of capital raised. The company has grown from 7 to 194 employees, developed two therapeutic candidates currently in clinical trials, and established partnerships with many multi-national drug developers such as Merck, GlaxoSmithKline and Johnson & Johnson, to name a few. Their success so far aside, Zymeworks could potentially see additional revenue in the multi-billion dollar range if they can bring effective drug treatments to market. With that in mind it may be hard to believe that when it was a start-up, the company went through periods when it had barely enough capital to cover its basic operating costs. Thanks to early support and funding through the National Research Council of Canada's Industrial Research Assistance Program (NRC IRAP), Zymeworks was able to move its technology through the early development stages to achieve working therapeutic models.
The collaborative partnership between Zymeworks and the NRC was formalized in 2009. The NRC's Human Health Therapeutics Research Centre was instrumental in helping Zymeworks grow, by providing laboratory expertise and infrastructure required for Zymeworks to shift its technology platform from cutting-edge theoretical models to practical reality.
"The data generated in collaboration with the NRC helped us convince our early pharmaceutical partners that we had a viable platform to develop targeted biologics," says Ryan Dercho, Senior Director, Corporate Affairs for Zymeworks.
Patrolling the human body
The human body is home to a vast array of antibodies – more than 100 million different ones patrol our bodies day and night to fight off infections and disease. When a cancer spreads, it is because it's somehow gotten past our natural defences. Chemotherapy is able to kill these intruding cancer cells, but it does so indiscriminately, often damaging healthy cells in the process. Therapeutic antibodies, on the other hand, are engineered to focus their attention specifically on cancer cells while leaving healthy ones intact. This makes them more efficient and effective, while also helping to avoid common side effects such as hair loss, fatigue or nausea.
Zymeworks' first therapeutic antibody, ZW25, targets cancer by going after a specific marker – called HER2 receptors – which are proteins on the surface of the cells of particular types of cancer cells that tell them to grow. However, instead of using a traditional antibody design that can only bind to one particular location, ZW25 is a bispecific antibody that can simultaneously bind at two different places on the HER2 receptors in question. This can lead to a clustering effect that creates a chain between HER2 receptors and more effectively blocks signalling pathways (preventing growth), and more efficiently stimulates a response from the immune system.
Developing bispecific antibodies is not trivial. They can be susceptible to a number of potential issues: the two parts of the molecule may not work together, break down under certain conditions, or favour one side over the other. The technology developed by Zymeworks enables bispecific antibodies that are highly stable and consistently asymmetrical, allowing them to consistently bind to two different targets, hence the name of the therapeutic platform – AzymetricTM.
But what works in a computational model might not in the real world. This is why laboratory testing was essential in determining whether or not the therapeutic model could potentially one day work in living subjects. This is where the NRC's support was essential – it houses the largest research and development team dedicated to biologics in Canada. Based on DNA sequences developed and provided by Zymeworks, NRC researchers were able to produce the molecules in question, as well as purify, characterize and test them.
The new battlefront
According to Dr. Tehrani, the biotechnology industry is experiencing a paradigm shift towards multifunctional biologics. Traditional antibodies are monospecific, which means they are designed by nature to recognize only one antigen at a time. Engineering bispecific antibodies allows for the simultaneous engagement of two distinct targets, which broadens their potential utility.
"We've developed several advanced technological platforms for the design of multifunctional therapeutics, but the key remains the treatments themselves," underscores Dr. Tehrani.
For example, antibody-drug conjugates (ADCs) like Zymeworks' ZW49 take the bispecific approach of ZW25 and add drug delivery into the mix – i.e. the antibody targets the HER2 receptors on the cancer tissue and once they've been clustered and internalized, a toxin is released to kill the cancer cells.
"Toxins such as the ones used to kill cancerous cells in chemotherapy are not very specific," says Ivan Lessard, the NRC's Lead Research Officer for the project. "The use of antibodies allows them to be much more specific and preferentially target cancer cells."
An ADC is a bit like a smart bomb for cancer – the engineered ZW49 antibody binds to the HER2 receptors that are highly present on the types of cancer in question, after which a toxin is released, killing it from the inside. This highly targeted and focused treatment could one day revolutionize the treatment of specific types of breast, stomach, and other cancers.
For all the excitement, Dr. Tehrani remains committed to the bigger picture. After all, 2019 marks a decade of formal collaboration between the NRC and Zymeworks, and work is ongoing.
"This is a long-term endeavour and there are many steps in the process. That's why it's been essential to have access to the NRC's expertise and capacity over the years," he says. "Investments in foundational research today form the cornerstone of tomorrow's breakthroughs. This collaboration with the NRC should serve as a template; only through a combination of vision, expertise and teamwork will we arrive at the next generation of cancer therapies."
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