With all the advances in cancer-fighting therapies, there remains a great need to find better ways to combat the disease. Following discussions that were initiated on the BIO 2001 conference in San Diego, USA, we recently added a new and important arm to our cancer drug hunting approach –antibody-based therapeutics – to complement our strengths in small molecule treatments.

In October 2003, we invested $100 million in forming a research alliance with the biopharmaceutical company Abgenix Inc. Together, our companies will discover and develop human therapeutic antibodies for up to 36 cancer targets to be commercialized worldwide exclusively by AstraZeneca with the potential for co-development by our parties of antibodies against a further 18 targets.

Why antibodies

Most traditional cancer drugs act as poisons in the body, damaging cancer cells and healthy tissue alike. Novel drugs take a more targeted approach. These new first-in-class therapeutics hone in on just the cancer cells, changing the biology of the disease at the molecular level, without the harsh side effects often experienced by patients undergoing chemotherapy. Still, there is no magic pill that works for all patients or all cancers.

According to Dr Jeff Hanke, vice president of AstraZeneca Cancer Discovery, “Cancer isn’t one disease; there are hundreds of types of cancer. Some interact with proteins in the body, others with enzymes or ion channels or membrane receptors. Protein interactions do not respond to small molecule drugs, but they are uniquely suited to treatment by antibodies."

Fully human monoclonal antibodies – the type generated and developed in the AstraZeneca-Abgenix partnership – seek out the specific cancer cells they were designed to find and either destroy the targeted cells or alter their activity. They are produced by transgenic XenoMouse® mice which generate 100% human antibodies rather than from genetic material from regular mice, as were the first monoclonal antibodies. Using human protein minimizes the risk of rejection and increases the effectiveness of therapy.

Combination therapies for better outcomes

Often, antibodies are used in combination with small molecule drugs to achieve a wider therapeutic margin of safety and better results for the patient.

“The time is here for using antibodies in a patient’s treatment regimen,” says Dr Hanke. “The scientific community has more than 25 years of understanding cancer at the molecular level. Now we can use that information to effectively tailor antibodies to specific mechanisms of action in cancer cells. As a result, AstraZeneca will be able to offer physicians a collection of therapies from which they can choose the best treatment combinations for their patients. It’s like having multiple shots on goal, and the patient wins no matter which one scores.”

Among pharmaceutical companies, there is great interest in moving beyond small molecules to antibodies, also called large molecules because they are approximately 500 times the size of traditional drugs produced by chemical synthesis. At the Pharmaceutical Strategic Alliances Conference, held in New York in September 2004, the featured session was “From Small Molecules to Large.” More than 400 leaders in the pharmaceutical and biotechnology industries attended as Dr Hanke and representatives from Lilly and Bristol-Myers Squibb discussed their approaches to incorporating large molecules into their research programs.

Early and ongoing collaboration

Dr Catherine Wheeler, AstraZeneca Global Product Director and physician involved in clinical development, says the Abgenix partnership is a long-term collaboration. “In our first year, we did what we said we would – come up with candidate antibodies for a range of cancer targets and assess their utility using laboratory models. We hope to begin taking these agents into clinical trials within a few years.

“The efficacy of any cancer therapeutic is only as good as the importance of the disease target you’re going after,” she says. “That’s why we’re working closely with our drug discovery colleagues at earlier stages in the process to identify the aspects of biology we can interfere with to have a positive impact on someone’s disease. On the clinical side, we’re sharing information about what kinds of cancer might be treated by the drugs being developed – and what tools we’ll need to assess how these drugs are working once we get them into clinical trials.”

NCI expert at AstraZeneca

The philosophy and practice of maintaining close working relationships between drug discovery and clinical scientists is one reason DrLouise Grochow joined us in October 2004 (see related story). A renowned researcher and former chief of the Investigational Drug Branch of the US National Cancer Institute (NCI), Dr. Grochow led the world’s largest cancer early drug development program. Under her leadership, the NCI early clinical trials programs were optimized to meet the challenges of evaluating targeted treatments for cancer.

“AstraZeneca is among the few pharmaceutical companies to insure clinical input is an integral part of the early discovery process,” says Dr Grochow. “In some companies, the handoff of candidate drugs from discovery into development involves completely different teams, with different mindsets. AstraZeneca’s culture of bringing together key functions makes the transitions smoother, with fewer gaps and disruptions in timelines, while adding a higher degree of confidence in the agents entering clinical trials.”

A good match

“We treat collaborative projects the same as internal ones, so that requires extensive communications to keep everything on track,” says Dr Campbell Wilson, director of Discovery Alliances within Cancer research. “The Abgenix collaboration is going very well, and we’re on target with our timelines and number of programs.”

Several options were reviewed once we decided to move ahead with antibodies: building expertise internally, collaborating with multiple partners on smaller projects or forming a large, strategic alliance. “We decided the match with Abgenix was just right,” he says. “We both have complementary skills and a desire to align with a significant partner.”

“We look to Abgenix for its expertise in the generation and screening of antibodies, process development and commercial manufacturing,” says Dr Wilson. “While Abgenix looks to AstraZeneca for our strong franchise in cancer therapeutics and our expertise in identifying cancer targets, developing drugs and marketing commercial medicines.”

More and better options for patients

With Abgenix and the move into therapeutic antibodies, we are building on our tradition of research excellence and innovation in cancer treatment. Our product pipeline is one of the strongest in the industry, with several leading therapies including a range of anti-proliferatives, anti-angiogenics, vascular targeting and anti-invasive agents. Further, there are more than 20 different anti-cancer projects in research and development.

“We have expanded our pipeline tremendously in recent years, with a variety of approaches and agents, so we can make the best choices in terms of developing effective therapies for patients,” says Dr. Wheeler. “No matter which technology we use – gene therapy, biologics, small molecules – the goal is finding a drug that demonstrates safe and effective performance in the clinic and ultimately improves the quality of patients’ lives.”

Published 13 June, 2005