From idea, to molecule, to medicine

For a drug discovery scientist, handing over a molecule you’ve seen from inception to early trials is a bit like sending your child to school for the first time.

That’s how it felt for Pablo Umaña and his team, when the time came to see the T-cell bispecific antibody they had developed with the broader Roche Pharma Research and Early Development (pRED) team taken on by colleagues in late-stage development. It was the culmination of years of work, and a moment of immense pride – one made possible by the extraordinary collaboration of a huge team of scientists at Roche.

The story of drug discovery is one littered all too often with failure. With every molecule that makes it to market requiring as many as seven million hours of work and six thousand experiments to prove their potential, resilience is a huge part of the process for the scientists involved in their development.

This is something Pablo’s team recognised early in their journey during the discovery and early development of another drug. At the start of the millennium, while investigating a potential drug candidate at their start-up company, Glycart Biotechnology, they had generated a novel glycoengineered antibody drug candidate. Few people thought it viable, but they believed that their antibody engineering approach could be a solution for treating blood cancer.

“In spite of the benefits that antibody medicines were offering, we knew there was more to be done for those patients who don’t respond, or who relapse,” Pablo explains. “So we asked ourselves the question: ‘What is limiting the mechanism?’ We hypothesised that we could increase the interaction between the anti-cancer antibody and immune cells, using our expertise in molecular engineering. That's how we generated our first molecule.”

Glycoengineering – a way of modifying the sugar chains on the surface of antibodies – gave the team a way of helping immune cells recognise antibodies more effectively. It also allowed them to enhance the antibody’s ability to kill cancer cells. The preclinical data showed promise, and Roche became interested in supporting the journey.

In 2005, Glycart became part of Roche, and the team grew from just 30 people to today’s team of 200, located at pRED’s Roche Innovation Center in Zurich.

In 2008, with the clinical development of glycoengineered antibodies now well underway, Pablo and his team switched their attention to a new area of research: how to improve therapies based on redirecting T-cells. This was an approach that would complement glycoengineering, and emerging evidence suggested it could be a powerful way of focusing a patient’s immune system on attacking their cancer. More effective antibody molecules that could reach more patients were still needed, and so the team accepted the challenge, embarking on the development of a novel, ‘bispecific’ antibody platform.

“The molecules we started to focus on are known as ‘T-cell bispecific’ antibodies,” notes Pablo. “They have two parts or “arms” – one that grabs the T cell (a type of ‘killer’ white blood cell), and one that grabs the cancer cell. Our hypothesis was that we could modify the bispecific antibody structure to enhance its biological activity and be more effective at fighting cancer.”

After several attempts, the team succeeded in developing a novel antibody structure. The new molecule, called a ‘2:1 T-cell bispecific antibody’ had two arms that recognised the cancer cell, and particularly flexible linkage between one of the anti-cancer cell arms and the T-cell-grabbing arm. Compared with other bispecific antibody molecular formats, this new structure led to improved tumour targeting and T-cell recruitment.

The team’s hypothesis was borne out by early studies. In 2010, Marina Bacac became the preclinical research leader for the first T-cell bispecific drug candidate project, leading the preclinical research activities aimed at B-cell lymphoma treatment within the discovery team. She takes up the story.

“From the early days, all our in vitro and in vivo experiments led us to recognise the potential of the molecule to make a difference, particularly in heavily pre-treated and aggressive forms of lymphoma. So a lot of the journey was about collaboration between the drug discovery, clinical development and safety teams to work out how we could optimally develop such an important new approach, and maximise the potency and activity of the molecule while maintaining safety.”

Soon, many more colleagues in pRED from the Large Molecule Research, Pharmaceutical Sciences, Technical Development and Oncology organisations joined the effort, and the momentum carried the bispecific platform from the discovery stage to the point of being handed over to the early clinical development colleagues.

“The entry into human trials and the transition from early- to late-stage clinical development were two very exciting moments,” notes Marina, “Moments in which we saw our preclinical findings translated into patients.”

For Pablo, it was the realisation not only of a great deal of hard work, but also a huge amount of hope. He notes: “As discovery scientists, we start with the dream that the work we are doing could one day really help patients. But we begin in a very scientific way, thinking about formulating hypotheses, and going one step at a time. It’s slow and methodical work, and it necessarily involves a degree of failure. So seeing a molecule move on to human trials, transition to late-stage clinical development, and then succeed in pivotal trials are extraordinary moments – the realisation of many years of hope.”

As the bispecifics journey continues, both Marina and Pablo remain closely involved, interacting regularly with the late-stage team to exchange information and provide insights. And it’s a characteristic of the development of the bispecifics platform that collaboration has always been at its heart. As well as being the realisation of an aspiration shared across their entire team, Marina and Pablo both credit Roche with an approach that accelerates innovation, and creates opportunity.

“Roche has a really fantastic way of integrating new groups, companies and ideas in a way that allows people like me and Marina to keep our scientific autonomy,” Pablo concludes. “But at the same time, it provides the opportunity to explore synergies and benefit from a huge bank of scientific expertise. Everything we’ve done has been made possible by the great collaboration we’ve enjoyed with our team and the wider organisation. I think we’ve had the best of both worlds. We’ve had the opportunity to design and come up with new ideas. But at the same time, we’ve had amazing support and great collaboration. And that’s why I’m optimistic about the future of bispecific antibodies, and incredibly excited to see what happens next.”