Reaching new antibody heights

Antibodies are biological products used as treatment options for a range of indications, from cancer to infectious diseases to ophthalmology and more.

Few efforts require the extreme preparation and dedication that it takes to scale the world’s wildest mountain ranges, especially when the way forward is unmapped. Even expert mountaineers must be careful in their pursuit of a far-off goal, with risks outside their control at every step. The early research and clinical development of medicines also requires a similar degree of planning and courage, especially for conditions and diseases that are little understood or have limited treatment options.

For Roche pRED scientists like Christoph Ullmer, Senior Principal Scientist, and Christian Klein, Distinguished Scientist, the peaks and valleys of early pharma research are familiar grounds. They make progress in these difficult conditions by leveraging pRED’s powerful research platform to find the “sweetspot” of drug discovery. This is where the team’s deep understanding of a disease, on both a biological and clinical level, combined with the latest technological advancements, allows them to develop promising molecules into real medicines. They reflect on more than a decade of blazing trails in bringing antibody therapeutics to new disease areas, and how the Roche pRED team was uniquely equipped to see the paths forward where no one else had.

Looking through the clouds to aim for the summit

“I am a strong believer in technology-driven innovation,” Christoph Ullmer explains. pRED’s advancements in bringing antibody technologies to new areas of need have been made not just by leveraging understanding disease biology, but have also been founded on developments in antibody engineering technologies required to make an investigational molecule in the first place. Such technologies can make the seemingly “undruggable” druggable or hit previously druggable targets in completely new ways.

What really enables the Roche pRED scientists to break new ground is their collective ability to think outside the box and continuously strive to advance their deep understanding of the underlying biology of disease, their clinical understanding, and their technological know-how. Christian Klein says, “Roche allows employees the freedom to pursue unconventional ideas,” reminiscing on one instance where the team were able to identify that the mode of action of a cancer drug candidate might allow it to have a therapeutic effect in a completely different indication. The scientists had a moment of inspiration when they saw a mechanistic overlap between two different pathologies which opened a new way forward. The collaborative nature of the wider team allowed those first inklings of an idea to flourish into a shared goal. Christian says he and his colleagues were able to launch a project for a disease area that, at the time, was not being investigated by pRED, but “we were given the opportunity to evaluate and champion the idea to show its potential.” This opportunity nicely illustrates how innovation happens at the interface of multiple disciplines.

Even with this perfect convergence of technology and science, turning this idea into innovation depended on the team’s ability to convince others of its merit. Matthias Rüth, Large Molecule Program Manager for that project, was impressed with the scientific grounding of the team’s hypothesis, and the potential impact of this particular molecule. Matthias says he “sensed the energy and conviction of the entire team despite facing many challenges,” and was proud of the team’s “courage to do experiments in an area outside of our core expertise,” which finally led pRED to give the official go-ahead. Securing this sort of internal approval is just the first step of many along the long climb to delivering a therapy to patients.

Being committed to the climb

Bringing a drug from the benchtop to the bedside is not a clear and easy path, and there are many that fail along the way. After developing and screening for an initial drug candidate, optimising a molecule for a given disease area has its own suite of scientific challenges. Scientists must ensure the stability and bioavailability of any new drug candidate in whichever part of the body it is administered. Sensitive and highly vascular regions in the body may need new drug options to be designed to reduce the risk of unwanted effects.

Roche has a long heritage in antibody engineering, having been one of the first companies to break into the space in the 1970s and being a pioneer in developing bispecific antibodies. The specificity and power scientists can exercise when designing new antibodies has come a long way since then. The innovation ofin 2011 allowed scientists to imagine new modes of action for bispecific antibodies, given the potential of binding to more than one molecular target with a single antibody, and the ability to reliably produce such complex antibody therapeutics at scale.

Christoph comments that development of the CrossMAb technology eliminated the need for “mixing two different antibody molecules,” letting the team produce their candidate bispecific molecules more reliably. Christian adds how pRED’s “expertise in how to apply CrossMAb technology and at the same time optimise the antibody constant Fc region (the ‘tail’ region of an antibody that facilitates part of its interaction with our immune systems)” gave the team an edge for developing unique antibodies that could be used in new indications throughout the body.

Even with a solid antibody candidate and the ability to produce it reliably, successful passage through a rigorous preclinical and clinical programme remains a challenge, especially for antibodies in a novel disease area. Matthias Rüth highlights the team’s “proactiveness” in running initial key experiments and “innovation” in designing studies for an unknown disease area. Sascha Fauser, Global Head of Ophthalmology, highlights that as a given molecule progresses into early-stage clinical trials, the team continues to “follow the science with the kind of determination and commitment that can move mountains.”

Reaching the summit, taking in the view….and moving forwards to the next

Scientists, who may spend years of their lives on a project, are inspired when their lab hypotheses are finally validated in the clinic. This is not necessarily easy or straightforward, because preclinical models, while useful, are still limited in their ability to predict what will actually happen once a molecule is in patients. Christian, reflecting on one of these experiences, notes “I clearly remember when we heard of the positive Proof of Concept in the clinic. This does not happen too often as you can imagine and is the biggest reward for us as researchers.”

With their shared passion, access to the latest technology, and diverse culture, the scientists of Roche pRED are exceptional at driving innovation and taking antibodies to new disease areas. Christian concludes that, with the patient at the heart of all we do, “pRED is strongly science-driven, which enables us to adopt unconventional ways of thinking, having a breakthrough-mindset to pursue a very good idea further.” While there will always be a new challenge to summit, the team at Roche pRED will always be ready to reach for the highest point!

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