Meet the antibody engineers

In the last several years, the COVID-19 pandemic has brought many scientific terms to the forefront of public awareness, so you might now be more familiar with words or acronyms like antibodies,  PPE (personal protective equipment), and mRNA (messenger ribonucleic acid). Antibodies are Y-shaped molecules that our immune systems make in response to exposure to particles, such as viruses, that our immune systems recognise as foreign. For example, as a result of infection or vaccination, our immune system makes antibodies that can attach to and recognise viral particles, prevent these particles from working, and mark them for the immune system that they should be destroyed. That is also how several antibody treatments could be developed against the virus causing COVID-19 by helping to supplement the body’s own immune response.

 Antibodies are highly versatile tools, not only in biology research, but also as medicines. And to make them even more effective, Roche researchers are leading the way in engineering new kinds of antibodies with new targets in disease contexts beyond traditional indications like immunology or cancer. “We get the starting points from nature, which provides an optimised framework, and then we endow them with superpowers,” explains Roche antibody engineer Hubert Kettenberger. Applying diverse expertise, drawing on a history of innovation, and using the many tools at their disposal, Roche antibody engineers like Kettenberger and his colleagues tailor their approaches to each disease individually.

Three of the Roche Group's autonomous and independent innovation engines, Roche Pharma Research and Early Development (pRED) in Europe, Genentech Research and Early Development (gRED) in the US and Chugai in Japan have each made important advances in engineering new therapeutic antibodies. One particular area of strength is in developing bispecific antibodies. Unlike the antibodies that our bodies can make which use two identical arms of the Y shaped molecule to recognise and attach to only one biological target, these engineered antibodies can recognise and bind to two different targets, one on each arm of the Y. This can be useful to connect an immune cell to a cancer cell, helping the immune cell to attack the cancer cell, for example. Bispecific antibodies can also block two molecules that together would cause a disease, or to bind to two different soluble factors. Although the benefits of these bispecific antibodies have long been known in theory, actually making them in a consistent manner for clinical development has been a long engineering journey in practice.

To make it easier and more efficient to produce bispecific antibodies, gRED tackled a specific engineering problem: how to get the right antibody parts to assemble in the right way. Antibodies are made up of four parts: two heavy chains, running the entire length of the Y shape, and two light chains, which sit parallel to the heavy chains in the top half of the Y. In 1997, Genentech scientists unveiled a “knob-into-hole” system, where one heavy chain has a hole, or dent, in its structure, and the other heavy chain a matching knob that fits into that hole, so that the heavy chains only fit together in one particular way. But that still left the assembly of the light chains to chance. Roche scientists at pRED, building an internal bispecific antibody platform, proposed a creative solution to this problem in 2011, known as CrossMab, to ensure that all four antibody parts come together in only one particular way.

Combining CrossMab and knob and hole allows Roche scientists to build antibodies quickly, in a straightforward manner - like swapping in and out building blocks, explain Kettenberger and his colleague Stefan Weigand. Their team used this innovative combination to develop new treatment options.

Collectively, research efforts across Chugai, gRED, and pRED have led to the development of a number of approved bispecific antibody treatments and Roche continues to innovate in this area. Bispecifics can be used to increase efficacy by neutralizing more than one soluble target, by improving antibody interactions with specific immune cells or making sure that antibodies only act in the parts of the body where they are needed to combat the disease. Other approaches are designed to getting antibodies across the blood-brain barrier or bringing two targets into close proximity. Many more are expected to come.

This success shows the strength of the unique approach across the Roche Group to science and innovation: having multiple autonomous and independent innovation engines, gives us a rich diversity of expertise and scientific thinking. Each innovation engine has the freedom to independently decide where to focus, how to address the problem and the innovation path to follow. This autonomy enables us to tackle the big questions in healthcare from many angles, tailoring solutions to different scientific challenges, often hand-in-hand with equally passionate partners. Working together, we hopefully increase our chances of success to discover and develop further breakthroughs for people.

A single platform or set of tools does not drive which disease researchers try to treat next - instead, the biology driving the disease does. “Antibody engineering is a vehicle to the biology we want to tackle,” says Stefan. “We hope to build on our initial successes to get to a better outcome for patients.”