Researchers analyzed the structure of antibodies that could be key to more effective cancer treatments

Researchers at the University of Southampton have gained unprecedented new insights into the key properties of antibodies needed to fight cancer.

The interdisciplinary study, published in Science Immunology, reveals how changing the flexibility of antibodies can stimulate a stronger immune response.

These findings enabled the Southampton team to design antibodies to activate important receptors on immune cells to “turn them on” and provide a more potent anti-cancer effect.

The scientists believe their findings could pave the way for improving antibody drugs that target cancer as well as other autoimmune diseases.

In the study, the team investigated antibody drugs that target the CD40 receptor for cancer treatment. Clinical development is hampered by a lack of understanding of how to stimulate receptors to appropriate levels. The problem is that if the antibodies are overactive, they can become toxic.

Previous Southampton studies have shown that a specific type of antibody called IgG2 is uniquely suited as a template for pharmaceutical intervention, as it is more active than other types of antibodies. However, the reason why it is more active has not been determined.

What is known, however, is that the structure between the antibody arms, called hinges, changes over time.

This new study takes advantage of this hinge property and explains how it works: the researchers call this process ‘disulfide transfer’.

In their study, the Southampton team analyzed the effect of hinge modification and used a combination of biological activity assays, structural biology, and computational chemistry to study how disulfide switching alters antibody structure and activity.

Dr Ivo Tews, Associate Professor in Structural Biology at the University of Southampton, said: “Our approach was to analyze the antibody structure in atomic detail, using X-ray crystallographic methods. While the resulting images are highly accurate, information about how they move their ‘arms’ is lost, and we need images of antibodies in solution, for which we use an X-ray scattering approach called SAXS. We then used a mathematical model and a computational chemical approach to analyze the data, using the Southampton IIRDIS High Performance Computing cluster.”

Through a detailed study of this hinge, the team revealed that the denser and stiffer antibodies were more active than their flexible counterparts.

Professor Mark Cragg, from the Center for Cancer Immunology at the University of Southampton, said: “This research has provided us with new information on how to engineer antibodies to provide a better immune response. We propose that more rigid antibodies allow receptors to bind more closely together on the cell surface, promoting receptor clustering and stronger signaling for activity. This means that by modifying the hinge, we can now produce more or less active antibody in a more predictable way.

“Excitingly, our findings could have broader implications as they could provide a highly controlled and easy way to develop antibodies for clinical use in future immunostimulator antibody drugs.”

The study was funded by Cancer Research UK and brought together structural biologists, immunologists, chemists and computer scientists from across the University. The collaboration with the Diamond Light Source at Oxford and the University of Hamburg in partnership with Southampton was instrumental in this study.

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