Researchers analyze the structure of antibodies that may hold the key to more effective cancer treatments

Researchers at the University of Southampton have gained unprecedented new insight into the key properties of an antibody needed to fight cancer.

The interdisciplinary study, published in Science Immunology, revealed how changing the flexibility of the antibody could stimulate a stronger immune response.

The findings have enabled the Southampton team to design antibodies to activate key receptors on immune cells to “jack up” them and deliver more potent anticancer effects.

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

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

Last Southampton investigation has shown that a specific type of antibody called IgG2 is ideally suited as a template for pharmaceutical intervention because it is more active than other antibody types. However, the reason why it is more active was not established.

It was known that the structure between the antibody arms, the so-called hinges, changes over time.

This latest study takes advantage of this property of the hinge and explains how it works: the researchers call this process “disulfide switching.”

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

dr. Ivo Tews, associate professor of structural biology at the University of Southampton, said: “Our approach was to analyze the structure of the antibody in atomic detail using the method of X-ray crystallography. Although the resulting image is very accurate, information about how they move their ‘arms’, and we needed an image of the antibody in solution, for which we used an X-ray scattering method called SAXS, and then we used mathematical models and a chemical computational approach to analyze the data, using the Southampton High Performance Computing cluster IRIDIS.”

Through this detailed study of the hinge, the team revealed that more compact, stiffer antibodies are more active than their flexible counterparts.

Professor Mark Cragg, from the Center for Cancer Immunology at the University of Southampton, said: “This study has given us new information on how we can develop antibodies to deliver a better immune response. We propose that stiffer antibodies make it possible that the receptors are bound closer together on the cell surface, promoting receptor clustering and stronger signaling for activity, meaning that by adjusting the hinge we can now generate more or less active antibodies in a more predictable way.

“It’s exciting that our findings could have broader implications as it could provide a highly controlled and tractable way to develop antibodies for clinical use in future immunostimulatory antibody drugs.”

The study was funded by Cancer Research UK and brought together structural biologists, immunologists, chemists and computer experts from across the university. Collaboration with the Diamond Light Source in Oxford and the University of Hamburg with which Southampton collaborates was essential for these studies.

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