Researchers on the University of Southampton have gained unprecedented latest insight into the important thing properties of an antibody needed to fight off cancer.

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

The findings have enabled the Southampton team to design antibodies to activate essential receptors on immune cells to “fire them up” and deliver more powerful anti-cancer effects.

The scientists imagine their findings could pave the strategy to improve antibody drugs that focus on cancer in addition to other automimmune diseases.

Within the study, the team investigated antibody drugs targeting the receptor CD40 for cancer treatment. Clinical development has been hampered by a lack of awareness of find out how to stimulate the receptors to the fitting level. The issue being that if antibodies are too energetic they will develop into toxic.

Previous Southampton research has shown that a selected form of antibody called IgG2 is uniquely suited as a template for pharmaceutical intervention, because it is more energetic than other antibody types. Nevertheless, the rationale why it’s more energetic had not been determined.

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

This latest research harnesses this property of the hinge and explains how it really works: the researchers call this process ‘disulfide-switching’.

Of their study, the Southampton team analysed the effect of modifying the hinge and used a mixture of biological activity assays, structural biology, and computational chemistry to review how disulfide switching alters antibody structure and activity.

Dr Ivo Tews, Associate Professor in Structural Biology on the University of Southampton, said: “Our approach was to analyse the structure of the antibody in atomic detail, using the tactic of X-ray crystallography. While the resulting picture could be very accurate, the knowledge on how they move their ‘arms’ is missing, and we wanted a picture of the antibody in solution, for which we used an X-ray scattering approach called SAXS. We then used mathematical models and a chemical-computing approach to analyse the information, using the Southampton High Performance Computing cluster IRIDIS.”

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

Professor Mark Cragg, of the Centre for Cancer Immunology on the University of Southampton, said: “This study has given us latest details about find out how to engineer antibodies to deliver a greater immune response. We propose that more rigid antibodies enable the receptors to be certain closer together on the cell surface, promoting receptor clustering and stronger signalling for activity. This implies by modifying the hinge we are able to now generate kind of energetic antibodies in a more predictable way.

“Excitingly, our findings could have wider implications as it could provide a highly controlled and tractable technique of developing 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 that Southampton is partnered with were instrumental to those studies.

Source:

University of Southampton

Journal reference:

10.1126/sciimmunol.abm3723