Researchers at the University of Southampton have gained unprecedented new insights into the key properties of an antibody needed to fight cancer.
The interdisciplinary study, published in Sciences Immunologyrevealed how changing the flexibility of the antibody could stimulate a stronger immune response.
The findings enabled the Southampton team to design antibodies to activate important receptors on immune cells to ‘excite’ them and produce more potent anti-cancer effects.
The scientists believe their findings could pave the way for improved antibodies targeting cancer as well as other autoimmune diseases.
In the study, the team investigated antibodies targeting the CD40 receptor for the treatment of cancer. Clinical development has been hampered by a lack of understanding of how to stimulate receptors at the correct level. The problem being that if the antibodies are too active, they can become toxic.
Previous research at Southampton has shown that a specific type of antibody called IgG2 is particularly suited as a model for pharmaceutical intervention, as it is more active than other types of antibody. However, the reason why he is more active has not been determined.
What was known, however, is that the structure between the antibody arms, the so-called hinges, changes over time.
This latest research exploits 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 modification and used a combination of biological activity, structural biology and computational chemistry assays to investigate how disulfide switching alters the structure and l antibody activity.
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 The resulting image is very accurate, the information on how they move their “arms” is missing, and we needed an image of the antibody in solution, for which we used an X-ray scattering approach called SAXS. We then used mathematical models and a chemical computational approach to analyze the data, using the IRIDIS cluster from Southampton High Performance Computing.”
Through this detailed study of the hinge, the team revealed that antibodies that are more compact and rigid 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 insights into how to design antibodies to provide a better immune response. We propose that stronger antibodies allow receptors to be bound closer to the cell surface, promoting clustering of receptors and stronger signaling of activity. This means that by modifying the hinge we can now generate more or less active antibodies of more predictable way.
“Excitingly, our findings may have broader implications as they may 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. The collaboration with the Diamond Light Source in Oxford and the University of Hamburg, with which Southampton is a partner, has been instrumental in these studies.
University of Southampton