Scientists gain unprecedented insight into the key properties of antibody needed to combat cancer

Researchers at the University of Southampton have gained unprecedented new insight into the key properties of an antibody needed to fight off 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 important receptors on immune cells to "fire them up" and deliver more powerful anti-cancer effects.

The scientists believe their findings could pave the way to improve antibody drugs that target cancer as well as other automimmune diseases.

In the study, the team investigated antibody drugs targeting the receptor CD40 for cancer treatment. Clinical development has been hampered by a lack of understanding of how to stimulate the receptors to the right level. The problem being that if antibodies are too active they can become toxic.

Previous Southampton research has shown that a specific type of antibody called IgG2 is uniquely suited as a template for pharmaceutical intervention, since it is more active than other antibody types. However, the reason why it is more active had 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 harnesses 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 modifying the hinge and used a combination of biological activity assays, structural biology, and computational chemistry to study how disulfide switching alters antibody structure and activity.

Our approach was to analyse the structure of the antibody in atomic detail, using the method of X-ray crystallography. While the resulting picture 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-computing approach to analyze the data, using the Southampton High Performance Computing cluster IRIDIS."

Dr Ivo Tews, Associate Professor in Structural Biology, University of Southampton

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

Professor Mark Cragg, of the Centre for Cancer Immunology at the University of Southampton, said: "This study has given us new information about how to engineer antibodies to deliver a better immune response. We propose that more rigid antibodies enable the receptors to be bound closer together on the cell surface, promoting receptor clustering and stronger signalling for activity. This means by modifying the hinge we can now generate more or less active antibodies in a more predictable way.

"Excitingly, our findings could have wider implications as it may provide a highly controlled and tractable means 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 these studies.

Source:
Journal reference:

Orr, C.M., et al. (2022) Hinge disulfides in human IgG2 CD40 antibodies modulate receptor signaling by regulation of conformation and flexibility. Science Immunology. doi.org/10.1126/sciimmunol.abm3723.

Comments

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
Post a new comment
Post

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions.

You might also like...
Study identifies six cancer susceptibility genes