Scientists analyze antibodies structure that could be key to combat cancer

UK: 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 autoimmune 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 is that if antibodies are too active they can become toxic.

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

The approach was to analyze 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 said the authors.

They concluded that this study has given new information about how to engineer antibodies to deliver a better immune response. They propose that more rigid antibodies enable the receptors to be bound closer together on the cell surface, promoting receptor clustering and stronger signaling for activity paving the path for cancer treatment.

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The study titled, "Hinge disulfides in human IgG2 CD40 antibodies modulate receptor signaling by regulation of conformation and flexibility," was published in the journal Science Immunology. 

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