Antibody structure may be the key to more effective cancer treatment

The flexible hinge allows the two antibody arms to move freely, reducing receptor activity.Credit: University of Southampton

Researchers at the University of Southampton have gained unprecedented new insights into the key properties of antibodies needed to fight cancer.

The Interdisciplinary researchWas announced in Scientific immunologyClarified how to stimulate a stronger immune response by changing the flexibility of the antibody.

The findings have allowed the Southampton team to design antibodies that activate key receptors. Immune cells “Launch them” and provide a stronger anti-cancer effect.

Scientists believe their findings can pave the way for improving antibody drugs that target cancer and other autoimmune diseases.

In this study, the team investigated antibody drugs that target the receptor CD40 for the treatment of cancer. Lack of understanding of how to stimulate receptors to appropriate levels has hampered clinical development. The problem is that if the antibodies are too active, they can become toxic.

Previous Southampton Study A particular type of antibody, called IgG2, has been shown to be uniquely suitable as a template for drug intervention because it is more active than other types of antibodies. However, it was not determined why it was more active.

However, it is known that the structure between antibody arms, the so-called hinges, changes over time.

Scientists analyze antibody structures that may be key to more effective cancer treatments

Rigid hinges with disulfide bonds (yellow) keep the two antibody arms constrained, resulting in stronger receptor activity.Credit: University of Southampton

This latest study takes advantage of this property of hinges to explain how it works. Researchers call this process “disulfide switching.”

In their study, the Southampton team analyzed the effect of changing the hinge and used a combination of bioactivity assays. Structural biologyWhen Computational chemistry Study how disulfide switching alters the structure and activity of antibodies.

Dr. Ivo Tews, an associate professor of structural biology at Southampton University, said: “Our approach was to analyze the structure of the antibody in atomic detail using X-ray crystallography methods. Missing information about how they move their” arms “. I needed an image of the antibody in the solution. To that end, we used an X-ray scattering approach called SAXS. Next, we analyzed using a mathematical model and a chemical calculation approach. Data using the Southampton High Performance Computing Cluster IRIDIS. “

Through this detailed study of hinges, the team found that more compact and rigid antibodies are more active than flexible antibodies.

Professor Mark Crag of the Center for Cancer Immunology, University of Southampton, said:Closer to Cell surface, Promotes receptor clustering and stronger signaling of activity. This means that changing the hinge can produce more or less active antibodies in a more predictable way.

“Excitingly, our findings have broader implications as they may provide a highly controlled and manageable means of developing antibodies. Clinical use With future immunostimulatory antibody drugs. ”

A “switch” that turns autoimmune drugs into powerful anti-cancer treatments

For more information:
Christian M. Orr et al, a hinged disulfide of human IgG2 CD40 antibody, regulates receptor signaling by regulating conformation and flexibility. Scientific immunology (2022). DOI: 10.1126 /sciimmunol.abm3723..

Quote: The structure of the antibody is obtained from on July 8, 2022 for more effective cancer treatment (2022). May be key (July 8th)

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Antibody structure may be the key to more effective cancer treatment

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