Anti-cancer antibodies were increased by reducing their grip

New research from the Center for Cancer Immunology shows that changing how tightly an antibody binds to a target could improve cancer treatment.

Antibodies detect and tag viruses and bacteria so that the body’s immune system can destroy them. To help prevent secondary infections our immune system fine-tunes these antibodies to have a strong grip on these targets, known as high affinity.

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Immunotherapy treatments for cancer use the same concept – directly targeting antibodies designed to detect and bind tightly to cancer cells so the immune system can kill them. These antibody therapies have proven successful for some cancers in the past few years, but many cancer patients still do not respond or become resistant.

In a new study published in nature, Southampton researchers have shown that a different type of therapeutic antibodies called “immunomodulatory antibodies” are successful in treating cancer when their grip is reduced.

Changing the tightness of the binding is called affinity engineering, and the research team believes it could provide a more effective, more flexible, way to treat cancer.

Immunomodulatory antibodies bind to receptors on immune cells rather than tumor cells and work by altering the signals transmitted to immune cells to make them more active and better at killing cancer cells.

In the study, the team examined three different receptors (CD40, 4-1BB and PD-1), and there was better clustering of the receptors and improved signaling to immune cells when the binding was loosened. For one of these, CD40, it has been shown to kill tumor cells.

Professor Mark Cragg, from the Center for Cancer Immunology, said: “Although the number of approved antibody drugs continues to grow, with more than 100 now in the clinic, some patients remain unresponsive to treatment. Therefore, developing new strategies to super-charge our antibodies through techniques such as affinity engineering is key to providing better treatments to patients.

“Our study suggests that by changing the affinity we can effectively fine-tune the antibody to the desired level and activity.

“Importantly, immunomodulatory antibodies target the same receptor on immune cells and therefore can in principle be used for many types of tumors, opening up more treatment opportunities for many people. The main applications are currently in oncology, but in principle the same approach for antibodies to treat autoimmune disorders and inflammatory diseases can be used.

Dr Xiaoji Yu, first author of the study and now an assistant professor in Westlake University’s School of Life Sciences, said: “High affinity binding has been the mantra of therapeutic antibody development for decades. The finding that a low affinity for antibody-mediated cellular signaling by immunomodulatory antibodies was favorable presents a powerful tool for developing new and more effective antibodies for the treatment of cancer and autoimmunity.

The study was funded by Cancer Research UK and the Cancer Immunology Fund, the university’s campaign to support the vital research being carried out at the centre, following a successful £25 million campaign to build the centre.

Catherine de Returto, associate director of development at the University of Southampton, said: “This exciting work is exactly what we had hoped for when we raised the funds to build the Cancer Immunology Centre. Many generous donors whose philanthropy has contributed to the centre, including those providing funding for the key equipment used in these experiments , the Southampton team should be very proud of the progress they are making.

Dr Ian Foulkes, Cancer Research UK’s executive director of research and innovation, said: “Cancer is a master at defying the immune system. We need to try many different strategies to help our bodies get rid of tumors and attack them.

“Immunomodulatory antibodies are one of the cornerstones of immunotherapy, which is quickly becoming a mainstay treatment in the clinic. But immunotherapy does not always work for everyone, and we must continue to refine it to ensure that it gives patients the best chance of a good outcome.”

“This research provides an exciting new approach to making antibody therapy work better and we hope to see it reach its full potential in the clinic in the future.”

Reference: Yu X, Orr CM, Chan HTC, et al. Affinity reduction as a strategy to promote immunomodulatory antibody agonism. Nature. 2023. doi: 10.1038/s41586-022-05673-2.

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