Anti-Tumor Activity Enhances When Immunomodulatory Antibodies Loosen Their Grip

Higher affinity is the primary goal in the production of therapeutic monoclonal antibodies that directly bind to foreign proteins on pathogens or abnormal proteins on cancer cells. A new study published in Nature, highlights a different kind of immunomodulatory therapeutic monoclonal antibody that binds immune cells instead (agonistic antibodies), that exhibits higher anti-tumor activity when they have a looser grip on immune cell receptors.

The study “Reducing affinity as a strategy to boost immunomodulatory antibody agonism” conducted by researchers at the University of Southampton, U.K., uncovers an efficient and tunable strategy for treating various cancers by engineering affinity to augment antibody agonism across different families of immune receptors.

“High affinity binding has been the mantra of therapeutic antibody development for decades. The finding that low affinity was conducive to antibody-mediated cellular signaling by the immunomodulatory antibodies presents a powerful tool for developing new and more effective antibodies for treating cancer and autoimmunity,” said Xiaojie Yu, PhD, first author of the study and now assistant professor at the School of Life Sciences at Westlake University.

Whereas it is established that direct-targeting monoclonal antibodies that bind viruses, bacteria or cancer cells, benefit from a tight grip on the antigen, little is known about the role of affinity, or the tightness of binding, in the activities of immunomodulatory antibodies that fine-tune signal transduction that modulates the humoral immune response by binding receptors on the surface of immune cells to make them more active and better at killing cancer cells.

Immunotherapy treatments for cancer generally use direct-targeting monoclonal antibodies that are designed to find and tightly bind cancer cells, so that the innate and adaptive immune system can identify malignant cells and kill them. Such immunotherapy has revolutionized oncology over the last few years, but many cancer patients do not respond to targeted immunotherapies or soon become resistant to them.

The new findings indicate a different strategy for treating cancer through agonistic immunomodulatory antibodies by tweaking the strength or affinity with which they bind immune receptors. The investigators believe the strategy could offer an efficient and more flexible opportunity to treat cancer.

In the current study, led by Mark Cragg, PhD, professor of experimental cancer biology at the center for cancer immunology at the University of Southampton, researchers examined three immunologically important receptors across two receptor superfamilies: CD40, 4-1BB and PD-1. They found these receptors clustered better when the immunomodulatory antibodies bound to them loosely. In the case of the receptor CD40, this increased clustering improved its ability to activate immune cells, expand T lymphocytes in vivo, and kill tumor cells.

“Although the number of approved antibody drugs is continually increasing, with over 100 now in clinic, some patients remain unresponsive to the treatment. Therefore, developing new strategies to super-charge our antibodies through techniques such as affinity engineering is key to providing better treatments for patients,” said Cragg. “Our study suggests that by changing the affinity we can effectively fine tune the antibody to the desired level and activity.”

“Immunomodulatory antibodies target the same receptor on immune cells and so can in theory, be used for very many different types of tumors, opening up more treatment opportunities for more people. The main applications currently are in oncology, but in principle the same approach could be used for antibodies treating autoimmune disorders and inflammatory diseases,” added Cragg.

The study was funded by Cancer Research UK and Southampton University’s Cancer Immunology Fund.

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