When less is more: reducing immunomodulatory antibody affinity boosts anticancer activity
Researchers discover that some low-affinity immunomodulatory antibodies have greater anticancer activity than those with high affinity.
Antibodies’ ability to bind specifically and tightly to target biomolecules makes them ideal therapeutics for a range of diseases including cancer; but is tight always best? Researchers from the University of Southampton (UK) have found that for some immunomodulatory antibodies, reducing their affinity actually boosted antitumor activity.
“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,” commented Mark Cragg, corresponding author of the study.
Most anticancer antibody therapeutics work by binding directly and tightly to antigens on cancer cells, flagging them for the immune system to kill. However, some antibody therapeutics, called immunomodulatory antibodies, work by binding to receptors on immune cells to modulate the signals that are transmitted to the cells and increase their cancer-killing activity.
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While the importance of high affinity in direct-binding antibodies is well reported, little is known about the affinity–function relationship in immunomodulatory antibodies. To address this, the team engineered antibodies with different affinities and studied the activity when they bind to three separate immunologically important immune cell receptors – CD40, 4-1BB and PD-1.
In a series of in vitro and in vivo mouse studies, they found that the antibodies with lower affinity delivered greater activity due to increased receptor clustering. For example, the lower affinity anti-CD40 antibody delivered higher immune-cell activation, in vivo T-cell expansion and antitumor activity. Low-affinity variants of the anti-PD-1 monoclonal antibody nivolumab, which is used to treat a number of cancers including melanoma and lung cancer, also mediated more potent signaling and increased T-cell activation.
This research could help improve current and develop novel anticancer therapies and could be applied to other diseases. “Importantly, 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,” explained Cragg.
