Human antibodies, immunoglobulin proteins, Immune system
Credit: Gilnature/Getty Images

Researchers from the University of Southampton in the U.K. have used a process called affinity engineering to show that immunomodulatory antibodies, a type of therapeutic antibody that can be used in cancer treatment, work better when less tightly bound to their targets.

The finding is in contrast to naturally-occurring or direct-targeting therapeutic antibodies which work best when they bind tightly to their targets, explained senior author Professor Mark Cragg, from the Centre for Cancer Immunology.

In nature, antibodies increase their affinity for their targets during an immune response – becoming tighter binding,” he said. This observation prompted researchers making therapeutic antibodies to mimic this process to generate high affinity antibodies.

Cragg noted that although this has been effective for directtargeting antibodies that, as the name suggests, directly target the tumor, the impact of binding strength has not been explored for other types of therapeutic antibody such as immunomodulatory antibodies. These work by binding to immune cell receptors rather than tumor receptors and then altering the signals that are transmitted to the immune cells to make them more active and effective at targeting and killing cancer cells.

To address this, Cragg and team initially focused on monoclonal antibodies targeting the tumor necrosis factor (TNF) receptor CD40, which is a potential target for cancer immunotherapy. Preclinical studies have shown that anti-CD40 agonists can promote dendritic cell maturation and improve their antigen presentation capabilities, which in turn can lead to the expansion of tumor antigen-specific cytotoxic T cells and the eradication of tumors.1

However, human anti-CD40 monoclonal antibodies (mAbshave displayed only modest anti-tumor activity in clinical trials among people with cancer and were characterized by low efficacy and dose-limiting toxicity.

In the current study, published in Nature, the researchers showed that reducing the affinity anti-CD40 mAbs inducedhigher levels of CD86 expression—a marker of dendritic cell activation—in human cells than did the higher affinity antibodies they were derived from. They determined that the effect was mediated through increased receptor clustering.

Next, the investigators explored whether the low-affinity-mediated agonism observed with anti-CD40 mAbs applied 4-1BB, another TNF receptor of interest in cancer immunotherapy. They generated low-affinity variants for utomilumab, an anti-4-1BB mAb that has not previously been shown to induce receptor clustering or activity.

Again, they showed that the low-affinity variant induced significantly higher levels of immune cell activation than the unmodified mAb, which was inactive.

Finally, Cragg and colleagues looked outside of the TNF receptor family to the clinically important immune checkpoint receptor PD-1. They created a low-affinity variant of nivolumab, which is routinely as an immune checkpoint inhibitor and has significant efficacy against many solid cancers. Cell-based experiments revealed that the low-affinity variant induced more potent PD-1 signaling and T cell suppression than unmodified nivolumab, suggesting that low-affinity targeting could be a general strategy to enhance receptor signaling beyond just TNF receptors.

Taken together the results indicate that “affinity engineering offers a broadly applicable, tractable, rational and highly tuneable solution to deliver desired antibody-mediated receptor activity, whereby a range of affinities mediate diverse activities suitable for translation in the human disease setting,” the authors conclude.

Cragg said that “the good thing about this approach is that it doesn’t target a specific neoantigen on the tumor cellswhich can be unique to each tumor, and so doesn’t need personalization and can be used in many different types of cancer.”

He added that affinity engineering could be used “to develop antibodies that are more effective at stimulating immune receptors, for example, in cancers where there is lots of immune suppression that needs reversing.

The team now plans to test the impact of affinity engineering in other antibodies against other receptors and look at combining this with other approaches to augment immunomodulatory antibodies.

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