“Lower Antibody Affinity Improves Effectiveness of Immunotherapy for Cancer and Autoimmune Diseases”

Among the actors of the immune system, the antibodies locate and cling to the viruses and bacteria which infect our organism. They activate our defenses and allow the destruction of intruders. In order to optimize this mechanism in the event of subsequent infection by the same pathogens, the immune system produces antibodies whose “affinity” with their target – the strength with which they bind to it – is improved. Immunotherapy treatments for cancer use the same mechanism: antibodies designed to detect cancer cells and bind firmly to them in order to prevent their proliferation and destroy them are administered to patients. This approach has been shown to be relatively effective against certain tumours, but its results remain disappointing in many cases. However, recently, the team of Mark Cragg, at the University of Southampton, in the United Kingdom, showed that modulating the strength with which an antibody binds to its target would improve the effectiveness of immunotherapy. And surprisingly, for some antibodies, a lower affinity would be more efficient.

While the immune system is naturally capable of identifying, attacking and eradicating tumor cells, these produce an immunosuppressive microenvironment around them which exhausts the lymphocytes and drastically reduces their effectiveness. But we know how to produce a particular class of antibodies, called “immunomodulators”, which act directly on these lymphocytes rather than on the targets to be destroyed. These antibodies bind to target proteins chosen so that the binding modulates the signals transmitted to the lymphocytes so that they are more active and effective in the fight against tumor cells. This modulation involves an aggregation mechanism: not only do the antibodies bind to their receptors present on the surface of the immune cells, but they group them together on part of the cell membrane.

Mark Cragg and his colleagues wanted to understand what factors encourage aggregation. They therefore examined three receptors in particular: CD40, CD137 and PD-1 and the corresponding antibodies. In doing so, they noticed that antibodies with intermediate affinity were better able to aggregate receptors compared to their higher affinity counterparts. An observation consistent with the mechanism that drives the aggregation. In fact, for such aggregation to occur, the antibodies must bind to two receptors using their two arms, for a short time, and then repeat the operation. Thus, when the hold of the antibodies on the receptors is stronger, the binding is far too stable.

The researchers found that the action of antibodies with intermediate affinity on CD40 receptors did indeed have a greater antitumor effect in mice. By altering the strength of antibody binding to their target immune cell, biologists believe it would be possible to develop much more flexible and effective immunotherapy treatments for cancer and autoimmune diseases.

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