The human immune system relies on antibodies to fight disease and this response is controlled by Fc gamma receptors (FcγRs). Humans have several ‘activating’ receptors that serve as accelerators to drive the immune response. However, there is also an ‘inhibitory’ receptor which acts as a brake to keep the immune system from overreacting. This receptor is called FcγRIIB and was the focus of the current study.

The researchers developed specific antibodies to influence the function of this inhibitory receptor in different ways. So-called agonistic antibodies can activate the receptor and put a brake on the immune system, ideal for treating autoimmune diseases, where immune responses are too strong. The study also shows how so-called antagonistic antibodies can block the receptor, resulting in a stronger immune response, useful in cancer immunotherapy by helping the body fight tumours.

The research attracts strong interest from pharmaceutical companies: antibodies such as the ones investigated here are already in clinical trials led by BioInvent, a key contributor to this study. (https://www.bioinvent.com/en/clinical-programs/our-programs/bi-1607). “Pushing the immune brakes with agonistic antibodies is a promising strategy for restoring health in autoimmunity. This landmark paper, describing how to design such antibodies to activate FcγRIIB, is a logical continuation of the tailor-made antagonists we developed to boost cancer immunotherapy”, says Björn Frendéus, CSO of BioInvent.

“Despite the relevance of this receptor and the potential of targeting it for new therapies linked to our immune system, until now we didn’t know how to deploy the antibodies to be agonists or antagonists”, explains Hayden Fisher, scientist at the ESRF’s beamline BM29 and co-first author of the publication along with Emma Sutton.

An optimal tool for antibody research

Mark Cragg, Professor in Experimental Cancer Biology at the University of Southampton and part of the team, alongside Professors Jonathan Essex and Ivo Tews, explains how the ESRF proved crucial for their research: “We investigated how agonistic and antagonist antibodies differ when they bind to the extracellular part of FcγRIIB. The structural biology techniques we used at the ESRF allowed us to study the geometry and strength of the interaction, together with biophysical analysis. A crucial step was to translate this and study how receptors move on the cell surface to identify receptor clustering that links to signaling”.

“The information gained from the crystallographic structure determination at ID30A3 gave us the essential atomic information on molecular recognition", says Professor Ivo Tews, “and spawned further analysis using X-ray scattering techniques (BioSAXS) on BM29 with subsequent molecular modelling and analysis”.

“BioSAXS at BM29 is an incredibly powerful tool for antibody research because it allows us to study these highly flexible molecules in their near-natural state – in solution” says Fisher. “Antibodies aren’t static; they move, they flex, and they change shape when interacting with other molecules. BM29 allows us to capture that dynamic behavior and directly observe these changes in interaction with targets like FcγRIIB. It gives us a crucial perspective that you simply can’t get from a rigid crystal structure alone.”

The research on BM29 revealed that activating antibody complexes are compact while inhibitory complexes are elongated. “We then generated computational models of the strongest antagonist complex, based on crystallographic data, that was compared to and validated by experimental SAXS data from BM29”, says Professor Jon Essex.

Towards more precise immunotherapies

The findings showed that whether an antibody acts as an agonist or antagonist comes down to its binding geometry and binding strength (affinity). It also showed that agonistic antibodies bind to a specific region of FcγRIIB that groups the receptors into tight clusters on the cell membrane, allowing them to activate downstream signals. Antagonists bind tightly to a different face of the receptor, creating an elongated geometry that keeps receptors apart and physically prevents the clustering.

“The structural understanding from this research helps explain the mechanism behind antagonist drugs that are already in Phase 1 and 2 clinical trials for cancer, such as BI-1206 and BI-1607”, says Cragg. “The results can also help move the drug discovery process from trial-and-error towards rational design, which means we can engineer more potent and precise immunotherapies” he concludes.

Reference:

Fisher, H. et al, Immunity, in press, available online 25 June 2026. https://doi.org/10.1016/j.immuni.2026.05.019