Harnessing multivalency and FcγRIIB engagement to augment anti-CD27 immunotherapy
- Marcus A. Widdess
- Anastasia Pakidi
- Hannah J. Metcalfe
- H. T. Claude Chan
- Tatyana Inzhelevskaya
- Chris A. Penfold
- C. Ian Mockridge
- Steven G. Booth
- Sonya James
- Sean H. Lim
- Stephen A. Beers
- Mark S. Cragg
- Aymen Al-Shamkhani
2025-12-20
Despite significant clinical progress, checkpoint blockade remains limited by variable response rates, resistance, and toxicity. Activating costimulatory receptors offers a promising alternative to enhance anti-tumor immunity. However, there is insufficient understanding of how to mimic physiological membrane-anchored costimulatory ligands. Here, we describe a strategy for developing effective agonists of the costimulatory receptor CD27 by increasing both antibody valency and FcγRIIB engagement. Engineered anti-CD27 antibodies capable of tetravalent binding to CD27 and selective FcγRIIB association exhibit potent T cell stimulatory activity and anti-tumor efficacy in pre-clinical models, compared to bivalent counterparts. The anti-tumor effects of the tetravalent antibody are mediated through CD8⁺ T cell activation without evidence of regulatory T cell depletion. Mechanistically, whereas the increase in avidity drives more efficient CD27 clustering, FcγRIIB engagement triggers polarization of receptor clusters to the cell-cell interface and reduces receptor internalization. This work provides a framework for developing more effective agonist-based T cell stimulatory therapies.