Harnessing multivalency and FcγRIIB engagement to augment anti-CD27 immunotherapy

TL;DR

Researchers improved anti-CD27 immunotherapy by engineering antibodies with higher valency and FcγRIIB engagement, leading to better T cell activation and tumor-fighting effects.

Contribution

A novel strategy for enhancing anti-CD27 immunotherapy through tetravalent antibodies and FcγRIIB engagement is introduced.

Findings

Tetravalent anti-CD27 antibodies show potent T cell stimulation and anti-tumor efficacy in pre-clinical models.

Enhanced CD27 clustering and receptor polarization at the cell interface are key mechanisms of action.

The tetravalent antibodies activate CD8⁺ T cells without depleting regulatory T cells.

Abstract

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.

CD27 is a key T-cell costimulatory receptor, but efforts to target CD27 have been limited by the poor clinical efficacy of first-generation anti-CD27 antibodies. The authors here engineer higher-valency antibodies by more effectively engaging CD27 and selectively binding to FcγRIIB, which enhance anti-tumor activity.

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