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Updated: Jan 7, 2026
Assessment of Human Natural Killer Cell Events Driven by FcγRIIIa Engagement in the Presence of Therapeutic Antibodies
Published on: May 22, 2020
Harnessing multivalency and FcγRIIB engagement to augment anti-CD27 immunotherapy
Marcus A Widdess1, Anastasia Pakidi1, Hannah J Metcalfe1
1Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
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.
Insights
Engineered tetravalent anti-CD27 antibodies enhance T cell activation and anti-tumor immunity by increasing antibody valency and Fc receptor engagement. This strategy improves T cell stimulatory therapies against cancer.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Checkpoint blockade immunotherapy shows promise but faces limitations like resistance and toxicity.
- Activating costimulatory receptors is a potential strategy to boost anti-tumor immunity.
- Mimicking physiological membrane-anchored costimulatory ligands requires further investigation.
Purpose of the Study:
- To develop effective agonists for the costimulatory receptor CD27.
- To enhance anti-tumor immunity by engineering antibody properties.
- To understand the mechanisms behind improved agonist efficacy.
Main Methods:
- Engineering tetravalent anti-CD27 antibodies with enhanced FcγRIIB engagement.
- Evaluating T cell stimulatory activity and anti-tumor efficacy in pre-clinical models.
- Investigating the mechanistic effects of antibody valency and FcγRIIB interaction on receptor clustering and internalization.
Main Results:
- Tetravalent anti-CD27 antibodies demonstrated potent T cell stimulation and anti-tumor efficacy compared to bivalent versions.
- Anti-tumor effects were mediated by CD8+ T cell activation without depleting regulatory T cells.
- Increased avidity enhanced CD27 clustering, while FcγRIIB engagement promoted cluster polarization and reduced internalization.
Conclusions:
- Engineered tetravalent antibodies targeting CD27 offer a promising approach for enhancing T cell-mediated anti-tumor immunity.
- The combination of increased antibody valency and FcγRIIB engagement represents a viable strategy for developing novel immunotherapies.
- This work provides a framework for designing next-generation agonist-based T cell stimulatory therapies.
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