Harnessing multivalency and FcγRIIB engagement to augment anti-CD27 immunotherapy

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.