Southampton Researchers Engineer ‘Four-Pronged’ Antibodies to Boost Cancer Immunotherapy

Researchers at the University of Southampton have developed a novel approach to enhance the body’s immune response to cancer, utilizing specially engineered antibodies designed to more effectively activate cancer-killing T cells. The findings, published in Nature Communications, detail the use of multi-pronged antibodies that ‘grab’ and ‘cluster’ immune cell receptors, amplifying the signal for T cells to attack cancer.

The Challenge of T Cell Activation

The team focused on the CD27 receptor, a key component in T cell activation. CD27 requires a specific ligand to initiate an immune response. Even as this ligand is readily produced during infection, cancer cells often lack this signal, resulting in a weak T cell response. Existing antibody treatments, typically Y-shaped with two prongs, can engage only two receptors at a time, sometimes proving insufficient for full T cell activation.

A New Approach: Tetravalent Antibodies

The researchers engineered antibodies with four prongs, enabling them to bind to more receptors simultaneously. Crucially, these antibodies also work in conjunction with a second cell, inducing the CD27 receptors to cluster together. This clustering amplifies the activation signal, mimicking the natural process of CD27 activation within the body.

“We already understood how the body’s natural CD27 signal switches on T cells, but turning that knowledge into a medicine was the real challenge,” explains Professor Aymen Al‑Shamkhani, who led the study at the University of Southampton’s Centre for Cancer Immunology. “Antibodies are reliable molecules that produce excellent drugs. However, the natural antibody format was not powerful enough, so we had to create a more effective version.”

Enhanced Anti-Tumor Response

Laboratory studies, utilizing both mice and human immune cells, demonstrated that the new antibodies were more effective at activating CD8⁺ T cells – often referred to as the ‘special forces’ of the immune system – compared to standard antibodies. This resulted in a more robust anti-tumor response.

FcγRIIB Engagement and Receptor Clustering

Further research, also published in Nature Communications, highlights the importance of both multivalency (the four-pronged structure) and engagement of the FcγRIIB receptor in augmenting the anti-CD27 immunotherapy. The tetravalent antibodies, coupled with selective FcγRIIB association, exhibited potent T cell stimulation and anti-tumor efficacy in preclinical models. The mechanism involves efficient CD27 clustering and polarization of receptor clusters to the cell-cell interface, reducing receptor internalization.

Implications for Future Immunotherapies

By enhancing the responsiveness of CD27 to therapeutic targeting, these findings provide a foundation for developing next-generation immunotherapies that can more effectively harness the immune system to combat cancer. Professor Al‑Shamkhani suggests this approach “could help improve future cancer treatments by allowing the immune system to work closer to its full potential.”

The research was funded by Cancer Research UK and underscores the Centre for Cancer Immunology’s commitment to advancing innovative cancer immunotherapies.