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New study provides framework for optimising the design of antibody therapeutics

WIMM

An illustration showing the surfaces of two cells coming together, with one at the top of the image and one at the bottom. A purple molecule protruding downwards from the top 'cell' and a green molecule protruding upwards from the bottom 'cell' are both bound to the same yellow molecule in the middle of the image. A red molecule protrudes downwards from the surface of the bottom cell. There is a large blue molecule to the right of the image that can't 'fit' between the two 'cells' where the interaction with the yellow molecule is occurring. © Lippert et al. 2024
The interaction of an antibody (yellow), with both a T cell immune receptor (green, bottom cell) and an Fc receptor (purple) present on an adjacent cell (top), leads to the exclusion of large phosphatases (blue), from the contact. The exclusion of the phosphatases, which would normally reduce the activity of tyrosine kinases (red) in the contact, instead enhances downstream signalling.

New research, published in Immunity by the Davis (RDM, MRC TIDU), Cornall (NDM, MRC TIDU) and Klenerman (University of Cambridge) groups, has uncovered how antibodies trigger immune receptors in T cells. This breakthrough provides an improved framework for designing therapeutic antibodies, which could be used in new and better therapies for cancer and autoimmune diseases.

Communication between cells relies on the transmission of signals through receptors embedded in the cell surface. Specialised white blood cells called T cells have receptors on their surface that can influence how they behave during an immune response. It’s long been known that antibodies, when used like drugs, can activate these “immune receptors” to produce signalling, but not why they can do this.

Some immune receptors are inhibitory. Therefore, antibodies that trigger these receptors can switch off unwanted immune responses, for example in autoimmune diseases. On the other hand, using antibodies to block signalling by immune receptors has become a very important part of immunotherapy. Antibodies against molecules like PD-1 and CTLA-4 have revolutionized cancer treatment.

In this new study, researchers led by Dr Anna Lippert (Klenerman Group) and Dr Chris Paluch (Davis and Cornall Groups) have determined the mechanism by which these activating (or ‘agonist’) antibodies trigger immune receptors. Their work extends a principle of receptor triggering proposed in 2006 by Professor Simon Davis and Professor Anton van der Merwe (Sir William Dunn School) in Oxford.

Read the full story on the WIMM website. 

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