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Harnessing natural killer cells for autoimmune disease

Monoclonal antibodies (Mabs) are of increasing importance in the treatment of cancers and autoimmune conditions such as non-Hodgkin's lymphoma (NHL) and rheumatoid arthritis (RA). However, some Mabs are more effective than others in targeting diseased cells.
Harnessing natural killer cells for autoimmune disease
Antibodies trigger the natural killer (NK) cells of the immune system to directly kill diseased target cells (B cells) through antibody-dependent cell cytotoxicity (ADCC). However, the molecular dynamics of ADCC and the means by which engineered Mabs induce ADCC have remained unclear.

The EU-funded ADCC project has imaged immune synapses (IS) during antibody-mediated killing to provide insight into designing antibodies for optimised treatment.

ADCC project members used state-of-the-art high-resolution microscopies to image IS and develop model systems. Rituximab was as it is a powerful Mab that mediates B cell depletion by targeting CD20 protein on the B cell surface. The drug works by triggering NK cells to kill diseased B cells coated with rituximab.

IS imaging revealed important structural changes that control immune cell communication during antibody-mediated killing. The behaviour of human B and NK cells co-cultured with rituximab was studied. This drug caused CD20 clustering leading to B cell polarisation. This polarisation effect was not seen in other drugs that targeted the CD20 proteins on B cells. The polarisation of B cells could explain the higher efficacy of rituximab in mediating ADCC.

ADCC project outcomes have revealed an important aspect in Mab drug design: cellular polarisation. Promising antibodies could be screened for their ability to induce cellular polarisation and modify target antigen organisation for better ADCC. The ability to induce polarisation could therefore be a predictor for drug efficacy in targeted treatment.

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