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Novel targeting of disease causing cells could transform treatment of autoimmune diseases

24 May 2017

There is a problem with the traditional treatment of autoimmune and inflammatory conditions. Steroid therapy doesn’t always work, and immunosuppressant drugs can have toxic side effects. Bristol researchers, with the help of an award from the Elizabeth Blackwell Institute, are working to overcome this using novel ways of targeting disease causing cells.

Dr Richard Lee and his team at the School of Clinical Sciences are exploring technology used in cancer therapy to target steroid-resistant immune cells and avoid damaging healthy non-immune tissues. This involves combining the active therapeutic agent (in this case an immunosuppressant) with a monoclonal antibody that targets a protein (antigen) specifically found on disease causing cells. These powerful therapeutic pairings are known as antibody drug conjugates (ADCs).

An EBI Translational Acceleration and Knowledge Transfer (TRACK) Award enabled Dr Lee and his team to gather crucial data with which to explore the potential of this technology. TRACK offers funding for health research that offers commercial promise or could translate into clinical practice.

The team had already identified a group of steroid-resistant immune cells as candidates for therapeutic targeting in a range of inflammatory conditions. They now proposed to deliver a calcineurin inhibitor in an ADC directed at a cell surface protein (CCR6) which they had identified as particular to steroid resistant cells.  

To get the pilot data needed to develop this further, researchers partnered with a University College of London spinout, Polytherics (now Abzena), to produce the ADC. Their project is also being developed in partnership with US National Institutes of Health.

First, they needed to confirm that the reaction between the antibody and target protein would cause the antibody to be internalised (ie absorbed into the cell). They then planned to test the effectiveness of the ADC in suppressing the cell.

Dr Emily Williams ran the lab work involving in vitro tests on cultures of human CD4+T cells. The results confirmed internalisation of the antibody and also recycling of the target protein onto the cell surface, crucial for repeated dosing of target cells.

Work with Polytherics established tacrolimus as the preferred immunosuppressant drug for the ADC. The researchers then tested the effectiveness of the ADD by incubating cells in the absence or presence of the antibody alone, tacrolimus only or a precursor of the ADC at different doses.

The study showed that while they had succeeded in creating an ADC with tacrolimus, free tacrolimus was not being released into the cell. This required further work with Polytherics to change the binding agent before they could test its effectiveness as a therapeutic agent.

The work resulted in a US patent application by the University of Bristol for ADCs for steroid refractory inflammatory disease. Discussions are continuing with potential commercial partners.

The University of Bristol featured the project as a vignette in a successful MRC Confidence in Concept proposal and is exploring forming a spin-out company with Imperial Innovations.

The research team has also secured a second grant from the Research and Enterprise Development (RED) Enterprise and Impact Development Fund. This is allowing further in vitro evaluation of the ADC, but also in vivo testing in humanised mice.

‘This technology could allow targeted treatment without associated toxicity, improve and save patients’ lives and reduce the burden on the NHS. Once validated there would be the opportunity to expand it to the full spectrum of steroid refractory conditions, such as multiple sclerosis, psoriasis, rheumatoid arthritis and inflammatory bowel disease.’

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