Title: Rapid, Sensitive Detection of Resistance to Therapeutic Antibodies Product Development
Funder: Department of Health and Social Care

Abstract: The proposed research aims to develop an in vitro diagnostic immunoassay technology comprising a novel synthetic bioluminescent reporter and a readout instrument for luminescent detection suitable for point of care testing. The assay platform will be rapid, sensitive and versatile, and is proposed for the measurement of patient antibody response to a broad range of potent biologic agents. Because of their antigenic nature as proteins, they are susceptible to neutralising antibodies raised by the patient. There is equal applicability to measurement of the antibody response to viral infection. Once the peptide sequence of any biologic agent is acquired, it is readily possible to design and produce an enzymic reporter molecule labelled antibody called GloBodyTM. New tests can be added using the same miniature instrument without optics/hardware changes, which makes it a suitable solution for therapeutic resistance tracking of emerging, expensive biologics, as well as for rapid testing for viral and other infectious disease. The number of patients being treated with biologic drugs is growing rapidly, most notably for autoimmune diseases. Whilst many biologics are humanised antibodies, they remain potentially immunogenic. The project will develop the testing platform for infliximab, adalimumab, golimumab and alemtuzumab. We expect add-on reporter development for these to be rapid and efficient, which would further allow us to add antibodies to ustekinumab (psoriasis) and vedolizumab (Crohn s/ulcerative colitis) ADAs as a stretch task. The project will also include a longitudinal study of patients and an expanded health economics evaluation. The planned start date is 01/11/2020 with completion at 36 months from this start date. Project planning and development at all stages will involve patient representatives, as well as clinical specialists (neurology, gastroenterology, surgery). Presentations will be made to patient groups, and outcomes also disseminated through publications and conferences.

Lay abstract: Antibodies are part of our immune system protecting us from damage due to foreign substances that enter the body. Thus, they can recognise and react to foreign proteins such as tailored antibodies used for therapy: biologic drugs. The immune response generated by the body here can neutralise the administered antibody and render it ineffective. To varying degrees, the patient s treatment then becomes ineffective. The project will develop a sensitive test giving rapid results directly at the point of care. It will allow testing of immune antibodies from the patient by means of a small, simple to use, low-cost device. Antibodies to be measured will be those against a biologic drug used to treat an autoimmune disease. Approximately four million people in the UK live with an autoimmune disease including IBD, RA and multiple sclerosis (MS). Specially designed antibodies have proven to be highly effective in severe cases, unless the patient develops resistance. Testing carried out at the point of care will allow for an early decision on whether to continue or to switch therapy. Such tailored antibodies are expensive, high-value-added drugs, amongst the costliest used by the NHS. The repeat use of such antibodies, when they no longer work, wastes resources and can also be harmful to the patient. Measurement of the patient s antibodies will be by means of single use probes on blood samples. The probes will have a surface that specifically attracts the patient antibody, to then emit a light signal. The amount of the signal produced will give a measure of the amount of the patient antibody in the blood sample. A novel, cheap and sensitive light detector will be used to detect the light signal. Different versions of the probe will allow different antibodies to be detected, beyond those for biologic drugs to those seen in viral diseases. The purchase price will be well below that of existing laboratory instruments. A steering group involving patients and lay members will oversee this project. The group will provide feedback and guidance on end user needs for ready access instrumentation no longer relying on laboratory measurements. The project will also communicate the wider healthcare opportunity to the wider public and patients using social media tools and blogs. Progress will also be reported through academic journals, public media and international conferences.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM