Title: Investigation of the analytical & clinical validity of anti-drug antibody assays in patients on anti-TNFa therapy for inflammatory bowel disease.
Funder: Health Education England

Abstract: Background Inflammatory bowel diseases (IBD) are incurable, chronic inflammatory conditions of the gastrointestinal tract affecting over 300,000 people in the UK. Biologic drugs infliximab and adalimumab have transformed IBD management, reducing inflammation in the gut resulting in mucosal healing. Treatment failure is common however, with some patients experience primary non-response (PNR), others loss of response over time (LOR) or adverse drug reactions (ADR) requiring treatment to be curtailed. Immunogenicity causes treatment failure, with pre-treatment antibodies present in patients before therapy and anti-drug antibodies (ADAs) generated during treatment reducing drug efficacy and safety. ADA populations are heterogeneous and different modes of action may be clinically relevant. Therapeutic drug monitoring (TDM) of drug and ADA levels is used to guide clinicians, however there is no consensus or standardisation of testing. There is disparity between the use of drug-tolerant (total) and drug-sensitive (free) ADA assays, more evidence is required for optimal methods and testing strategies as recommended by NICE diagnostic guideline 22 (DG22). Aim To establish the optimal analytical methods and testing strategies for investigating immunogenicity to infliximab and adalimumab in IBD. Objectives To perform interference experiments to determine the accuracy of drug and ADA assays in the presence of ADA and drug respectively. To determine the diagnostic utility of free versus total antibody titres and/or their function to predict treatment failure outcomes. To determine the optimal analytical method for detection of pre-treatment antibodies to infliximab and adalimumab and their significance in relation to treatment failure.Methods Study 1: Interference experimentsAssessment of the invitro performance of i) drug level, ii) free ADA, iii) total ADA ELISA assays to detect drug in the presence of ADA and vice-versa comparing % analyte recovery from spiked samples compared to baseline (un-spiked samples). Study 2: Investigating free, total and functional anti-drug antibody assaysInvestigation of the relationship between both free and total ADA titre with drug level and treatment outcome to determine which is most clinically useful in a large longitudinal prospective cohort study (n=9500). Analysis of positive ADA samples using a cell-based assay to detect and quantify neutralising antibodies followed by correlation of ADA type with treatment outcomes. Study 3: Investigating pre-treatment antibodiesUse of a commercially available total ADA and specific pre-existing antibody ELISA assays for detection and quantification of pre-treatment antibodies in a large cohort of IBD patients before treatment (n=1610). Correlation of pre-treatment antibody titre with treatment outcomes including PNR, LOR and ADRs. Anticipated impact and dissemination Optimising analytical methods for ADA quantification and characterisation will allow meaningful interpretation of drug and ADA concentrations for clinicians thus improving treatment outcomes. Detecting pre-treatment antibodies before treatment will allow clinicians to predict drug efficacy and safety, enabling targeted use of immunomodulators and treatment based on the risk/benefit profile for the individual. Outcomes of this research will be communicated back to NICE and to clinical and academic communities through publication in peer reviewed journals and presentations at scientific conferences. Clinically relevant findings will be communicated on the Exeter IBD research and Exeter laboratory websites.

Lay abstract: This project is aimed at investigating the best laboratory tests for monitoring people suffering from a condition known as inflammatory bowel disease (IBD) who are being treated with a type of medicine called a 'biologic' such as infliximab and adalimumab. Inflammatory bowel disease includes Crohn's disease and ulcerative colitis; these are long-term conditions involving inflammation of the gut affecting over 300,000 people in the UK. Symptoms of IBD include abdominal pain, diarrhoea, weight loss and extreme tiredness. There is currently no cure for IBD, and damage to the digestive system caused by ongoing inflammation can result in patients requiring an operation to remove the damaged section of the gut. The drugs infliximab and adalimumab are used to treat patients with severe cases of Crohn's disease or ulcerative colitis as a final option when other types of medicine have been tried but have not worked. For most patients these drugs work very well at reducing inflammation and making symptoms better. In some cases, however they can have serious side effects and are very expensive for the NHS (costing over 500 million pounds per year in the UK) it is therefore very important that these drugs are used when they are most likely to work and least likely to harm patients. For some IBD patients these drugs never work, this is called primary non-response. For other patients treated with these drugs they start off working well with symptoms getting better, then the drug stops working, and the disease gets worse again; this is called secondary loss of response. One of the main causes of loss of response is when a patient's immune system sees the drug as a potential threat rather than a medicine, and makes proteins called antibodies against the drug which stop it working. In the last few years doctors have started sending blood samples to laboratories to test drug levels, and to detect if the drug is being rejected by the body by measuring antibodies in patients' blood. This is called therapeutic drug monitoring and it informs the healthcare team if the drug is working or if it needs to be stopped or swapped. This prevents the patient's disease getting worse and avoids wasting a very expensive drug. Some patients might have antibodies in their blood before treatment which stops them working or leads to loss of response or side effects; if we could test for these antibodies before treatment doctors could use a different medicine which is more likely to work and cause less harm to the patient. This research project will investigate the best way for the NHS to test if a patient has the right drug level and if antibodies are present Different laboratories use different types of tests for therapeutic drug monitoring and there is no agreement on which way is best. This project will investigate the laboratory methods for monitoring, to ensure the most accurate way of testing is being used in the NHS to maximise treatment looking at the following areas: What are the best tests to monitor patients during treatment, so that doctors can make decisions about the best drugs to treat them with, and how much to give them. What is the best way to test a person before receiving treatment for the first time, to see if they have antibodies which might stop infliximab and adalimumab working properly? This would save money for the NHS and would result in better patient outcomes.The outcome of this work will inform best practise for therapeutic drug monitoring tests for infliximab and adalimumab in the UK.

Research activity codes: 6.1 PHARMACEUTICALS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: ORAL AND GASTROINTESTINAL