ANTIBODIES TO INFLIXIMAB IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE: CLINICAL AND MOLECULAR TARGETS

Infliximab was the first biological therapy to be approved for use in inflammatory bowel disease (IBD). Similar to other biological therapies, secondary loss of response to infliximab occurs in up to 50% of patients at 1 year follow up. In the case of infliximab, antibodies to infliximab (ATI) are likely to contribute towards secondary loss of response. This PhD thesis aims to identify the associated clinical outcomes of ATI, assess a strategy of infliximab dose escalation (DE) and to identify epitopes on infliximab using phage display. In a retrospective review of 214 patients, ATI were detected in 64% of patients during the first year of infliximab treatment. They were significantly associated with loss of clinical response, reduced infliximab levels and adverse drug reactions. Assessment of infliximab DE in 92 patients with subtherapeutic drug levels, showed it was effective at significantly increasing infliximab levels in those with and without ATI. DE was also associated with a high rate of clinical remission at 6 months. Pooled sera from eight patients with positive ATI and differing clinical outcomes was used for biopanning of two phage display libraries. Three distinct linear epitopes were heavily enriched from a novel whole gene fragment library (GFL), all mapped to complementarity determining regions of infliximab. Using a random peptide library (RPL), three different peptides were enriched. Using Pepsurf, a mimotope prediction programme, three conformational epitopes were predicted using the enriched peptides. One of the predicted epitopes from the RPL overlapped with a linear epitope selected from the GFL. In increasing our understanding of immunogenicity to infliximab, this may lead to an identification of an epitope associated with loss of response, a biomarker, and will help aid treatment decisions when ATI are detected