Optimisation of analytical methods for monitoring monoclonal antibody therapy in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis (UC). These chronic inflammatory conditions of the gastrointestinal (GI) tract can be successfully treated with the monoclonal antibody therapies Infliximab and adalimumab. However, low drug levels and immunogenicity (development of anti-drug antibodies) are associated with treatment failure. Therapeutic drug monitoring, using drug and anti-drug antibody measurements improves treatment outcomes. This thesis aims to optimise and understand the limitations of the most used assays for therapeutic drug monitoring of monoclonal antibody therapy in IBD. In Chapter 1 I determine lower positivity thresholds for the IDKmonitor® total infliximab and adalimumab antibodies; 9 and 6 AU/mL compared to the manufacturer’s threshold of 10AU/mL. Adalimumab drug levels were lower in the newly classified antibody positive group (median 8.1, interquartile range [IQR] 5.5-11.0 mg/L) compared to those below it (≤5AU/mL) (median 9.9, IQR 7.1-13.0 mg/L; P < 0.0001). These reclassified antibody-positive individuals were also more likely to be in primary non-response (25/68 [37%] vs. 64/332 [19%], P = 0.0035), and non-remission at week 54 (51/62 [82%] vs. 168/279 [60%], P = 0.0011). No differences were observed lowering the anti-infliximab threshold. This indicates that it is appropriate to lower the positivity threshold of the IDKmonitor® total adalimumab to 6AU/mL and this may give an earlier indication of clinically relevant immunogenicity. In Chapter 2 I found that pre-existing antibodies to infliximab and adalimumab in treatment naïve individuals are common 7.3% [95% CI 6.1 - 8.8] (112/1525), but do not neutralise drug activity in vitro, promote drug clearance or influence subsequent treatment response. This indicates that pre-existing antibodies are ‘false positives’ caused by analytical interference. 3 In Chapter 3 I found no evidence of anti-hinge antibody interference, confirmed that pre existing antibodies are not drug-specific and were not detected when using the drug sensitive IDKmonitor® ‘free’ antibody assay indicating that the false positive signal observed is related to the specific formulation of the ‘total’ assay. In Chapter 4 I demonstrate that patient-led capillary blood sampling has potential as a key adjunct to telemedicine for remote patient monitoring, offering a safe, reliable, convenient alternative to conventional venepuncture. I demonstrate equivalence and acceptability of capillary blood sampling compared to venepuncture for drug and anti-drug antibody testing. More than 87% [90/103] of patients stated intracapillary testing was easy and 69% [71/103] preferred it to conventional venepuncture.<p></p>

Author dc:creator

• Rachel Nice (21040325)

• IBD
• Crohn's
• UC
• Infliximab
• adalimumab
• TDM

Statement dc:rights

• All rights reserved

Identifier

10779/exe.32219961.v1

OAI identifier oai:identifier

oai:figshare.com:article/32219961