The Molecular Landscape of Anti-Drug Antibodies (ADA) Following Treatment with Monoclonal Antibodies

Since the commercialization of the first therapeutic monoclonal antibody (mAb) in 1986 more than forty mAbs have been approved in the US or Europe. However, these potent bio-therapeutics can be highly immunogenic and even induce undesirable immune responses leading in anaphylaxis and occasionally life threatening autoimmunity. Moreover, the immunogenic response, mainly governed by the production of anti-drug-antibodies (ADA), alters drug pharmacokinetics or pharmacodynamics that in turn reduces drug efficacy and bioavailability. The TNF-a antagonist, Infliximab is routinely used to treat certain types of arthritis, inflammatory bowel diseases, and psoriasis. However, up to 40% of treated patients who initially respond to Infliximab lose response to the drug due to the development of ADAs. We have used Infliximab as a model to investigate molecular aspects related to the development of ADAs. Initially, we developed a new simple, accurate, sensitive immunoassay to quantify ADAs following Infliximab infusion. The developed immunoassay utilizes a modified variant of the drug, enabling the detection of serum ADAs while maintaining low background signals. Further modification of the immunoassay provides qualitative measures of the neutralizing capacity of ADAs in a given patient sample. Next, the immune response following Infliximab infusion was investigated. We have found that Infliximab mounts a vaccine like response reflected in a rapid rise of peripheral lymphocytes 7-10 days post infusion. Infliximab-specific lymphocytes were isolated and their repertoire features were determined by ultra deep sequencing. Collectively, we will describe the tools and data that provide means to profile and monitor the molecular landscape of ADAs. Ultimately, the developed immunoassay and data can be used to monitor the development of ADAs against other therapeutic mAbs and facilitate improved medical intervention.