Insight into mechanisms of immunogenicity following treatment with therapeutic monoclonal antibodies

Over 30 years since the approval of the first therapeutic monoclonal antibody (mAb) for clinical use, the therapeutic mAb industry has expanded exponentially and is the fastest growing class of pharmaceutics. While mAbs hold significant promise for improving human health, repeated administration of therapeutic mAbs often leads to the induction of undesirable Anti-Drug Antibodies (ADA), which can interfere with or neutralize the effect of the drug. The generation of ADA towards mAbs can also be associated with important clinical adverse reactions, including alterations in drug pharmacokinetics and bioavailability, reductions in drug efficacy, cross-reaction with endogenous proteins and inhibition of the latter`s physiological function, and allergic drug reactions. We aimed to address questions related to the molecular processes involved in the generation of ADA. We chose as a model that comprises patients treated with TNFa antagonists (Infliximab and Adalimumab). We employed serological and Immunogenetic approaches to elucidate the: i) composition of ADA following therapeutic mAb infusion and differentiate between binding and neutralizing ADAs; ii) the nature of the B cell response post infusion and iii) the molecular composition of ADA using NGS technologies. The data obtained in the study will help to assess the immunogenicity of biologics under development and help to revise treatment strategies that may result in increased drug efficacy. Moreover, the methods developed in the study can be readily used in the clinic and facilitate decision making during treatment with biologics.