Adverse events/mode of action relationship of monoclonal antibodies-based therapies : overview of marketed produts in the European Union

Tese de mestrado, Ciências Biofarmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2014In the past few years, great discoveries and improvements have been done in drug development field and a market that was previously populated just by chemical drugs is now growing to include the so called biopharmaceuticals. As biotechnologically-derived drugs rely on the fundamental understanding of the related disease, it can be predicted that they will play a major – if not dominant – role in the drug development arena of the next decades. Following the success of recombinant proteins, therapeutic Monoclonal Antibodies (mAbs) represent the second wave of innovation created by the biotechnology industry. Overcoming the problems initially raised by these biopharmaceuticals, the recent generations of mAbs have managed to reduce some of the immunogenicity problems observed with murine mAbs. Other concerns remain, however, and the adverse events arising during the long-life experience will continue to be an important factor to monitor. The target specificity of mAbs associated to the fact that they are large protein molecules make the emergence of off-target or metabolite–related toxicities less probable, being immunogenicity and target-mediated effects the most relevant determinants of toxicity. This project focus was in the correlation and comparison of mAbs’ adverse events with their specific mechanism of action. The data here analysed comprises mainly European data (EMA) but also some United States data [1]. Due to the large diversity of mechanisms for the marketed mAbs, the analysis has been restricted to three pharmacological classes of mAbs: anti-TNFα, anti-VGEF and anti-CD20 mAbs. Adverse events were compared within each mAb class and then compared through all mAbs classes. There were antibody-related adverse events reported transversally for all mAbs but there were also some class-related adverse events which were only reported in specific classes, with specific mechanisms of action. For class-related adverse events it was observed that additional key factors – like administration routes, mAbs structural configurations and profile of patients receiving those mAbs – may also impact the adverse events and cannot be excluded in safety profile characterisation. It was confirmed that the adverse events reported for all mAbs analysed were strictly related to mAbs’ mechanism of action. Hence, characterisation of each mAb specifities together with a precise understanding of the mAbs mechanism of action is crucial for mAbs safety profile characterisation