Thesis defense Karin van Schie
On 12 October 2017 (14:00 hrs) Karin van Schie defended her PhD thesis 'Immunogenicity of therapeutic antibodies: Immunological mechanisms & clinical consequences' at the University of Amsterdam
Promotor: Prof Marieke van Ham PhD
Copromotores: Theo Rispens PhD and Gertjan Wolbink MD PhD
Venue: Agnietenkapel, University of Amsterdam
Therapeutic antibodies are effectively used to treat various diseases, including cancer and inflammatory diseases. Unfortunately, in a subset of patients these therapeutics are immunogenic, resulting in anti-drug antibody (ADA) formation. ADA reduce the efficacy of the drug and may cause clinical non-response. Although nowadays immunogenicity is an accepted phenomenon and the clinical effects regarding lower therapeutic efficacy are well-studied, the mechanisms involved in inflicting these clinical adverse events remain largely unknown. The focus of this thesis therefore lies on elucidating the immunological mechanisms behind the observed unwanted clinical effects.
By studying the binding site of ADA on five different therapeutic antibodies, it was shown that the vast majority of ADA bind the antigen binding site of the drug, resulting in competition between ADA and the drug’s target. These results explain at least in part how ADA reduce the therapeutic efficacy.
Furthermore, in ADA+ patients that are treated with a therapeutic antibody, ADA and drug will form antibody complexes. Although this inevitably happens in all ADA positive patients, the biological effects and eventual fate of these complexes is unknown. Results from our study show that these complexes are generally small, and even though they are not efficiently phagocytosed by macrophages, they are also unable to activate the immune system, likely making them harmless.
Only in rare cases, when the ADA and drug concentration is high, larger complexes are formed and parts of the immune system can be activated. This could potentially lead to adverse events, but more research is required to confirm this.