Immunogenicity of therapeutic antibodies Immunological mechanisms & clinical consequences

Monoclonal antibody therapy has revolutionized the treatment of many diseases, including chronic inflammatory diseases and cancer. Antibody therapy can unfortunately also elicit an unwanted immune response, leading to anti-drug antibodies (ADA). It is well known that ADA can lower the level of free drug, which may lead to a reduced clinical response. Additionally, for some antibody therapeutics, more adverse events are reported in ADA positive patients. A rather neglected result of immunogenicity is the formation of immune complexes between drug and ADA that likely occurs in all ADA positive patients. Although the high dosages drug and ADA could possibly lead to a very high amount of immune complexes, the biological and clinical effects of these complexes are largely unknown. The aim of this thesis is to provide a detailed characterization of the ADA response and its associated immune complex formation, to better understand the causes and mechanisms behind the adverse clinical observations.