Unwanted immunogenicity of therapeutic proteins

In contrast with vaccines, therapeutic proteins such as monoclonal antibodies, insulin, and interferons should be non-immunogenic. Unfortunately, practically all therapeutic proteins induce antibodies in patients upon chronic treatment. These anti-drug antibodies can lead to serious clinical problems, because they neutralize the activity of the drug, induce allergic or anaphylactic reactions, or cross-react with the endogenous counterpart of the drug.
This research line aims to elucidate the causative factors and mechanisms of antibody formation against therapeutic proteins. Transgenic immune-tolerant animals are used to test which product-related factors (e.g., protein structure, formulation, impurities) can break immune tolerance, which is the most likely mechanism by which patients treated with recombinant human proteins produce antibodies. These studies are performed in close collaboration with Prof. Schellekens (Utrecht University).

To support the studies on structure-immunogenicity relationships, state-of-the-art analytical methods to characterize proteins to detect unfolded or aggregated proteins are used and developed. These techniques include, amongst others, spectroscopic methods, separation techniques and light scattering methods. The sensitive detection of low levels of aggregated protein species, which are thought to be responsible for enhanced immunogenicity, receives particular attention. Furthermore, stabilization approaches to inhibit the formation of specific immunogenic degradation products during storage and handling are investigated.