Sticky & Dirty Proteins – or on the poorly characterised, peculiar, pharmacokinetic and immunostimulatory aspects of biopharmaceuticals

Reijers, J.A.A. (2018)

Doctoral Thesis

Biopharmaceuticals are among the most celebrated drugs. However, despite decades of experience, our understanding of many in vivo pharmacokinetic and adverse effects of biopharmaceuticals is still limited. These include the delay in reaching the maximum plasma concentration for an intravenously administered therapeutical protein, and the highly variable plasma concentration during elimination of monoclonal antibodies. Both observations can be explained by dynamical binding (‘stickiness’) of proteins to various (bodily) surfaces.
Biopharmaceuticals also frequently contain (non-human) impurities, some of which are harmful when administered (‘dirtiness’). This toxicity often is the result of an intricate interplay of multiple cell types and effector pathways which can be difficult to simulate in the laboratory. More sophisticated test platforms are available, which can detect a number of untoward reactions that would previously not have been discovered. However, no laboratory test is fail-safe, and awareness of the possibility of adverse immunostimulation caused by biopharmaceuticals is the most important aspect for early detection and prevention of such cases in the future.

• Biopharmaceuticals
• Biologicals
• Clinical pharmacology
• Pharmacokinetics
• Adverse immunostimulation
• Immunotoxicity
• Drug impurity
• Drug contamination
• Monoclonal antibody

• All authors: Reijers, J.A.A.
• Supervisor: Burggraaf, J.; Cohen, A.F.
• Co-supervisor: Moerland, M.
• Committee: Huizinga, T.W.J.; Guchelaar, H.J.; Swart, E.L.; Schellekens, H.
• Qualification: Doctor (dr.)
• Awarding Institution: Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2018-03-14
• ISBN (print): 9789082830408
• Sponsorship: Centre for Human Drug Research (CHDR)