Public Defence: Jeannette Nilsen

M.Sc. Jeannette Nilsen at Institute of Clinical Medicine will be defending the thesis “Of Mice and Men: Dissecting the albumin-FcRn interaction across species” for the degree of PhD (Philosophiae Doctor).

Trial Lecture – time and place

See Trial Lecture.

Adjudication committee

  • First opponent: Emeritus Associate Professor Ulrich Kragh-Hansen, Department of Biomedicine, University of Aarhus, Denmark
  • Second opponent: Senior Scientist Alicia Martinez Llorente, Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital
  • Third member and chair of the evaluation committee: Professor II Guttorm Haraldsen, Faculty of Medicine, University of Oslo

Chair of the Defence

Professor Frode Lars Jahnsen, Faculty of Medicine, University of Oslo

Principal Supervisor

 Associate Professor Jan Terje Andersen, Faculty of Medicine, University of Oslo

Summary

Albumin and IgG are the most abundant proteins in the blood. While monoclonal IgG antibodies have revolutionized treatment of cancer, autoimmunity and infectious diseases, albumin is used to improve the pharmacokinetics of drugs that are genetically fused or conjugated. Importantly, both albumin and IgG have an exceptionally long serum half-life of three weeks in humans. Responsible is the neonatal Fc receptor (FcRn), a broadly expressed cellular receptor, that rescues its ligands from intracellular degradation via a cellular recycling pathway. This knowledge has led to a great interest in developing engineered albumin and IgG variants with improved FcRn binding and extended half-life. In this thesis, the development of a novel cellular recycling assay is described, in which albumin and IgG are recycled in an FcRn-dependent manner. The assay discriminates between engineered variants, each of which showed unique recycling properties that correlated with serum half-life in human FcRn transgenic mice. The assay is a simple, sensitive and cost-effective tool that may be used to study FcRn-mediated recycling of albumin and IgG, and to screen engineered variants prior to in vivo evaluation. Moreover, new structural knowledge of how albumin binds FcRn in mice and man is provided. The thesis shows that there are different requirements to human and mouse albumin, which both consist of three domains (DI, DII and DIII) and use DIII as the principal FcRn binding domain. Interestingly, whereas DI of human albumin was shown to be important for receptor binding, DI of mouse albumin played a minor role. Furthermore, the C-terminal leucine residue (L585) of human albumin, which is missing in mouse albumin, proved to be required for optimal binding and long serum half-life. Strikingly, enzymatic cleavage of the C-terminal L585 reduced the serum half-life from 20 to 3 days in humans. The findings will guide rational design and preclinical testing of novel albumin-based therapeutics.

Additional information

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Published Aug. 27, 2019 1:27 PM - Last modified Aug. 27, 2019 2:31 PM