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FRIMED2-FRIPRO forskerprosjekt, medisin og helse

New Perspectives on FcRn Biology

Alternative title: Nye perspektiver på FcRn biologi

Awarded: NOK 8.2 mill.

Antibodies and albumin have pivotal functions in both immunological and non-immunological processes. While antibodies are key players in our daily fight against infections, albumin acts as a molecular taxi transporting a plethora of important substances such as fatty acids and hormones as well as toxins throughout the body. A particularly interesting feature of these unrelated proteins is that they share a long plasma half-life of roughly 3 weeks, which is a result of their interaction with a common cellular receptor named FcRn. Our laboratory has gained new molecular insights into how FcRn binds and transports the ligands, which have tremendous implications for our understanding of their biology. As these ligands are increasingly utilized in medicine, new basic knowledge will pave the way for design of antibody and albumin molecules with tailored FcRn binding and transport properties. We here aim to make a quantum leap in our understanding of how FcRn regulates cellular transport and plasma half-life. We will take an interdisciplinary approach with a clear link between cutting-edge basic and innovative translational research. Since we initiated the project, we have designed and produced panels with recombinant antibody variants with a wide range of variable sequences that prove to affect cellular uptake, ability to be sorted, degraded or saved from degradation very differently. The differences are strikingly large, and studies in a new mouse model show how these unique phenotypes transfer into distinct pharmacokinetic profiles. These papers will be published are very soon in press. We have also prepared a comprehensive review article, which also will be published soon. Some findings have also given rise to ideas for new antibody technology, which we are now exploring. We have also established a robust system for the production of albumin-infused antibody fragments that are functional. This work is now submitted for peer review. The postdoc employee on the project has recently resigned due to moving to the United States. We have just succeeded in recruiting a new postdoc, and the project will be revised immediately in light of a few adjustments when the start date is set.

Antibodies and albumin have pivotal functions in both immunological and non-immunological processes. While antibodies are key players in our daily fight against infections, albumin acts as a molecular taxi transporting a plethora of important substances such as fatty acids and hormones as well as toxins throughout the body. A particularly interesting feature of these unrelated proteins is that they share a long plasma half-life of roughly 3 weeks, which is a result of their interaction with a common receptor, the neonatal Fc receptor (FcRn). FcRn is expressed in a number of cell types and tissues and has a crucial role in recycling or transcytosis of the ligands. Our laboratory has gained new molecular insights into how FcRn binds and transports the ligands, which have tremendous implications for our understanding of their biology. As these ligands are increasingly utilized in medicine, new basic knowledge will pave the way for design of antibody and albumin molecules with tailored FcRn binding and transport properties. Our laboratory is in the international forefront on studies of FcRn and its ligands, and we here seek funding to make a quantum leap in our understanding of how the receptor regulates cellular transport and plasma half-life. We will take an interdisciplinary approach by combining bioinformatics, structural, cellular and in vivo studies with a clear link between cutting-edge basic and innovative translational research. These efforts will be done in collaboration with leading national and international investigators.

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FRIMED2-FRIPRO forskerprosjekt, medisin og helse