New Perspectives on FcRn Biology

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. Based on deep molecular and cellular insights, we have designed and produced panels of recombinant antibody variants with a large range of variable sequences that exhibit very different biophysical properties regarding cellular uptake, the ability to be sorted, degraded or saved from intracellular degradation. We have determined which factors that are FcRn-dependent and FcRn-independent. The differences are incredibly large, and extensive studies in humanized mouse models show how these unique phenotypes translate into distinct pharmacokinetic profiles, such as half-life and biodistribution. The features are of great importance for how antibodies can be tailored for optimal properties for given indications. Several works have been published while there is a number of manuscripts that are near submission. Overview articles have also been published with international partners that shed light on the importance of our findings in the context state-of-the-art. We have also combined this knowledge with unique antibody technologies, which give advantages in the design of long-acting antibodies. Furthermore, we have established a robust system for production of albumin-fused antibody fragments that are functional and where the effect of variable sequences have been characterized. The results from thorough in-depth studies have revealed major cellular and pharmacokinetic differences in the use of human albumin compared with the use of the antibody's constant part as a fusion partner. Some of the findings have give rise to innovations, which will now be explored in various innovation projects. A postdoc has been trained on the project who has conducted several career advancement courses, in accordance with the plan, and has now continued his career as a researcher. Furthermore, a PhD candidate has submitted her thesis to the faculty for evaluation. They have both attended conferences and presented their research.

Prosjektet har ført frem til grunnleggende ny kunnskap om sammenhengen mellom struktur og funksjon av antistoffer og albumin, og hvordan ulike biofysiske egenskaper knytte til de variable regionene til antistoffene eller andre former for fusjonspartnere, påvirker hvordan proteinene blir håndtert på et cellulært nivå og i modellmus som etterligner human biologi. Funnene utfordrer dagens praksis, og er forventet å guide videre biologiske studier samt utvikling av protein-baserte legemidler med favoriserende egenskaper, som kan gi bedre og mer treffsikker medisin. Denne kunnskapen og kompetansen vil omsettes i form av design av ny biomedisinsk teknologi og skreddersydde proteiner som kan føre frem til nye legemiddelkandidater, utviklet av akademiske laber eller industri, eller i samarbeid mellom partene. Prosjektet har allerede ført frem til nye former for samarbeid, både med internasjonale laber og næringsliv. Videre er det avslørt ny biologisk innsikt som legger grunnlaget for nye innovasjoner som vil bli utforsket som del av ulike innovasjonsprosjekter. Derav gir prosjektets resultater et mulighetsrom for eksperimentell innovasjon, som kan føre frem til nye behandlingsstrategier/alternativer i det lange løp.

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.