Publications
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Felice, Sofia De; Buratto, Christian; Savio, Alessia; Morbidelli, Maria; Papini, Emanuele & Acquasaliente, Laura
[Show all 12 contributors for this article]
(2026).
Structural conservation and expanded functionality of hyper-stable human serum albumin variants.
bioRxiv - the preprint server for biology.
doi:
10.64898/2026.04.10.717531.
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Abstract Human serum albumin (hSA) is the most abundant protein in human plasma, and its pharmacological properties, such as long plasma half-life mediated by the neonatal Fc receptor (FcRn) and its ability to bind endogenous and exogenous molecules, make it attractive for biotechnological applications. Currently, most wild type (WT) SAs are derived from human or bovine serum or produced in yeast and mammalian cells. Although well established, these methods are costly, difficult to reproduce, and not environmentally sustainable. Building on a previous study to design highly mutated hSA sequences, we extend the validation through an in-depth analysis of three engineered hSA variants; hSA1, hSA2, and hSA3, containing 16, 25, or 73 amino acid substitutions, respectively. These variants were designed for enhanced solubility, stability, and expression in Escherichia coli. All three variants showed low- micromolar affinities for hFcRn at pH 5.5, and negligible binding at pH 7.4. In a human endothelial cell-based recycling assay (HERA), the engineered hSA variants were recycled by hFcRn to the same extent as hSA isolated from serum. Exploring the properties of canonical drug-binding sites, warfarin affinity was comparable to WT hSA, whereas ibuprofen binding differed. Complementary cytotoxicity assays on human macrophages confirmed negligible toxicity and biocompatibility. A cryo-electron microscopy structure of hSA3 revealed that, despite extensive engineering, the native heart-shape of hSA, folding of domains, and its open conformation were preserved. These findings validate the structural integrity and functional adaptability of engineered hSA variants, underscoring their potential as versatile, animal-free solutions for next-generation therapeutics and biotechnological applications.
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Nilsen, Jeannette; Sand, Kine Marita Knudsen; Al-Khabbaz, Hana J.; Ligtenberg, Lennart Maximilian van; mester, simone & Mathiesen, Line
[Show all 28 contributors for this article]
(2026).
Fusion of IgG antibodies to albumin inhibits transport across the placenta.
Science immunology.
11(122).
doi:
10.1126/sciimmunol.aee5151.
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Immunoglobulin G (IgG)–based monoclonal antibodies are effective therapies for cancer, autoimmune diseases, and migraine. However, they are actively transported across the placenta by the neonatal Fc receptor (FcRn), limiting their use during pregnancy. Using mouse models and an ex vivo human placental perfusion system, we show that although FcRn binds albumin independently of IgG, albumin is not transported to the fetus in mice or across human placental tissue. Fusion of IgG to albumin markedly reduced transplacental transport in both models while preserving the prolonged plasma half-life conferred by FcRn. Similarly, fragment antigen–binding fragments fused to engineered albumin with enhanced FcRn binding showed minimal fetal exposure. In a mouse model of fetal and neonatal alloimmune thrombocytopenia, albumin fusion of an anti–human platelet antigen IgG reduced fetal antibody transfer and attenuated thrombocytopenia in the offspring. These findings identify albumin as an attractive fusion partner for biologics intended to minimize fetal exposure during pregnancy.
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Aaen, Kristin Hovden; Testa, Maria Francesca; Nilsen, Jeannette; Tarantino, Rebecca; Canepari, Cesare & Benedusi, Mascia
[Show all 16 contributors for this article]
(2025).
Tailored collagen binding of albumin-fused hyperactive coagulation factor IX dictates in vivo distribution and functional properties.
Nature Communications.
16.
doi:
10.1038/s41467-025-62955-9.
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The efficacy of hemophilia B (HB) replacement therapy is evaluated by coagulation factor IX (FIX) activity in plasma, although FIX bound to extravascular type IV collagen (Col4) also contributes to efficient hemostasis. Here, we investigated the impact of engineering FIX for improved (K5R) or reduced (K5A) Col4 binding on the pharmacokinetic properties of FIX Padua, fused to human serum albumin (HSA QMP ) engineered for favorable neonatal Fc receptor (FcRn) engagement. Hyperactive features and extended plasma half-life in human FcRn expressing mice, attributed to FIX Padua and HSA QMP engineering, respectively, was confirmed. In HB mice, Padua KA -HSA QMP exhibited negligible extravascular distribution and the highest plasma levels at early time points followed by the steepest decay. Conversely, Padua KR -HSA QMP showed increased extravascular distribution and a 3-fold longer functional half-life (80 hours). These findings support the use of Padua KA -HSA QMP and Padua KR -HSA QMP as hyperactive short- or long-term therapeutics, respectively, with opportunities for tailored HB replacement therapy.
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Trabjerg, Esben; Nilsen, Jeannette; gjølberg, torleif; Andersen, Jan Terje; Leitner, Alexander & Rand, Kasper D.
(2025).
Identification of a direct interaction between the Fab domains of IgG antibodies and human FcRn upon IgG-FcRn complex formation.
Communications Biology.
8(1).
doi:
10.1038/s42003-025-08252-z.
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IgGs have become successful drug scaffolds by combining specific target binding with the ability to induce cellular cytotoxicity. Furthermore, IgGs possess unusually long half-lives in the blood (2-3 weeks). IgGs achieve such extraordinary half-lives through a pH-dependent interaction with the FcRn-receptor whereby IgGs are recycled. No high-resolution structure of FcRn in complex with a full-length IgG is available, and the interaction was long thought to be mediated solely via the IgG-Fc. However, some IgGs with identical Fc-parts, but different Fab-domains, exhibit different half-lives, suggesting involvement of the Fab-domains in FcRn binding. Here, we employ structural mass spectrometry (HDX-MS and XL-MS) to explore the interaction of full-length IgGs with FcRn. HDX-MS and XL-MS experiments confirm an interaction between FcRn and the Fc-region of IgGs, through three cross-links between FcRn and the IgG-Fc-domain and a reduction in HDX in both the receptor and the Fc-region upon complex formation. However, FcRn-induced changes in HDX are also observed in the Fab-domains, supported by cross-links between the Fab-domains and the α3-domain of FcRn. Our results thus provide direct evidence for an IgG Fab-FcRn interaction. We envision that these results could advance the engineering of IgG-antibodies with tailored pharmacokinetics and enhanced efficacy.
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Anthi, Aina Karen; Kolderup, Heidi Anette; Vaage, Eline Benno; Bern, Malin C.; Benjakul, Sopisa & Tjärnhage, Elias
[Show all 32 contributors for this article]
(2025).
An intranasal subunit vaccine induces protective systemic and mucosal antibody immunity against respiratory viruses in mouse models.
Nature Communications.
16(1),
p. 1–16.
doi:
10.1038/s41467-025-59353-6.
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Although vaccines are usually given intramuscularly, the intranasal delivery route may lead to better mucosal protection and limit the spread of respiratory virus while easing administration and improving vaccine acceptance. The challenge, however, is to achieve delivery across the selective epithelial cell barrier. Here we report on a subunit vaccine platform, in which the antigen is genetically fused to albumin to facilitate FcRn-mediated transport across the mucosal barrier in the presence of adjuvant. Intranasal delivery in conventional and transgenic mouse models induces both systemic and mucosal antigen-specific antibody responses that protect against challenge with SARS-CoV-2 or influenza A. When benchmarked against an intramuscularly administered mRNA vaccine or an intranasally administered antigen fused to an alternative carrier of similar size, only the albumin-based intranasal vaccine yields robust mucosal IgA antibody responses. Our results thus suggest that this needle-free, albumin-based vaccine platform may be suited for vaccination against respiratory pathogens.
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Nilsen, Jeannette; Aaen, Kristin Hovden; Benjakul, Sopisa; Ruso-Julve, Fulgencio; Greiner, Thomas Uwe & Bejan, Daniela
[Show all 11 contributors for this article]
(2025).
Enhanced plasma half-life and efficacy of engineered human albumin-fused GLP-1 despite enzymatic cleavage of its C-terminal end.
Communications Biology.
8(1).
doi:
10.1038/s42003-025-08249-8.
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Albumin has a long plasma half-life due to engagement of the neonatal Fc receptor (FcRn), which prevents intracellular degradation. However, its C-terminal end can be cleaved by carboxypeptidase A, and removal of the last leucine residue (L585) weakens receptor binding, reducing its half-life from 20 days to 3.5 days in humans. This biology has so far been overlooked when designing human albumin-fused biologics. Thus, there is a need for an engineering strategy to secure favorable FcRn binding and pharmacokinetic properties. Here, we show that a branched aliphatic amino acid or methionine at position 585 of albumin is required for optimal receptor binding, which cannot be replaced to prevent enzymatic cleavage without negatively affecting FcRn engagement. As a solution, we report that C-terminally cleaved albumin can be efficiently rescued from intracellular degradation by introducing amino acid substitutions that improve FcRn binding. This albumin-engineering strategy was also effective when applied with a therapeutic fusion partner, glucagon-like peptide 1 (GLP-1), resulting in a 2-fold increase in plasma half-life and prolonged efficacy in human FcRn transgenic mice. We demonstrate how human albumin fusions should be tailored to ensure a long plasma half-life and enhanced efficacy of fused biologics, despite potential C-terminal cleavage in vivo.
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mester, simone; Chan, Chilam; Lustig, Marta; Foss, Stian; Jansen, J. H. Marco & Herigstad, Marie Leangen
[Show all 17 contributors for this article]
(2025).
Engineering of anticancer human immunoglobulin A equipped with albumin for enhanced plasma half-life.
PNAS Nexus.
4(2).
doi:
10.1093/pnasnexus/pgaf042.
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Most therapeutic antibodies are based on immunoglobulin G (IgG) due to their potent effector functions and long plasma half-life. However, also monomeric IgA has emerged as an attractive candidate for cancer treatment as, upon specific binding to tumor cells, it can activate myeloid cells, like polymorphonuclear leukocytes and macrophages, to kill the tumor cells by engaging the Fc α receptor I (FcαRI). Despite this favorable property, human IgA has a short plasma half-life in both mice and humans, which is clearly limiting preclinical studies in a translational perspective. Here, we report on albumin-equipped designs of human IgA antibodies that are long acting due to tailored binding to the human form of neonatal Fc receptor (FcRn), which is a natural plasma half-life regulator of albumin. Importantly, this was achieved without compromising the ability of IgA to engage and activate FcαRI-expressing effector cells for tumor cell killing in vitro and in vivo in a new mouse model transgenic for the human forms of FcRn and FcαRI. We further show that the potency of the engineered long-acting human IgA against tumor cells with intermediate target antigen expression levels could be enhanced by myeloid checkpoint inhibitors targeting the signal regulatory protein α-CD47 axis.
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Grevys, Algirdas; Frick, Rahel; Mester, Simone; Flem-Karlsen, Karine; Nilsen, Jeannette & Foss, Stian
[Show all 13 contributors for this article]
(2022).
Antibody variable sequences have a pronounced effect on cellular transport and plasma half-life.
iScience.
25:103746(2),
p. 1–22.
doi:
10.1016/j.isci.2022.103746.
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Monoclonal IgG antibodies are the fastest growing class of biologics, but large differences exist in their plasma half-life in humans. Thus, to design IgG antibodies with favorable pharmacokinetics, it is crucial to identify the determinants of such differences. Here, we demonstrate that the variable region sequences of IgG antibodies greatly affect cellular uptake and subsequent recycling and rescue from intracellular degradation by endothelial cells. When the variable sequences are masked by the cognate antigen, it influences both their transport behavior and binding to the neonatal Fc receptor (FcRn), a key regulator of IgG plasma half-life. Furthermore, we show how charge patch differences in the variable domains modulate both binding and transport properties and that a short plasma half-life, due to unfavorable charge patches, may partly be overcome by Fc-engineering for improved FcRn binding.
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Mester, Simone; Evers, Mitchell; Meyer, Saskia; Nilsen, Jeannette; Greiff, Victor & Sandlie, Inger
[Show all 8 contributors for this article]
(2021).
Extended plasma half-life of albumin-binding domain fused human IgA upon pH-dependent albumin engagement of human FcRn in vitro and in vivo.
mAbs.
ISSN 1942-0862.
13:1893888(1),
p. 1–14.
doi:
10.1080/19420862.2021.1893888.
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Albumin has a serum half-life of 3 weeks in humans. This feature can be used to improve the pharmacokinetics of shorter-lived biologics. For instance, an albumin-binding domain (ABD) can be used to recruit albumin. A prerequisite for such design is that the ABD-albumin interaction does not interfere with pH-dependent binding of albumin to the human neonatal Fc receptor (FcRn), as FcRn acts as the principal regulator of the half-life of albumin. Thus, there is a need to know how ABDs act in the context of fusion partners and human FcRn. Here, we studied the binding and transport properties of human immunoglobulin A1 (IgA1), fused to a Streptococcus protein G-derived engineered ABD, in in vitro and in vivo systems harboring human FcRn. IgA has great potential as a therapeutic protein, but its short half-life is a major drawback. We demonstrate that ABD-fused IgA1 binds human FcRn pH-dependently and is rescued from cellular degradation in a receptor-specific manner in the presence of albumin. This occurs when ABD is fused to either the light or the heavy chain. In human FcRn transgenic mice, IgA1-ABD in complex with human albumin, gave 4-6-fold extended half-life compared to unmodified IgA1, where the light chain fusion showed the longest half-life. When the heavy chain-fused protein was pre-incubated with an engineered human albumin with improved FcRn binding, cellular rescue and half-life was further enhanced. Our study reveals how an ABD, which does not interfere with albumin binding to human FcRn, may be used to extend the half-life of IgA.
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Merten, Hannes; Brandl, Fabian; Zimmermann, Martina; Schaefer, Jonas V.; Irpinio, Linda & Sand, Kine M.K.
[Show all 10 contributors for this article]
(2021).
Half-life extension of efficiently produced DARPin serum albumin fusions as a function of FcRn affinity and recycling.
European journal of pharmaceutics and biopharmaceutics.
ISSN 0939-6411.
167,
p. 104–113.
doi:
10.1016/j.ejpb.2021.07.011.
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Serum albumin shows slow clearance from circulation due to neonatal Fc receptor (FcRn)-mediated recycling and has been used for half-life extension. We report here fusions to a high-affinity DARPin, binding to Epithelial Cell Adhesion Molecule (EpCAM). We developed a novel, efficient expression system for such fusion proteins in Pichia pastoris with titers above 300 mg/L of lab-scale shake-flask culture. Since human serum albumin (HSA) does not bind to the murine FcRn, half-lives of therapeutic candidates are frequently measured in human FcRn transgenic mice, limiting useable tumor models. Additionally, serum albumins with extended half-life have been designed. We tested HSA7, motivated by its previously claimed extraordinarily long half-life in mice, which we could not confirm. Instead, we determined a half-life of only 29 h for HSA7, comparable to MSA. The fusion of HSA7 to a DARPin showed a similar half-life. To rationalize these findings, we measured binding kinetics and affinities to murine and human FcRn. Briefly, HSA7 showed affinity to murine FcRn only in the micromolar range, comparable to MSA to its cognate murine FcRn, and an affinity in the nanomolar range only to the human FcRn. This explains the comparable half-life of MSA and HSA7 in mice, while wild-type-HSA has a half-life of only 21 h, as it does not bind the murine FcRn and is not recycled. Thus, HSA-fusions with improved FcRn-affinity, such as HSA7, can be used for preclinical experiments in mice when FcRn transgenes cannot be used, as they reflect better the complex FcRn-mediated recycling and distribution mechanisms.
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Azevedo, Cláudia; Pinto, Soraia; Benjakul, Sopisa; Nilsen, Jeannette; Santos, Helder A. & Traverso, Giovanni
[Show all 8 contributors for this article]
(2021).
Prevention of diabetes-associated fibrosis: Strategies in FcRn-targeted nanosystems for oral drug delivery.
Advanced Drug Delivery Reviews.
ISSN 0169-409X.
175.
doi:
10.1016/j.addr.2021.04.016.
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Diabetes mellitus is a chronic disease with an elevated risk of micro- and macrovascular complications, such as fibrosis. To prevent diabetes-associated fibrosis, the symptomatology of diabetes must be controlled, which is commonly done by subcutaneous injection of antidiabetic peptides. To minimize the pain and distress associated with such injections, there is an urgent need for non-invasive oral transmucosal drug delivery strategies. However, orally administered peptide-based drugs are exposed to harsh conditions in the gastrointestinal tract and poorly cross the selective intestinal epithelium. Thus, targeting of drugs to receptors expressed in epithelial cells, such as the neonatal Fc receptor (FcRn), may therefore enhance uptake and transport through mucosal barriers. This review compiles how in-depth studies of FcRn biology and engineering of receptor-binding molecules may pave the way for design of new classes of FcRn-targeted nanosystems. Tailored strategies may open new avenues for oral drug delivery and provide better treatment options for diabetes and, consequently, fibrosis prevention.
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Lombardi, Silvia; Aaen, Kristin Hovden; Nilsen, Jeannette; Ferrarese, Mattia; Gjølberg, Torleif Tollefsrud & Bernardi, Francesco
[Show all 9 contributors for this article]
(2021).
Fusion of engineered albumin with factor IX Padua extends half-life and improves coagulant activity.
British Journal of Haematology.
ISSN 0007-1048.
194(2),
p. 453–462.
doi:
10.1111/bjh.17559.
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The short half-life of coagulation factor IX (FIX) for haemophilia B (HB) therapy has been prolonged through fusion with human serum albumin (HSA), which drives the neonatal Fc receptor (FcRn)-mediated recycling of the chimera. However, patients would greatly benefit from further FIX-HSA half-life extension. In the present study, we designed a FIX-HSA variant through the engineering of both fusion partners. First, we developed a novel cleavable linker combining the two FIX activation sites, which resulted in improved HSA release. Second, insertion of the FIX R338L (Padua) substitution conferred hyperactive features (sevenfold higher specific activity) as for FIX Padua alone. Furthermore, we exploited an engineered HSA (QMP), which conferred enhanced human (h)FcRn binding [dissociation constant (KD) 0·5 nM] over wild-type FIX-HSA (KD 164·4 nM). In hFcRn transgenic mice, Padua-QMP displayed a significantly prolonged half-life (2·7 days, P < 0·0001) versus FIX-HSA (1 day). Overall, we developed a novel FIX-HSA protein with improved activity and extended half-life. These combined properties may result in a prolonged functional profile above the therapeutic threshold, and thus in a potentially widened therapeutic window able to improve HB therapy. This rational engineering of both partners may pave the way for new fusion strategies for the design of engineered biotherapeutics.
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Aaen, Kristin Hovden; Anthi, Aina Karen; Sandlie, Inger; Nilsen, Jeannette; Mester, Simone & Andersen, Jan Terje
(2020).
The neonatal Fc receptor in mucosal immune regulation.
Scandinavian Journal of Immunology.
ISSN 0300-9475.
doi:
10.1111/sji.13017.
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Bern, Malin C.; Nilsen, Jeannette; Ferrarese, Mattia; Sand, Kine Marita Knudsen; Gjølberg, Torleif Tollefsrud & Lode, Heidrun Elisabeth
[Show all 24 contributors for this article]
(2020).
An engineered human albumin enhances half-life and transmucosal delivery when fused to protein-based biologics.
Science Translational Medicine.
ISSN 1946-6234.
12(565),
p. 1–13.
doi:
10.1126/scitranslmed.abb0580.
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Needle-free uptake across mucosal barriers is a preferred route for delivery of biologics, but the efficiency of unassisted transmucosal transport is poor. To make administration and therapy efficient and convenient, strategies for the delivery of biologics must enhance both transcellular delivery and plasma half-life. We found that human albumin was transcytosed efficiently across polarized human epithelial cells by a mechanism that depends on the neonatal Fc receptor (FcRn). FcRn also transported immunoglobulin G, but twofold less than albumin. We therefore designed a human albumin variant, E505Q/T527M/K573P (QMP), with improved FcRn binding, resulting in enhanced transcellular transport upon intranasal delivery and extended plasma half-life of albumin in transgenic mice expressing human FcRn. When QMP was fused to recombinant activated coagulation factor VII, the half-life of the fusion molecule increased 3.6-fold compared with the wild-type human albumin fusion, without compromising the therapeutic properties of activated factor VII. Our findings highlight QMP as a suitable carrier of protein-based biologics that may enhance plasma half-life and delivery across mucosal barriers.
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Nilsen, Jeannette; Trabjerg, Esben; Grevys, Algirdas; Azevedo, Claudia; Brennan, Stephen O. & Stensland, Maria
[Show all 14 contributors for this article]
(2020).
An intact C-terminal end of albumin is required for its long half-life in humans.
Communications Biology.
3(1).
doi:
10.1038/s42003-020-0903-7.
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Albumin has an average plasma half-life of three weeks and is thus an attractive carrier to improve the pharmacokinetics of fused therapeutics. The half-life is regulated by FcRn, a cellular receptor that protects against intracellular degradation. To tailor-design the therapeutic use of albumin, it is crucial to understand how structural alterations in albumin affect FcRn binding and transport properties. In the blood, the last C-terminal residue (L585) of albumin may be enzymatically cleaved. Here we demonstrate that removal of the L585 residue causes structural stabilization in regions of the principal FcRn binding domain and reduces receptor binding. In line with this, a short half-life of only 3.5 days was measured for cleaved albumin lacking L585 in a patient with acute pancreatitis. Thus, we reveal the structural requirement of an intact C-terminal end of albumin for a long plasma half-life, which has implications for design of albumin-based therapeutics.
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Nilsen, Jeannette; Sandlie, Inger; Roopenian, Derry C. & Andersen, Jan Terje
(2018).
Animal models for evaluation of albumin-based therapeutics.
Current Opinion in Chemical Engineering.
19,
p. 68–76.
doi:
10.1016/j.coche.2017.11.007.
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Albumin has a long serum half-life due to its unique ability to bind the cellular neonatal Fc receptor (FcRn), which provides protection from intracellular degradation. The interaction can be capitalized to improve the efficacy of drugs by extending their serum persistence. However, species-specific binding of albumin to FcRn Challenges preclinical development. The goal of this brief review is to provide Insights into how FcRn and cross-species binding differences affect the pharmacokinetics of human serum albumin (HSA) in different animal models, and gives an overview of genetically modified mice that may serve as improved models for testing of albumin-based drugs.
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Grevys, Algirdas; Nilsen, Jeannette; Sand, Kine Marita Knudsen; Daba, Muluneh Bekele; Øynebråten, Inger & Bern, Malin C.
[Show all 15 contributors for this article]
(2018).
A human endothelial cell-based recycling assay for screening of FcRn targeted molecules.
Nature Communications.
9.
doi:
10.1038/s41467-018-03061-x.
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Albumin and IgG have remarkably long serum half-lives due to pH-dependent FcRn-mediated cellular recycling that rescues both ligands from intracellular degradation. Furthermore, increase in half-lives of IgG and albumin-based therapeutics has the potential to improve their efficacies, but there is a great need for robust methods for screening of relative FcRn-dependent recycling ability. Here, we report on a novel human endothelial cell-based recycling assay (HERA) that can be used for such pre-clinical screening. In HERA, rescue from degradation depends on FcRn, and engineered ligands are recycled in a manner that correlates with their half-lives in human FcRn transgenic mice. Thus, HERA is a novel cellular assay that can be used to predict how FcRn-binding proteins are rescued from intracellular degradation.
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Bern, Malin C.; Sand, Kine Marita Knudsen; Nilsen, Jeannette; Sandlie, Inger & Andersen, Jan Terje
(2015).
The role of albumin receptors in regulation of albumin homeostasis: Implications for drug delivery.
Journal of Controlled Release.
ISSN 0168-3659.
211,
p. 144–162.
doi:
10.1016/j.jconrel.2015.06.006.
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Sand, Kine Marita Knudsen; Bern, Malin C.; Nilsen, Jeannette; Noordzij, Hanna Theodora; Sandlie, Inger & Andersen, Jan Terje
(2015).
Unraveling the interaction between FcRn and albumin: Opportunities for design of albumin-based therapeutics.
Frontiers in Immunology.
5:682.
doi:
10.3389/fimmu.2014.00682.
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The neonatal Fc receptor (FcRn) was first found to be responsible for transporting antibodies of the immunoglobulin G (IgG) class from the mother to the fetus or neonate as well as for protecting IgG from intracellular catabolism. However, it has now become apparent that the same receptor also binds albumin and plays a fundamental role in homeostatic regulation of both IgG and albumin, as FcRn is expressed in many different cell types and organs at diverse body sites. Thus, to gain a complete understanding of the biological function of each ligand, and also their distribution in the body, an in-depth characterization of how FcRn binds and regulates the transport of both ligands is necessary. Importantly, such knowledge is also relevant when developing new drugs, as IgG and albumin are increasingly utilized in therapy. This review discusses our current structural and biological understanding of the relationship between FcRn and its ligands, with a particular focus on albumin and design of albumin-based therapeutics.
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Published
June 21, 2022 2:18 PM
- Last modified
June 23, 2022 11:43 AM
