simonem

• gjølberg, torleif; mester, simone; Calamera, Gaia; Telstad, Jenny Skjermo; Sandlie, Inger & Andersen, Jan Terje (2025). Targeting the Neonatal Fc Receptor in Autoimmune Diseases: Pipeline and Progress. BioDrugs. ISSN 1173-8804. 39(3), p. 373–409. doi: 10.1007/s40259-025-00708-2. Full text in Research Archive Show summary

  Autoimmune diseases are highly prevalent and affect people at all ages, women more often than men. The most prominent immunological manifestation is the production of antibodies directed against self-antigens. In many cases, these antibodies (Abs) drive the pathogenesis by attacking the body’s own healthy cells, causing serious health problems that may be life threatening. Most autoantibodies are of the immunoglobulin G (IgG) isotype, which has a long plasma half-life and potent effector functions. Thus, there is a need for specific treatment options that rapidly eliminate these pathogenic IgG auto-Abs. In this review, we discuss how the neonatal Fc receptor (FcRn) acts as a regulator of the high levels of not only IgG Abs, but also albumin, by rescuing both these soluble proteins from cellular catabolism, and how a molecular and cellular understanding of this complex biology has spurred an intense interest in the development of FcRn-targeting strategies for the treatment of IgG-driven autoimmune diseases. We find that this emerging therapeutic class demonstrates efficacy within several autoimmune diseases with distinct pathophysiology. This offers hope for both new therapeutic avenues for highly prevalent diseases currently treated by other means, and rare diseases with no approved therapies to date. In addition, we elaborate on studies that have led to approval of the first FcRn antagonists, the clinical progress and structural design of molecules in the pipeline, their position in the overall therapeutic landscape of autoimmunity, the design of next-generation antagonists as well as the use of this receptor-targeting principle for other therapeutic applications.

• 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. Full text in Research Archive Show summary

  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.

• Foss, Stian; Sakya, Siri Aastedatter; Aguinagalde, Leire; Lustig, Marta; Shaughnessy, Jutamas & Cruz, Ana Rita [Show all 25 contributors for this article] (2024). Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria. Nature Communications. 15(1). doi: 10.1038/s41467-024-46321-9. Full text in Research Archive Show summary

  Monoclonal IgG antibodies constitute the fastest growing class of therapeutics. Thus, there is an intense interest to design more potent antibody formats, where long plasma half-life is a commercially competitive differentiator affecting dosing, frequency of administration and thereby potentially patient compliance. Here, we report on an Fc-engineered variant with three amino acid substitutions Q311R/M428E/N434W (REW), that enhances plasma half-life and mucosal distribution, as well as allows for needle-free delivery across respiratory epithelial barriers in human FcRn transgenic mice. In addition, the Fc-engineered variant improves on-target complement-mediated killing of cancer cells as well as both gram-positive and gram-negative bacteria. Hence, this versatile Fc technology should be broadly applicable in antibody design aiming for long-acting prophylactic or therapeutic interventions.

• Jørstad, Øystein Kalsnes; Foss, Stian; gjølberg, torleif; mester, simone; Nyquist-Andersen, Mari & Sivertsen, Magne S. [Show all 10 contributors for this article] (2023). Pharmaceutical compounding and storage of faricimab in a syringe for intravitreal injection do not impair stability and bi-specific binding properties. International Journal of Retina and Vitreous (IJRV). 9(1). doi: 10.1186/s40942-023-00507-3. Full text in Research Archive Show summary

  Background Intravitreal injection (IVI) of antibody biologics is a key treatment approach in ophthalmology. Pharmaceutical compounding and storage of prefilled syringes for IVI must take place without impairing the structure and function of the biologics. This study investigated the effect of withdrawing and storing the therapeutic antibody faricimab (Vabysmo, Roche, Basel, Switzerland) in the Zero Residual silicone oil-free, 0.2-mL syringe (SJJ Solutions, The Hague, the Netherlands). Methods To assess the effect of syringe withdrawal on faricimab, we compared samples from syringes prepared at day 0 with samples taken directly from faricimab vials. To assess the effect of syringe storage on faricimab, we kept prefilled syringes in the dark at 4 oC for 7, 14, or 37 days and compared samples from these syringes with day 0. We measured protein concentration (with spectrophotometry), stability and integrity (with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), size-exclusion chromatography (SEC), and melting temperature (Tm)), as well as binding of faricimab to its cognate antigens: vascular endothelial growth factor A (VEGF-A) and angiopoietin-2 (Ang-2) (with enzyme-linked immunosorbent assay (ELISA)). Results Faricimab migrated in line with its expected molecular mass under both reducing and non-reducing conditions for all time points when analyzed with SDS-PAGE, without any sign of degradation products or aggregation. The SEC elution profiles were identical for all time points. There were slight variations in Tm for different time points compared to day 0 but without consistent relationship with storage time. ELISA did not detect differences in VEGF-A or Ang-2 binding between time points, and faricimab did not bind the neonatal Fc receptor. Conclusions Withdrawal and storage of faricimab in syringes for up to day 37 did not impair the structure and bi-specific binding properties of the therapeutic antibody.

• Lustig, Marta; Chan, Chilam; Jansen, J. H. Marco; Bräutigam, Maria; Kölling, Max A. & Gehlert, Carina Lynn [Show all 16 contributors for this article] (2023). Disruption of the sialic acid/Siglec-9 axis improves antibody-mediated neutrophil cytotoxicity towards tumor cells. Frontiers in Immunology. 14, p. 1–15. doi: 10.3389/fimmu.2023.1178817. Full text in Research Archive Show summary

  Upregulation of surface expressed sialoglycans on tumor cells is one of the mechanisms which promote tumor growth and progression. Specifically, the interactions of sialic acids with sialic acid-binding immunoglobulin-like lectins (Siglecs) on lymphoid or myeloid cells transmit inhibitory signals and lead to suppression of anti-tumor responses. Here, we show that neutrophils express among others Siglec-9, and that EGFR and HER2 positive breast tumor cells express ligands for Siglec-9. Treatment of tumor cells with neuraminidases or a sialyl transferase inhibitor significantly reduced binding of a soluble recombinant Siglec-9-Fc fusion protein, while EGFR and HER2 expression remained unchanged. Importantly, the cytotoxic activity of neutrophils driven by therapeutic EGFR or HER2 antibodies in vitro was increased by blocking the sialic acid/Siglec interaction, either by reducing tumor cell sialylation or by a Siglec-9 blocking antibody containing an effector silenced Fc domain. In vivo a short-term xenograft mouse model confirmed the improved therapeutic efficacy of EGFR antibodies against sialic acid depleted, by a sialyltransferase inhibitor, tumor cells compared to untreated cells. Our studies demonstrate that sialic acid/Siglec interactions between tumor cells and myeloid cells can impair antibody dependent tumor cell killing, and that Siglec-9 on polymorphonuclear cells (PMN) is critically involved. Considering that PMN are often a highly abundant cell population in the tumor microenvironment, Siglec-9 constitutes a promising target for myeloid checkpoint blockade to improve antibody-based tumor immunotherapy.

• gjølberg, torleif; Lode, Heidrun Elisabeth; Melo, Gustavo B.; mester, simone; Probst, Christine & Sivertsen, Magne S. [Show all 9 contributors for this article] (2022). A Silicone Oil-Free Syringe Tailored for Intravitreal Injection of Biologics. Frontiers in Ophthalmology. 2. doi: 10.3389/fopht.2022.882013. Full text in Research Archive
• 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. Full text in Research Archive Show summary

  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.

• Gjølberg, Torleif Tollefsrud; Frick, Rahel; Mester, Simone; Foss, Stian; Grevys, Algirdas & Høydahl, Lene Støkken [Show all 11 contributors for this article] (2022). Biophysical differences in IgG1 Fc-based therapeutics relate to their cellular handling, interaction with FcRn and plasma half-life. Communications Biology. 5(1), p. 1–17. doi: 10.1038/s42003-022-03787-x. Full text in Research Archive Show summary

  Abstract Antibody-based therapeutics (ABTs) are used to treat a range of diseases. Most ABTs are either full-length IgG1 antibodies or fusions between for instance antigen (Ag)-binding receptor domains and the IgG1 Fc fragment. Interestingly, their plasma half-life varies considerably, which may relate to how they engage the neonatal Fc receptor (FcRn). As such, there is a need for an in-depth understanding of how different features of ABTs affect FcRn-binding and transport behavior. Here, we report on how FcRn-engagement of the IgG1 Fc fragment compare to clinically relevant IgGs and receptor domain Fc fusions, binding to VEGF or TNF-α. The results reveal FcRn-dependent intracellular accumulation of the Fc, which is in line with shorter plasma half-life than that of full-length IgG1 in human FcRn-expressing mice. Receptor domain fusion to the Fc increases its half-life, but not to the extent of IgG1. This is mirrored by a reduced cellular recycling capacity of the Fc-fusions. In addition, binding of cognate Ag to ABTs show that complexes of similar size undergo cellular transport at different rates, which could be explained by the biophysical properties of each ABT. Thus, the study provides knowledge that should guide tailoring of ABTs regarding optimal cellular sorting and plasma half-life.

• 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. Full text in Research Archive Show summary

  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.

• 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. Full text in Research Archive

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• Andersen, Jan Terje; mester, simone & gjølberg, torleif (2024). Slik skjøt oppstartsraketten Authera fart. [Internet]. Medwatch.no. Full text in Research Archive
• Ruso-Julve, Fulgencio; Herigstad, Marie Leangen; mester, simone; Foss, Stian & Andersen, Jan Terje (2024). An antibody concept for tailored engagement of immune cells and eradication of tumor cells. Full text in Research Archive
• Anthi, Aina Karen; mester, simone; Bern, Malin C.; Sandlie, Inger & Andersen, Jan Terje (2023). HemoMagic: Anemia Meets Unleashed Innovation. Full text in Research Archive
• Ruso-Julve, Fulgencio; Sakya, Siri A; Lode, Heidrun Elisabeth; Foss, Stian; Benjakul, Sopisa & Nilsen, Jeannette [Show all 10 contributors for this article] (2022). Engineered albumin as a scaffold for improving the pharmacokinetic properties of antibody fragments. Full text in Research Archive

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