Differential effects of FcRn antagonists on the subcellular trafficking of FcRn and albumin
Guanglong Ma, … , Bianca Balbino, E. Sally Ward
Guanglong Ma, … , Bianca Balbino, E. Sally Ward
Published May 7, 2024
Citation Information: JCI Insight. 2024;9(10):e176166. https://doi.org/10.1172/jci.insight.176166.
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Research Article Immunology

Differential effects of FcRn antagonists on the subcellular trafficking of FcRn and albumin

Abstract

The homeostasis of IgG is maintained by the neonatal Fc receptor, FcRn. Consequently, antagonism of FcRn to reduce endogenous IgG levels is an emerging strategy for treating antibody-mediated autoimmune disorders using either FcRn-specific antibodies or an engineered Fc fragment. For certain FcRn-specific antibodies, this approach has resulted in reductions in the levels of serum albumin, the other major ligand transported by FcRn. Cellular and molecular analyses of a panel of FcRn antagonists have been carried out to elucidate the mechanisms leading to their differential effects on albumin homeostasis. These analyses have identified 2 processes underlying decreases in albumin levels during FcRn blockade: increased degradation of FcRn and competition between antagonist and albumin for FcRn binding. These findings have potential implications for the design of drugs to modulate FcRn function.

Authors

Guanglong Ma, Andrew R. Crowley, Liesbeth Heyndrickx, Ilse Rogiers, Eef Parthoens, Jolien Van Santbergen, Raimund J. Ober, Vladimir Bobkov, Hans de Haard, Peter Ulrichts, Erik Hofman, Els Louagie, Bianca Balbino, E. Sally Ward

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Figure 7

Effects of FcRn antagonists on HSA levels in mice humanized to express hFcRn and HSA.

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Effects of FcRn antagonists on HSA levels in mice humanized to express h...
Female or male 14- to 15-week-old Albumus Rag1-deficient (KO) mice were IP injected with antagonist (100 mg/kg for N027 or HL161BK, n = 5 per treatment group; 35 mg/kg for ARGX-113, n = 8) or PBS (n = 3) on days 0, 7, 14, and 21. We collected 20 μL blood samples to establish baseline levels of endogenous HSA on days –13 and –6 (predose). We collected 20 μL blood samples from each mouse 1 hour after each injection and samples on days 3, 10, 17, 24, 28, and 35. HSA concentrations were assessed by ELISA. (A) Schematic representation of dosing and sample collection. (B) HSA levels normalized to day –6; black arrows indicate days of IP injections. Data for PBS, HL161BK, and N027 are representative of 2 individual experiments (n = 3 for PBS, n = 5 for HL161BK and N027 in each experiment); data for ARGX-113 (n = 8) are from 1 experiment. Statistical analysis for each day was performed with a longitudinal model, and significant differences compared with the PBS control are denoted above each time point: *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. One-way ANOVA with Dunnett’s multiplicity adjustment was used for the analysis of the overall average percentage changes in HSA levels from baseline (PBS control; D0–D35) for the individual mouse profiles over time, summarized as AUC (significant differences denoted on the right of the key). Error bars indicate the standard error of the mean.