Perspective – FcRn transports albumin: relevance to immunology and medicine

Anderson, Clark L.; Chaudhury, Chaity; Kim, Jonghan; Bronson, C. L.; Wani, Mohd Lateef; Mohanty, Sudhasri

doi:10.1016/j.it.2006.05.004

Cited by 179 publications

(140 citation statements)

References 40 publications

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“…55 Significant reductions in plasma albumin concentrations in patients would be undesirable, therefore during development, the anti-FcRn variable region (1519.g57) was selected for its lack of inhibition of the FcRn-albumin interaction. We have demonstrated that the binding epitope of 1519.g57 Fab’ was separate from that of albumin.…”

Section: Resultsmentioning

confidence: 99%

Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration

Smith

Kießling

Lledó-García

et al. 2018

mAbs

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Rozanolixizumab (UCB7665), a humanized high-affinity anti-human neonatal Fc receptor (FcRn) monoclonal antibody (IgG4P), has been developed to reduce pathogenic IgG in autoimmune and alloimmune diseases. We document the antibody isolation and compare rozanolixizumab with the same variable region expressed in various mono-, bi- and trivalent formats. We report activity data for rozanolixizumab and the different molecular formats in human cells, FcRn-transgenic mice, and cynomolgus monkeys. Rozanolixizumab, considered the most effective molecular format, dose-dependently and selectively reduced plasma IgG concentrations in an FcRn-transgenic mouse model (no effect on albumin). Intravenous (IV) rozanolixizumab dosing in cynomolgus monkeys demonstrated non-linear pharmacokinetics indicative of target-mediated drug disposition; single IV rozanolixizumab doses (30 mg/kg) in cynomolgus monkeys reduced plasma IgG concentration by 69% by Day 7 post-administration. Daily IV administration of rozanolixizumab (initial 30 mg/kg loading dose; 5 mg/kg daily thereafter) reduced plasma IgG concentrations in all cynomolgus monkeys, with low concentrations maintained throughout the treatment period (42 days). In a 13-week toxicology study in cynomolgus monkeys, supra-pharmacological subcutaneous and IV doses of rozanolixizumab (≤ 150 mg/kg every 3 days) were well tolerated, inducing sustained (but reversible) reductions in IgG concentrations by up to 85%, with no adverse events observed. We have demonstrated accelerated natural catabolism of IgG through inhibition of IgG:FcRn interactions in mice and cynomolgus monkeys. Inhibition of FcRn with rozanolixizumab may provide a novel therapeutic approach to reduce pathogenic IgG in human autoimmune disease. Rozanolixizumab is being investigated in patients with immune thrombocytopenia (NCT02718716) and myasthenia gravis (NCT03052751).

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Section: Resultsmentioning

confidence: 99%

Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration

Smith

Kießling

Lledó-García

et al. 2018

mAbs

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“…In contrast, the mouse J pro was the same as J rmr [10,13]. The more efficient albumin recycling in the mouse may suggest a larger J max (e.g., increase in FcRn density per kg body weight) and/or a smaller K m compared with human.…”

Section: Fcrn-mediated Kinetics For Human Albuminmentioning

confidence: 87%

“…These unique characteristics had been explained by a saturable receptor-mediated mechanism that protects both IgG [3] and albumin [4] from intracellular degradation after nonspecific pinocytic uptake, allowing them to be recycled to the cell surface and into the extracellular milieu for continuing circulation. In the last decade the responsible receptor was identified as FcRn, a nonclassical MHC class-I molecule, that bears distinct and independent binding sites for both ligands [5][6][7][8][9][10]. FcRn is also largely responsible for the peripartum transport of IgG from mother to offspring [11].…”

Section: Introductionmentioning

confidence: 99%

“…FcRn is also largely responsible for the peripartum transport of IgG from mother to offspring [11]. It is further known that animals deficient in FcRn catabolize IgG and albumin more rapidly than the normal animal and manifest low plasma concentrations of both molecules [5][6][7][8][9][10]12,13].…”

Section: Introductionmentioning

confidence: 99%

“…First, familial hypercatabolic hypoproteinemia (FHH) [2,16], showing hypercatabolism and low plasma concentrations of both IgG and albumin, results from a deficiency of FcRn due to a mutant β2-microglobulin (B2m) gene [10,17]. Second, patients with myotonic dystrophy (DM) show hypercatabolism and plasma deficiency of only IgG but not albumin.…”

Section: Introductionmentioning

confidence: 99%

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Kinetics of FcRn-mediated recycling of IgG and albumin in human: Pathophysiology and therapeutic implications using a simplified mechanism-based model

Kim

Hayton

Robinson

et al. 2007

Clinical Immunology

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175

122

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The nonclassical MHC class-I molecule, FcRn, salvages both IgG and albumin from degradation. Here we introduce a mechanism-based kinetic model for human to quantify FcRn-mediated recycling of both ligands based on saturable kinetics and data from the literature using easily measurable plasma concentrations rather than unmeasurable endosomal concentrations. The FcRn-mediated fractional recycling rates of IgG and albumin were 142% and 44% of their fractional catabolic rates, respectively. Clearly, FcRn-mediated recycling is a major contributor to the high endogenous concentrations of these two important plasma proteins. While familial hypercatabolic hypoproteinemia is caused by complete FcRn deficiency, the hypercatabolic IgG deficiency of myotonic dystrophy could be explained, based on the kinetic analyses, by a normal number of FcRn with lowered affinity for IgG but normal affinity for albumin. A simulation study demonstrates that the plasma concentrations of IgG and albumin could be dynamically controlled by both FcRn-related and -unrelated parameters.

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Association of Albumin Levels With Outcome in Intravenous Immunoglobulin–Treated Guillain-Barré Syndrome

et al. 2017

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IMPORTANCE There is an urgent need for biomarkers to monitor treatment efficacy and anticipate outcome in patients with Guillain-Barré syndrome (GBS).OBJECTIVE To assess whether there is an association between serum albumin levels, a widely used and relatively easily measurable biomarker of health and inflammation, and the clinical course and outcome of GBS in patients treated with intravenous immunoglobulin (IVIG). DESIGN, SETTING, AND PARTICIPANTSWe used serum samples derived from a cohort of patients with GBS admitted to hospitals across the Netherlands participating in national GBS studies from May 5, 1986, through August 2, 2000. Serum albumin was measured from January 13 to 20, 2011. Analysis was performed from February 25, 2013, to September 6, 2016. All patients fulfilled the criteria for GBS and had severe disease (defined as not being able to walk unaided >10 m). Patients misdiagnosed as having GBS were retrospectively excluded from the study. Serum samples were obtained before and after IVIG treatment at 4 standardized time points from 174 patients. Albumin levels were determined by routine diagnostic turbidimetry and related to demographics and clinical course during a follow-up of 6 months.MAIN OUTCOMES AND MEASURES Serum albumin concentration was determined before and after treatment with IVIG and related to clinical outcome: muscle weakness (measured by Medical Research Council sum score), respiratory failure (measured by requirement and duration of mechanical ventilation), and ability to walk (measured by GBS disability score).RESULTS Serum albumin levels were determined in 174 patients with GBS (mean [SD] age, 49.6 [20.1] years; 99 males [56.9%]). Before treatment, the median serum albumin level was 4.2 g/dL (interquartile range, 3.8-4.5 g/dL), with hypoalbuminemia (albumin, <3.5 g/dL) in 20 (12.8%) of 156 patients. Two weeks after commencing treatment with IVIG (2 g/kg), the median serum albumin level decreased to 3.7 g/dL (interquartile range, 3.2-4.1 g/dL) (P < .001), and the number with hypoalbuminemia increased to 60 (34.5%) of 174 (P < .001). Hypoalbuminemia was associated with an increased chance of respiratory failure before (16 [36.4%] of 44, P = .001) or after (29 [54.7%] of 53, P < .001) IVIG treatment, inability to walk unaided (21 [35.0%] of 60 vs 6 [5.3%] of 114, P < .001), and severe muscle weakness at 4 weeks (Medical Research Council sum score, 31.8 vs 52.9, P < .001) and 6 months (Medical Research Council sum score, 49.4 vs 58.4, P < .001). CONCLUSIONS AND RELEVANCEPatients with GBS may develop hypoalbuminemia after treatment with IVIG, which is related to a more severe clinical course and a poorer outcome. Further studies are required to confirm that serum albumin can be used as a biomarker to monitor disease activity and treatment response to IVIG in patients with GBS.

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Perspective – FcRn transports albumin: relevance to immunology and medicine

Cited by 179 publications

References 40 publications

Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration

Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration

Kinetics of FcRn-mediated recycling of IgG and albumin in human: Pathophysiology and therapeutic implications using a simplified mechanism-based model

Association of Albumin Levels With Outcome in Intravenous Immunoglobulin–Treated Guillain-Barré Syndrome

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