Cross-species Binding Analyses of Mouse and Human Neonatal Fc Receptor Show Dramatic Differences in Immunoglobulin G and Albumin Binding

Andersen, Jan Terje; Daba, Muluneh Bekele; Berntzen, Gøril; Michaelsen, Terje E.; Sandlie, Inger

doi:10.1074/jbc.m109.081828

Cited by 171 publications

(189 citation statements)

References 59 publications

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“…Because mouse albumin binds to, and is recycled by, human FcRn, 47 the effect of FcRn blockade on mouse plasma albumin concentration in the human FcRn transgenic mouse was measured. Neither rozanolixizumab, nor any other 1519.g57 format (with the exception of IgG1 for unknown reasons), was observed to have an effect on endogenous mouse plasma albumin concentration (Supplementary Figure 7A and 7B), indicating little or no blockade of albumin binding, even by those formats that included or bound mouse albumin (Fab-albumin fusion or conjugate, or FabFv).…”

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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“…Recent experiments have shown that some humanized therapeutic antibodies have a higher FcRn binding affinity in rodents and NHPs than the endogenous equivalent (Andersen et al 2010;Giragossian et al 2013). Thus, the titers of endogenous antibodies at birth in model species may underestimate the extent of embryo-fetal exposure to maternally administered humanized IgGs (DeSesso et al 2012).…”

Section: Methodsmentioning

confidence: 99%

FcRn Expression on Placenta and Fetal Jejunum during Early, Mid-, and Late Gestation in Minipigs

Jacobsen

Hill

Reynaud³

et al. 2015

Toxicol Pathol

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Developmental toxicity testing of therapeutic antibodies is most often conducted in nonhuman primates owing to lack of crossreactivity in other species. Minipigs may show cross-reactivity for some humanized antibodies but have not been used for developmental toxicity testing due to an assumed lack of embryo-fetal exposure. Unlike in humans, maternal IgGs do not cross the porcine placenta to reach the fetus. Some humanized IgGs, however, have a higher affinity for the neonatal Fc receptor (FcRn) and are more likely than endogenous antibodies to cross the placenta of animals. The major site of prenatal IgG transfer is the placenta, though FcRn in fetal intestine could also uptake maternal IgGs from swallowed amniotic fluid. Using immunohistochemistry and in situ hybridization in this experiment, FcRn was found in minipig placenta and fetal intestine during early, mid-, and late gestation. To date, however, fetal exposure to maternally administered IgGs has never been demonstrated in the minipig.

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“…Mouse FcRn cannot bind to human albumin, while human FcRn can bind to mouse albumin. 22 The intracellular pathway of FcRn mediated IgG transport begins with fluid phase pintocytosis of IgG (assuming neutral pH at the membrane surface), and binding to FcRn only occurs after endosome acidification. From there, IgG may be transcytosed to the opposite membrane surface, recycled back to IgG is believed to enter the cell by fluid phase pintocytosis (assuming neutral pH condition) and does not bind to FcRn until the endosome is acidified.…”

Section: Fcrn Functions In Organsmentioning

confidence: 99%

Neonatal Fc receptor and IgG-based therapeutics

Kuo

Aveson²

2011

mAbs

200

191

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Cross-species Binding Analyses of Mouse and Human Neonatal Fc Receptor Show Dramatic Differences in Immunoglobulin G and Albumin Binding

Cited by 171 publications

References 59 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

FcRn Expression on Placenta and Fetal Jejunum during Early, Mid-, and Late Gestation in Minipigs

Neonatal Fc receptor and IgG-based therapeutics

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