Investigation of the interaction between the class I MHC-related Fc receptor and its immunoglobulin G ligand

Raghavan, Malini; Chen, Marcus Y; Gastinel, Louis N.; Björkman, Pamela J.

doi:10.1016/1074-7613(94)90082-5

Cited by 142 publications

(138 citation statements)

References 39 publications

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“…As expected, no binding was seen at pH 7.4. Thus, the histidine mutations in shFcRn do not affect hIgG3 binding, and the results are in agreement with data obtained from studies concerning rat FcRn [21,22].…”

Section: Shfcrn-ligand Interaction Studies By Elisasupporting

confidence: 90%

The conserved histidine 166 residue of the human neonatal Fc receptor heavy chain is critical for the pH‐dependent binding to albumin

2006

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The MHC class I-related neonatal Fc receptor (FcRn) serves in the homeostatic regulation of IgG and albumin by increasing their half-lives. FcRn may bind IgG and albumin simultaneously, and in a pH-dependent manner, with ligand binding at pH 6.0-6.5 and release at pH 7.0-7.4. The FcRn-IgG interaction has been extensively characterized at the amino acid level and shown to depend on conserved histidine residues in the IgG-Fc part that interact with negatively charged residues in the a-2 domain of FcRn. The recently discovered FcRn-albumin interaction remains to be elucidated. Guided by the pH dependence of the FcRn-albumin interaction, we compared the sequence of the FcRn a-2 domain from eleven different species, and identified histidine residues that were conserved in all (H166) or seven (H161) of these. Both residues are located directly opposite to the IgG interaction site in the folded molecule. We did in vitro mutagenesis (H161A or H166A) in combination with interaction studies (ELISA and surface plasmon resonance) with recombinant, soluble, purified receptors and IgG and albumin to investigate the role of the two histidine residues. Our results show clear evidence that the conserved H166 is a key player in the FcRn-albumin interaction.

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Section: Shfcrn-ligand Interaction Studies By Elisasupporting

confidence: 90%

The conserved histidine 166 residue of the human neonatal Fc receptor heavy chain is critical for the pH‐dependent binding to albumin

2006

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“…18-20 Disease amelioration following administration of an anti-FcRn antibody has been demonstrated in a number of experimental autoimmune disease models in animals. 5,21-25 Thus, inhibition of the FcRn-dependent IgG salvage pathway in autoimmune conditions could lead to lower plasma concentrations of pathogenic IgG and may result in therapeutic benefits.…”

Section: Introductionmentioning

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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“…For instance, newborns receive immunoglobulins from mother's milk through binding to receptors on intestinal epithelial cells (Raghavan et al, 1994). Signaling and adapter molecules in the cytoplasm interact with the cytoplasmic tails of receptors embedded in the plasma membrane (Goldstein and Dembo, 1995).…”

Section: Introductionmentioning

confidence: 99%

The Effect of a Receptor Layer on the Measurement of Rate Constants

Edwards

2001

Bulletin of Mathematical Biology

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Many cellular reactions involve a reactant in solution binding to or dissociating from a reactant attached to a surface. Most studies assume that the reactions occur on this surface, when in actuality the receptors usually lie in a thin layer on top of it. The effect of this layer is considered, particularly as it relates to the BIAcore TM measurement device, though the results are applicable to biological systems. A dimensionless parameter measuring the strength of the effect of the receptor layer is found. Asymptotic and singular perturbation techniques are used to analyse association and dissociation kinetics, though the effect of the receptor layer need not be small. Linear and nonlinear integral equations result from the analysis; explicit and asymptotic solutions are constructed for physically realizable cases. In addition, effective rate constants are derived that illustrate the combined effects of transport and the receptor layer on the measured rate constants. All these expressions provide a direct way to estimate rate constants from BIAcore TM binding data.

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Investigation of the interaction between the class I MHC-related Fc receptor and its immunoglobulin G ligand

Cited by 142 publications

References 39 publications

The conserved histidine 166 residue of the human neonatal Fc receptor heavy chain is critical for the pH‐dependent binding to albumin

The conserved histidine 166 residue of the human neonatal Fc receptor heavy chain is critical for the pH‐dependent binding to albumin

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

The Effect of a Receptor Layer on the Measurement of Rate Constants

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