Investigation of the Influence of FcRn on the Distribution of IgG to the Brain

Garg, Amit; Balthasar, Joseph P.

doi:10.1208/s12248-009-9129-9

Cited by 108Monoclonal and Polyclonal Antibodies ResearchBarrier Structure and Function StudiesDrug Transport and Resistance Mechanisms

Investigation of the Influence of FcRn on the Distribution of IgG to the Brain

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Garg, Amit, Balthasar, Joseph P.·2009·The AAPS Journal

DOI 10.1208/s12248-009-9129-9PMC PMC2758122

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Abstract

It has been suggested that the neonatal Fc receptor (FcRn) is a primary determinant of the distribution of IgG to the brain. In the present report, (125)I-labeled 7E3, a monoclonal IgG1 antibody, was injected intravenously to groups of FcRn-deficient mice and C57BL/6J control mice. Sub-groups of three mice were sacrificed at several time points. Blood and brain tissue were harvested and radioactivity was assessed. Antibody concentrations in brain were corrected for residual blood using (51)Cr-labeled red blood cells. Data were analyzed via WinNonlin, and areas under plasma and tissue concentration vs. time curves (AUCs) were assessed via the Bailer method. The apparent plasma elimination half-life and clearance of 7E3 were 13.61 +/- 0.61 days and 6.5 +/- 0.10 ml/day/kg in control mice and 0.70 +/- 0.05 days and 63.5 +/- 2.7 ml/day/kg in the knockout mice. Plasma and brain AUCs (0-10 days) were found to be 3,338.7 +/- 50.4 and 7.46 +/- 0.5 nM day in control animals and 781.2 +/- 16.6 and 1.65 +/- 0.1 nM day in FcRn-deficient animals. There was no significant difference between brain-to-plasma AUC ratios in control and FcRn-deficient mice (0.0022 +/- 0.00015 vs. 0.0021 +/- 0.00011, p = 0.3347). Two-way analysis of variance showed no significant differences, at any time point, between brain-to-plasma concentration ratios determined from control and knockout animals. The results suggest that FcRn does not contribute significantly to the "blood-brain barrier" for IgG in mice, and the data suggest that FcRn is not responsible for the low exposure of IgG in the brain relative to plasma.

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In preclinical species and humans, mAbs are known to have minimal brain penetration, at around 0.1-0.4% of mAb plasma concentration.
“In preclinical species and humans, mAbs are known to have minimal brain penetration, at around 0.1–0.4% of mAb plasma concentration35,36.”
From A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings (2024) · cites this paper as [35]

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Authors: Garg, A., & Balthasar, J. P.
Affiliations: University at Buffalo, State University of New York (US)
Corresponding author: Balthasar, Joseph P.
ORCID: Garg, Amit
Balthasar, Joseph P.
Venue: The AAPS Journal
Publisher: Springer Science and Business Media LLC
Published: 2009-07-28
Volume: 11
Issue: 3
Pages: 553-7
ISSN: 1550-7416 (ISSN-L)
DOI: 10.1208/s12248-009-9129-9
PMC: PMC2758122
OpenAlex: W2045301605
Cited by: 108
References: 42
Citations by year: 2026: 3 · 2025: 8 · 2024: 9 · 2023: 5 · 2022: 9 · 2021: 9 · 2020: 7 · 2019: 5 · 2018: 11 · 2017: 3 · 2016: 7 · 2015: 5 · 2014: 6 · 2013: 6 · 2012: 8
FWCI: 3.78
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
Locations: The AAPS Journal (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Eli Lilly and Company
National Institutes of Health
National Institute of Allergy and Infectious Diseases (AI60687, R01AI060687)
Topics: Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords: neonatal Fc receptor, IgG, brain distribution, blood-brain barrier, antibody clearance, plasma half-life, brain-to-plasma ratio, passive immunization
MeSH terms: Animals, beta 2-Microglobulin, Brain, Immunoglobulin G, Iodine Radioisotopes, Mice, Inbred C57BL, Receptors, Fc, Histocompatibility Antigens Class I, Mice, Knockout, Mice

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Investigation of the Influence of FcRn on the Distribution of IgG to the Brain

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