The effect of the neonatal Fc receptor on human IgG biodistribution in mice.
The neonatal Fc receptor (FcRn) plays a pivotal role in IgG homeostasis, i.e., it salvages IgG antibodies from lysosomal degradation following fluid-phase pinocytosis, thus preventing rapid systemic elimination of IgG. Recombinant therapeutic antibodies are typically composed of human or humanized sequences, and their biodistribution, or tissue distribution, is often studied in murine models, although, the effect of FcRn on tissue distribution of human IgG in rodents has not been investigated. In this report, an (125)I-labeled human IgG1 antibody was studied in both wild type C57BL/6 (WT) and FcRn knockout (KO) mice. Total radioactivity in both plasma and tissues (0-96hr post-dose) was measured by gamma-counting. Plasma exposure of human IgG1 were significantly lower in FcRn KO mice, which is consistent with the primary function of FcRn. Differences in biodistribution of human IgG to selected tissues were also observed. Among the tissue examined, the fat, skin and muscle showed a decrease in tissue-to-blood (T/B) exposure ratio of human IgG1 in FcRn KO mice comparing to the WT mice, while the liver, spleen, kidney, and lung showed an increase in the T/B exposure ratio in FcRn KO mice. A time-dependent change in the T/B ratios of human IgG1 was also observed for many tissues in FcRn KO mice. These results suggest that, in addition to its role in IgG elimination, FcRn may also play a role in antibody biodistribution.
Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism; Merck Research Laboratories; West Point, PA USA.
Nancy
N
Chen
Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism; Merck Research Laboratories; West Point, PA USA.
Weirong
W
Wang
Department of Laboratory Animal Resources; Merck Research Laboratories; West Point, PA USA.
Scott
S
Fauty
Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism; Merck Research Laboratories; West Point, PA USA.
Yulin
Y
Fang
Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism; Merck Research Laboratories; West Point, PA USA.
Lora
L
Hamuro
Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism; Merck Research Laboratories; West Point, PA USA.
Azher
A
Hussain
Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism; Merck Research Laboratories; West Point, PA USA.
Thomayant
T
Prueksaritanont
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000378:metabolism*; D007457:Iodine Radioisotopes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011961:Receptors, Fc / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution
D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D011961:Receptors, Fc; C100688:Fc receptor, neonatal
FcRn; IgG; biodistribution; monoclonal antibody; pharmacokinetics; tissue distribution