Human and Non-Human Primate Intestinal FcRn Expression and Immunoglobulin G Transcytosis

ABSTRACT Purpose To evaluate transcytosis of immunoglobulin G (IgG) by the neonatal Fc receptor (FcRn) in adult primate intestine to determine whether this is a means for oral delivery of monoclonal antibodies (mAbs). Methods Relative regional expression of FcRn and localization in human intestinal...

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Published in:Pharmaceutical research 2014-04, Vol.31 (4), p.908-922
Main Authors: Hornby, Pamela J., Cooper, Philip R., Kliwinski, Connie, Ragwan, Edwin, Mabus, John R., Harman, Benjamin, Thompson, Suzanne, Kauffman, Amanda L., Yan, Zhengyin, Tam, Susan H., Dorai, Haimanti, Powers, Gordon D., Giles-Komar, Jill
Format: Article
Language:English
Subjects:
Adult
Animals
Bioavailability
Biochemistry
Biomedical and Life Sciences
Biomedical Engineering and Bioengineering
Biomedicine
Caco-2 Cells
Cellular biology
Cynomolgus
Digestive system
Drug delivery systems
Female
Gene Expression Regulation
Histocompatibility Antigens Class I - biosynthesis
Humans
Immunoglobulin G - metabolism
Immunoglobulins
Intestinal Mucosa - metabolism
Macaca fascicularis
Male
Medical Law
Middle Aged
Monoclonal antibodies
Organ Culture Techniques
Pharmaceutical sciences
Pharmacology/Toxicology
Pharmacy
Primates
Protein expression
Rats
Receptors, Fc - biosynthesis
Research Paper
RNA, Messenger - biosynthesis
Transcytosis - physiology
Young Adult
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Summary:ABSTRACT Purpose To evaluate transcytosis of immunoglobulin G (IgG) by the neonatal Fc receptor (FcRn) in adult primate intestine to determine whether this is a means for oral delivery of monoclonal antibodies (mAbs). Methods Relative regional expression of FcRn and localization in human intestinal mucosa by RT-PCR, ELISA & immunohistochemistry. Transcytosis of full-length mAbs (sandwich ELISA-based detection) across human intestinal segments mounted in Ussing-type chambers, human intestinal (caco-2) cell monolayers grown in transwells, and serum levels after regional intestinal delivery in isoflurane-anesthetized cynomolgus monkeys. Results In human intestine, there was an increasing proximal-distal gradient of mucosal FcRn mRNA and protein expression. In cynomolgus, serum mAb levels were greater after ileum-proximal colon infusion than after administration to stomach or proximal small intestine (1–5 mg/kg). Serum levels of wild-type mAb dosed into ileum/proximal colon (2 mg/kg) were 124 ± 104 ng/ml ( n  = 3) compared to 48 ± 48 ng/ml ( n  = 2) after a non-FcRn binding variant. In vitro , mAb transcytosis in polarized caco-2 cell monolayers and was not enhanced by increased apical cell surface IgG binding to FcRn. An unexpected finding in primate small intestine, was intense FcRn expression in enteroendocrine cells (chromagranin A, GLP-1 and GLP-2 containing). Conclusions In adult primates, FcRn is expressed more highly in distal intestinal epithelial cells. However, mAb delivery to that region results in low serum levels, in part because apical surface FcRn binding does not influence mAb transcytosis. High FcRn expression in enteroendocrine cells could provide a novel means to target mAbs for metabolic diseases after systemic administration.
ISSN:0724-8741
1573-904X
DOI:10.1007/s11095-013-1212-3