Human and Non-Human Primate Intestinal FcRn Expression and Immunoglobulin G Transcytosis
| Autor: | Gordon Powers, John R. Mabus, Amanda L. Kauffman, Jill Giles-Komar, Suzanne E. Thompson, Connie Kliwinski, Philip Cooper, Zhengyin Yan, Haimanti Dorai, Edwin Ragwan, Tam Susan H, Pamela J. Hornby, Benjamin C. Harman |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Adult
Male medicine.drug_class Fc receptor Pharmaceutical Science Receptors Fc Monoclonal antibody Immunoglobulin G Young Adult Neonatal Fc receptor Organ Culture Techniques medicine Animals Humans Pharmacology (medical) RNA Messenger Intestinal Mucosa Receptor Pharmacology biology epithelial cell Organic Chemistry Histocompatibility Antigens Class I Middle Aged Molecular biology Epithelium Rats Macaca fascicularis medicine.anatomical_structure Transcytosis oral bioavailability Gene Expression Regulation Caco-2 monoclonal antibody Immunology drug delivery biology.protein Molecular Medicine Female Caco-2 Cells Biotechnology Research Paper |
| Zdroj: | Pharmaceutical Research |
| ISSN: | 1573-904X 0724-8741 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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