Human and non-human primate intestinal FcRn expression and immunoglobulin G transcytosis.
OBJECTIVE
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.
Biologics Research, Biotechnology CoE, Janssen Pharmaceutical J&J, Radnor, Pennsylvania, 19087, USA, PHornby@its.jnj.com.
Pamela J
PJ
Hornby
Philip R
PR
Cooper
Connie
C
Kliwinski
Edwin
E
Ragwan
John R
JR
Mabus
Benjamin
B
Harman
Suzanne
S
Thompson
Amanda L
AL
Kauffman
Zhengyin
Z
Yan
Susan H
SH
Tam
Haimanti
H
Dorai
Gordon D
GD
Powers
Jill
J
Giles-Komar
D000328:Adult; D000818:Animals; D018938:Caco-2 Cells; D005260:Female; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011961:Receptors, Fc / Q000096:biosynthesis*; D057900:Transcytosis / Q000502:physiology*; D055815:Young Adult
D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D012333:RNA, Messenger; D011961:Receptors, Fc; C100688:Fc receptor, neonatal