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FcRn binding is not sufficient for achieving systemic therapeutic levels of immunoglobulin G after oral delivery of enteric‐coated capsules in cynomolgus macaques
Journal article   Open access   Peer reviewed

FcRn binding is not sufficient for achieving systemic therapeutic levels of immunoglobulin G after oral delivery of enteric‐coated capsules in cynomolgus macaques

Salman Muzammil, John R. Mabus, Philip R. Cooper, Randall J. Brezski, Courtney B. Bement, Rob Perkinson, Norman D. Huebert, Suzanne Thompson, Dalia Levine, Connie Kliwinski, …
Pharmacology research & perspectives, v 4(3), pp 1-n/a
Jun 2016
DOI: https://doi.org/10.1002/prp2.218
PMID: 27433338
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1002/prp2.218View
Published, Version of Record (VoR) Open

Abstract

Original
Although much speculation has surrounded intestinally expressed FcRn as a means for systemic uptake of orally administered immunoglobulin G (IgG), this has not been validated in translational models beyond neonates or in FcRn‐expressing cells in vitro. Recently, IgG1 intestinal infusion acutely in anesthetized cynomolgus resulted in detectable serum monoclonal antibody ( mA b) levels. In this study, we show that IgG2 has greater protease resistance to intestinal enzymes in vitro and mice in vivo, due to protease resistance in the hinge region. An IgG2 mA b engineered for FcRn binding, was optimally formulated, lyophilized, and loaded into enteric‐coated capsules for oral dosing in cynomolgus. Small intestinal pH 7.5 was selected for enteric delivery based on gastrointestinal pH profiling of cynomolgus by operator‐assisted IntelliCap System ® . Milling of the lyophilized IgG2 M428L FcRn‐binding variant after formulation in 10 mmol/L histidine, pH 5.7, 8.5% sucrose, 0.04% PS 80 did not alter the physicochemical properties nor the molecular integrity compared to the batch released in PBS . Size 3 hard gel capsules (23.2 mg IgG2 M428L ~3 mg/kg) were coated with hydroxypropyl methylcellulose acetate succinate for rapid dissolution at pH 7.5 in small intestine and FcRn binding of encapsulated mA b confirmed. Initial capsule dosing by endoscopic delivery into the small intestine achieved 0.2 + 0.1 ng/mL ( n  = 5) peak at 24 h. Weekly oral capsule dosing for 6 weeks achieved levels of 0.4 + 0.2 ng/mL and, despite increasing the dose and frequency, remained below 1 ng/mL. In conclusion, lyophilized milled mA b retains FcRn binding and molecular integrity for small intestinal delivery. The low systemic exposure has demonstrated the limitations of intestinal FcRn in non‐human primates and the unfeasibility of employing this for therapeutic levels of mA b. Local mA b delivery with limited systemic exposure may be sufficient as a therapeutic for intestinal diseases.

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Web of Science research areas
Pharmacology & Pharmacy
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