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Neuropharmacology. 2018 May 1;133:345-353. doi: 10.1016/j.neuropharm.2018.02.002. Epub 2018 Feb 8.

Recombinant IgG1 Fc hexamers block cytotoxicity and pathological changes in experimental in vitro and rat models of neuromyelitis optica.

Author information

1
Departments of Medicine and Physiology, University of California, San Francisco, CA, USA.
2
CSL Behring AG, Bern, Switzerland.
3
CSL Limited, Victoria, Australia.
4
Departments of Medicine and Physiology, University of California, San Francisco, CA, USA. Electronic address: https://www.ucsf.edu/verklab.

Abstract

Intravenous human immunoglobulin G (IVIG) may have therapeutic benefit in neuromyelitis optica spectrum disorders (herein called NMO), in part because of the anti-inflammatory properties of the IgG Fc region. Here, we evaluated recombinant Fc hexamers consisting of the IgM μ-tailpiece fused with the Fc region of human IgG1. In vitro, the Fc hexamers prevented cytotoxicity in aquaporin-4 (AQP4) expressing cells and in rat spinal cord slice cultures exposed to NMO anti-AQP4 autoantibody (AQP4-IgG) and complement, with >500-fold greater potency than IVIG or monomeric Fc fragments. Fc hexamers at low concentration also prevented antibody-dependent cellular cytotoxicity produced by AQP4-IgG and natural killer cells. Serum from rats administered a single intravenous dose of Fc hexamers at 50 mg/kg taken at 8 h did not produce complement-dependent cytotoxicity when added to AQP4-IgG-treated AQP4-expressing cell cultures. In an experimental rat model of NMO produced by intracerebral injection of AQP4-IgG, Fc hexamers at 50 mg/kg administered before and at 12 h after AQP4-IgG fully prevented astrocyte injury, complement activation, inflammation and demyelination. These results support the potential therapeutic utility of recombinant IgG1 Fc hexamers in AQP4-IgG seropositive NMO.

KEYWORDS:

AQP4; Astrocyte; Complement; Fc multimer; Immunoglobulin; NMO; Neuroinflammation

PMID:
29428821
PMCID:
PMC6322534
DOI:
10.1016/j.neuropharm.2018.02.002
[Indexed for MEDLINE]
Free PMC Article

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