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Routes of administration and dose optimization of soluble antigen arrays in mice with experimental autoimmune encephalomyelitis.

Journal of pharmaceutical sciences (2014-12-03)
Sharadvi Thati, Christopher Kuehl, Brittany Hartwell, Joshua Sestak, Teruna Siahaan, M Laird Forrest, Cory Berkland
ABSTRACT

Soluble antigen arrays (SAgAs) were developed for treating mice with experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. SAgAs are composed of hyaluronan with grafted EAE antigen and LABL peptide (a ligand of ICAM-1). SAgA dose was tested by varying injection volume, SAgA concentration, and administration schedule. Routes of administration were explored to determine the efficacy of SAgAs when injected intramuscularly, subcutaneously, intraperitoneally, intravenously, or instilled into lungs. Injections proximal to the central nervous system (CNS) were compared with distal injection sites. Intravenous dosing was included to determine if SAgA efficiency results from systemic exposure. Pulmonary instillation (p.i.) was included as reports suggest T cells are licensed in the lungs before moving to the CNS. Decreasing the volume of injection or SAgA dose reduced treatment efficacy. Treating mice with a single injection on day 4, 7, and 10 also reduced efficacy compared with injecting on all three days. Surprisingly, changing the injection site did not lead to a significant difference in efficacy. Intravenous administration showed efficacy similar to other routes, suggesting SAgAs act systemically. When SAgAs were delivered via p.i., however, EAE mice failed to develop any symptoms, suggesting a unique lung mechanism to ameliorate EAE in mice.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Pyridoxal 5′-phosphate hydrate, ≥98%
Sigma-Aldrich
Pyridoxal 5′-phosphate monohydrate, ≥97.0% (NT)
Sigma-Aldrich
Pyridoxal 5′-phosphate hydrate, powder, BioReagent, suitable for cell culture