Glatiramer acetate persists at the injection site and draining lymph nodes via electrostatically-induced aggregation.

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Song JY, Larson NR, Thati S, Torres-Vazquez I, Martinez-Rivera N, Subelzu NJ, Leon MA, Rosa-Molinar E, Schoneich C, Forrest ML, Middaugh CR, Berkland CJ

Glatiramer acetate persists at the injection site and draining lymph nodes via electrostatically-induced aggregation.

J Control Release. 2019 Jan 10;293:36-47. doi: 10.1016/j.jconrel.2018.11.007. Epub 2018 Nov 7.

PubMed ID
30414463 [ View in PubMed
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Abstract

Glatiramer acetate (GA) is widely prescribed for the treatment of relapsing-remitting multiple sclerosis, however, the mechanism of action is still not fully understood. We investigated the structural properties of GA and examined alterations to the drug upon injection into the subcutaneous space. First, a variety of biophysical characterization techniques were employed to characterize GA in solution. GA was found to exist as alpha helices in solution with a hydrodynamic radius of ~3nm in size. To simulate GA behavior at the site of injection, GA was injected into a solution of 1.5MDa hyaluronic acid (HA). Visible aggregates were observed immediately upon injection and subsequent testing indicated aggregation was driven by electrostatic interactions between the positively-charged GA and negatively-charged HA. In vivo testing confirmed GA formed spherical particles in the nano- to micrometer size range, suggesting this mechanism contributes to persistence at the injection site and in draining lymph nodes. The aggregates were found to associate with glycosaminoglycans, suggesting an electrostatic mechanism of induced aggregation like the simulated injection. These novel observations may help explain the complex immunomodulatory mechanisms of GA and adverse injection site reactions seen in patients.

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