Abstract
A synthetic peptide, K-PLP, consisting of 11-unit poly-lysine (K11) linked via polyethylene glycol (PEG) to proteolipid protein epitope (PLP) was synthesized, characterized, and evaluated for efficacy in ameliorating experimental autoimmune encephalomyelitis (EAE) induced by PLP. K-PLP was designed to mimic the cationic nature of the relapsing-remitting multiple sclerosis treatment, glatiramer acetate (GA). With a pI of ~10, GA is able to form visible aggregates at the site of injection via electrostatic interactions with the anionic extracellular matrix. Aggregation further facilitates the retention of GA at the site of injection and draining lymph nodes, which may contribute to its mechanism of action. K-PLP with a pI of ~11, was found to form visible aggregates in the presence of glycosaminoglycans and persist at the injection site and draining lymph nodes in vivo, similar to GA. Additionally, EAE mice treated with K-PLP showed significant inhibition of clinical symptoms compared to free poly-lysine and to PLP, which are the components of K-PLP. The ability of the poly-lysine motif to retain PLP at the injection site, which increased the local exposure of PLP to immune cells may be an important factor affecting drug efficacy.
Highlights
Glatiramer acetate (GA), the active ingredient in Copaxone®, is currently one of the most popular treatments for relapsing-remitting multiple sclerosis (RRMS) due to its safety, ease of patient selfadministration, and its effectiveness in reducing the relapse rate of RRMS patients [1, 2]
K-proteolipid protein epitope (PLP) consists of an 11-unit poly-lysine and MS antigen PLP 139-151 bridged by a flexible region comprised of four units of polyethylene glycol (PEG) (Figure 1A)
We have successfully constructed, characterized, and tested a model peptide consisting of 11-unit poly-lysine connected to MS/EAE antigen PLP designed to mimic GA’s behavior at the site of injection
Summary
Glatiramer acetate (GA), the active ingredient in Copaxone®, is currently one of the most popular treatments for relapsing-remitting multiple sclerosis (RRMS) due to its safety, ease of patient selfadministration, and its effectiveness in reducing the relapse rate of RRMS patients [1, 2]. Systemic exposure of GA is near zero, suggesting a key part of the drug mechanism may be local to the site of administration. It is unclear if certain structural elements of GA may be extrapolated as a design principle for other autoimmune interventions such as antigenspecific immunotherapy. Lysine is the predominant amino acid at ~34% of the molar mass, which imbues a strong cationic character (pI ~10). GA forms large, visible aggregates in the presence of glycosaminoglycans such as hyaluronic acid (HA) almost immediately upon contact [15]. The large aggregated particles were observed in vivo when GA was injected into the footpads of mice. Considering the aggregation of GA likely occurs prior to all other immunological events, the ability to form aggregates via electrostatic interaction with glycosaminoglycans may be an important property that contributes to the mechanism of GA
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