Slow Subcutaneous Release of Glatiramer Acetate or CD40-Targeting Peptide KGYY6 Is More Advantageous in Treating Ongoing Experimental Autoimmune Encephalomyelitis.

Abstract

Background/objectives: One of the first-line disease-modifying treatments of multiple sclerosis (MS) is Glatiramer Acetate (GA), which requires daily or three-times-weekly subcutaneous injections. Disease progression, while slowed, still occurs with time. Increasing the impact of the treatment while decreasing the frequency of injections would be ideal. The mechanism of action of GA remains undefined. We developed an alternate approach, KGYY₆, whose mechanism of action targets the CD40 receptor with promising results in an Experimental Autoimmune Encephalomyelitis (EAE) model.

Methods: GA and a CD40-targeting peptide, KGYY₆, were formulated as slow-release particles used to treat EAE in C57BL/6 mice.

Results: Compared to liquid formulations, the particle formulations vastly improved drug efficacy in both cases, which would be advantageous in treating MS. GA is a combination of randomly generated peptides, in the size range of 5000-9000 Da, using the amino acids E, A, Y, and K. This approach introduces batch differences that impacts efficacy, a persistent problem with GA. KGYY₆ is generated in a controlled process and has a motif, K-YY, which could be generated when manufacturing GA. When testing two different lots of GA or KGYY₆, the latter performed equally well across lots, while GA did not.

Conclusions: Slow-release formulations of both GA and KGYY₆ vastly improve the efficacy of both, and KGYY₆ is more consistent in efficacy across different lots.