BioProject

Glatiramer acetate (GA; Copaxone), is a complex mixture of synthetic polypeptides approved for treatment of multiple sclerosis (MS). GA is an altered peptide ligand (APL) of myelin basic protein (MBP), an encephalitic autoantigen implicated in MS. GA induces GA-reactive T cells, which upregulate expression of anti-inflammatory and neurotrophic substances in the CNS. The antigenic sequences in glatiramoids cannot be completely characterized; nevertheless, differences among them can cause toxicity. We conducted microarray analyses to determine whether gene expression by GA-reactive lymphocytes from mouse spleens could differentiate GA from other glatiramoids. Expression of 135 genes was unique to cells reactivated by GA vs by intentionally altered GA and other glatiramoids. Significantly (p<0.01) altered expression of 207 genes was observed by cells reactivated by GA vs purported generic GA. Some APLs of MBP have caused serious adverse effects in MS patients. The influence of altered gene expression on glatiramoid safety warrants further investigation. Overall design: Glatiramoid samples for SPL cell activation were grouped into four categories: 1) Verified GA, which included GA-RS (22 samples) and GA drug product (GA-DP, 34 samples from 30 batches) manufactured by Teva; 2) Deliberately Modified GA (DM-GA; 9 samples), which included glatiramoids made by Teva that were similar to GA but modified in a variety of ways: prepared with different ingredients (e.g., missing a constituent amino acid); prepared with the same amino acids in the same molar ratio as GA, but with defined amino acid sequences and different molecular weights (referred to as peptide markers TV-35 and TV-66); synthesized by a different process (e.g., changing acetolytic cleavage conditions, alternating polymerization initiator); exposed to destabilizing conditions (e.g., degradation by acid, base, and heat); 3) Unverified Glatiramoids, which included 4 samples, TV-5010 and 3 glatiramoids synthesized to be similar to GA but not manufactured using the Teva-patented manufacturing process; and 4) Unverified Generic GA, which included samples from 2 glatiramoids (“GA-N” 11 samples from 5 different batches, and 2 “GA-C” samples from a single batch) marketed as generic GA manufactured by companies other than Teva. Please note that GSE61901 is another series on the same data as GSE40566. GSE61901 includes the individual technical replicates, and was utilized for the manuscript: Towfic F, Funt JM, Fowler KD, Bakshi S et al. Comparing the biological impact of glatiramer acetate with the biological impact of a generic. PLoS One 2014;9(1):e83757. PMID: 24421904. GSE40566 was preprocessed to average the technical replicates, and was utilized for the manuscript: Bakshi S, Chalifa-Caspi V, Plaschkes I, Perevozkin I et al. Gene expression analysis reveals functional pathways of glatiramer acetate activation. Expert Opin Ther Targets 2013 Apr;17(4):351-62. PMID: 23469939.