Gene expression studies of a human monocyte cell line identify dissimilarities between differently manufactured glatiramoids

Abstract

Glatiramer Acetate (GA) has provided safe and effective treatment for multiple sclerosis (MS) patients for two decades. It acts as an antigen, yet the precise mechanism of action remains to be fully elucidated, and no validated pharmacokinetic or pharmacodynamic biomarkers exist. In order to better characterize GA’s biological impact, genome-wide expression studies were conducted with a human monocyte (THP-1) cell line. Consistent with previous literature, branded GA upregulated anti-inflammatory markers (e.g. IL10), and modulated multiple immune-related pathways. Despite some similarities, significant differences were observed between expression profiles induced by branded GA and Probioglat, a differently-manufactured glatiramoid purported to be a generic GA. Key results were verified using qRT-PCR. Genes (e.g. CCL5, adj. p < 4.1 × 10−5) critically involved in pro-inflammatory pathways (e.g. response to lipopolysaccharide, adj. p = 8.7 × 10−4) were significantly induced by Probioglat compared with branded GA. Key genes were also tested and confirmed at the protein level, and in primary human monocytes. These observations suggest differential biological impact by the two glatiramoids and warrant further investigation.

Compositional differences between Copaxone and Glatopa are reflected in altered immunomodulation ex vivo in a mouse model

“…An example of differences found in similar studies and alterations in the efficacy and safety of FoGAs compared with GA is the gene expression research that detected differences between GA and Mexico‐FoGA, and the results of an analysis of information collected by Teva's patient support program in Mexico . Differences between GA and Mexico‐FoGA were identified in dozens of immunologically relevant genomic pathways, some of which overlap with the differences reported above. And following the approval of the Mexico‐FoGA PROBIOGLAT ® (Probiomed), altered efficacy and safety was noted upon switching of patients from GA to Mexico‐FoGA .…”

“…Once USA‐FoGA received regulatory approval in 2015, it became possible to obtain samples and characterize them using an expanded set of methods, including high‐resolution physicochemical methods and gene expression studies with adequate sensitivity in a model system that includes multiple cell types. This expanded set of methods has been used since 2008 by the manufacturer of GA, Teva Pharmaceutical Industries (which employs the authors of the present report) to characterize the chemical composition and biological attributes of FoGAs that have been approved in several countries; the results of those studies have been shared with the scientific community in a series of peer‐reviewed publications …”

A pharmacogenetic signature of high response to Copaxone in late-phase clinical-trial cohorts of multiple sclerosis

“…ZAK , a member of the MAP3K family, is known to be activated by stress and inflammation [49], while CDCA7 variants are associated with cell division and brain lesion formation in multiple sclerosis [50]. Thus, the signature spans a multitude of mechanisms which are consistent with Copaxone’s complex MoA and are supported by gene-expression [13, 14] and physicochemical studies [51, 52]. Collectively, findings from the current study as well as other studies [13, 14, 51, 52] suggest that the association of the signature to treatment response is unique to Copaxone’s MoA, which depends on its physicochemical properties and distinguishes it from other glatiramoids and follow-on products.…”

Polymers and Nanomedicine: Considerations on Variability and Reproducibility When Combining Complex Systems

“…Hasson further discussed the endeavor of competitors to develop generics of the commercially highly successful drug and how TEVA attempted to fight the competitors off. Most interestingly, Dr Hasson pointed out that while standard analytical techniques such as amino acids analysis and SEC revealed little or no significant differences, the would-be generics behaved apparently quite distinct to Copaxone in high-resolution assays in terms of composition, aggregation and biological assays [26,27]. This example is interesting for different reasons.…”