Contributions
Abstract: P413
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Genetics /Epigenetics and Pharmacogenetics
Background: Copaxone (glatiramer acetate) has provided a safe, effective treatment option for multiple sclerosis (MS) patients for decades. Copaxone is thought to act through complex immune mechanisms related to its antigenic nature. Recently, a differently manufactured glatiramoid, Glatopa, was launched in the US. Since genome-wide expression profiling measures biological impact across many pathways, this unbiased method was applied to characterize both glatiramoids.
Objectives: To characterize biological effects of Copaxone and Glatopa in a mouse interchangeability model, and in a human monocyte cell line.
Methods: Gene expression profiles induced by Copaxone and Glatopa were measured in two model systems: 1) ex-vivo exposure of Copaxone/Glatopa stimulated splenocytes (mouse) and 2) in vitro stimulation of THP-1 cells.
Results: Copaxone significantly modulated thousands of genes and dozens of pathways in mouse splenocytes, many of which exhibit immunogenic functionality. Copaxone upregulated key anti-inflammatory cytokine IL-10 (FC=1.54, adj p< 1.8e-16), and the cytokine-cytokine receptor interaction pathway was enriched among top upregulated genes (adj p< 5e-6). These findings are concordant with previously reported effects of Copaxone. Glatopa also upregulated IL-10 (FC=1.46, adj p< 9.9e-12), among thousands of genes modulated similarly by Glatopa and Copaxone.Alongside these similarities, hundreds of genes (FC range -1.6 to 1.5) enriching for multiple biological pathways were significantly differentially expressed between Copaxone and Glatopa. Observed differences included higher expression with Glatopa of genes and pathways such as TH17 related genes IL-6 and IL-1b, and the cytokine-cytokine receptor interaction pathway (adj p< 2e-4). Enrichment of this pathway was confirmed in studies comparing Glatopa to Copaxone in THP-1 cells (Gene Set Enrichment Analysis, p< 0.001). This pathway among others was differentially expressed in prior studies comparing Copaxone with glatiramoids Polimunol (Hasson et al, 2016) and Probioglat (Kolitz et al, 2015).
Conclusions: Gene expression studies in different models identify many genes as similarly modulated by Copaxone and Glatopa, alongside a subset of immune-related genes and pathways that demonstrate significant differences. These functional differences, coupled with observed physicochemical differences between the two glatiramoids, warrant further investigation to ensure the safety of MS patients.
Disclosure:
SK, KF, and BZ are employees of Immuneering Corporation which is partially owned by Teva Pharmaceutical Industries to perform studies included in this report.
DL, TH, SB, IG and MRH performed studies in this report and are employees of Teva Pharmaceutical Industries.
Abstract: P413
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Genetics /Epigenetics and Pharmacogenetics
Background: Copaxone (glatiramer acetate) has provided a safe, effective treatment option for multiple sclerosis (MS) patients for decades. Copaxone is thought to act through complex immune mechanisms related to its antigenic nature. Recently, a differently manufactured glatiramoid, Glatopa, was launched in the US. Since genome-wide expression profiling measures biological impact across many pathways, this unbiased method was applied to characterize both glatiramoids.
Objectives: To characterize biological effects of Copaxone and Glatopa in a mouse interchangeability model, and in a human monocyte cell line.
Methods: Gene expression profiles induced by Copaxone and Glatopa were measured in two model systems: 1) ex-vivo exposure of Copaxone/Glatopa stimulated splenocytes (mouse) and 2) in vitro stimulation of THP-1 cells.
Results: Copaxone significantly modulated thousands of genes and dozens of pathways in mouse splenocytes, many of which exhibit immunogenic functionality. Copaxone upregulated key anti-inflammatory cytokine IL-10 (FC=1.54, adj p< 1.8e-16), and the cytokine-cytokine receptor interaction pathway was enriched among top upregulated genes (adj p< 5e-6). These findings are concordant with previously reported effects of Copaxone. Glatopa also upregulated IL-10 (FC=1.46, adj p< 9.9e-12), among thousands of genes modulated similarly by Glatopa and Copaxone.Alongside these similarities, hundreds of genes (FC range -1.6 to 1.5) enriching for multiple biological pathways were significantly differentially expressed between Copaxone and Glatopa. Observed differences included higher expression with Glatopa of genes and pathways such as TH17 related genes IL-6 and IL-1b, and the cytokine-cytokine receptor interaction pathway (adj p< 2e-4). Enrichment of this pathway was confirmed in studies comparing Glatopa to Copaxone in THP-1 cells (Gene Set Enrichment Analysis, p< 0.001). This pathway among others was differentially expressed in prior studies comparing Copaxone with glatiramoids Polimunol (Hasson et al, 2016) and Probioglat (Kolitz et al, 2015).
Conclusions: Gene expression studies in different models identify many genes as similarly modulated by Copaxone and Glatopa, alongside a subset of immune-related genes and pathways that demonstrate significant differences. These functional differences, coupled with observed physicochemical differences between the two glatiramoids, warrant further investigation to ensure the safety of MS patients.
Disclosure:
SK, KF, and BZ are employees of Immuneering Corporation which is partially owned by Teva Pharmaceutical Industries to perform studies included in this report.
DL, TH, SB, IG and MRH performed studies in this report and are employees of Teva Pharmaceutical Industries.