Contributions
Abstract: P422
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. Polimunol is a glatiramoid manufactured by a different manufacturer (Synthon) and authorized in Argentina. Recently Synthon obtained approval for their glatiramoid in Europe. Genome-wide expression profiling was used to characterize both glatiramoids in a mouse interchangeability model and a human monocyte (THP-1) cell line (Hasson et al, 2016). Here we show further analyses and study outcomes, including use of stricter fold change (FC) criteria.
Objectives: To further explore the biological effects of Copaxone and Polimunol by applying multiple methodologies to data from a mouse model and THP-1 cells.
Methods: Gene expression profiles induced by Copaxone and Polimunol were assessed in two model systems:
1) ex-vivo treatment of splenocytes from mice immunized with Copaxone or Polimunol and
2) in vitro stimulation of THP-1 cells.
Results: Copaxone significantly modulated many genes and pathways in mouse splenocytes. Consistent with well-documented Copaxone mechanisms, these effects included key anti-inflammatory genes Il10 (FC=2.7, adj p< 2.3x10-24) and Foxp3 (FC=1.9, adj p< 3.4x10-23). Polimunol also upregulated Il10 (FC=3.0, adj p< 1.3x10-13) and Foxp3 (FC=2.0, adj p< 3.7x10-12) among thousands of genes modulated similarly by Polimunol and Copaxone.
Using a strict threshold of FC ≥1.4, differences were observed between Copaxone and Polimunol. 70 probesets were significantly differentially expressed (adj. p < 0.05) between Copaxone and Polimunol, and enriched for biologically relevant pathways including immune response
(adj p< 6.8x10-9), response to virus (adj p< 2.3x10-8), RIG-I-like receptor signaling (adj p< 9.2x10-5), cytokine activity (adj p< 0.03), and cytokine-cytokine receptor interaction (adj p< 0.04). Cytokine-cytokine receptor interaction (adj p< 1.9x10-5) and immune response (adj p < 1.5-5) pathways were also enriched comparing Polimunol to Copaxone in THP-1 cells at a threshold of FC ≥ 1.1.
Conclusions: While the gene expression profiles of Copaxone and Polimunol share many similarities, Polimunol induces pro-inflammatory genes and pathways to a greater extent than Copaxone. These consistent and biologically relevant observations suggest a need for further study in the interest of MS patient safety.
Disclosure:
DL, TH, AK, SB, IG and MRH are employees of Teva Pharmaceutical Industries, Israel.
SK, KF, and BZ are employees of Immuneering Corporation which is partially owned by Teva Pharmaceutical Industries, Israel.
Abstract: P422
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. Polimunol is a glatiramoid manufactured by a different manufacturer (Synthon) and authorized in Argentina. Recently Synthon obtained approval for their glatiramoid in Europe. Genome-wide expression profiling was used to characterize both glatiramoids in a mouse interchangeability model and a human monocyte (THP-1) cell line (Hasson et al, 2016). Here we show further analyses and study outcomes, including use of stricter fold change (FC) criteria.
Objectives: To further explore the biological effects of Copaxone and Polimunol by applying multiple methodologies to data from a mouse model and THP-1 cells.
Methods: Gene expression profiles induced by Copaxone and Polimunol were assessed in two model systems:
1) ex-vivo treatment of splenocytes from mice immunized with Copaxone or Polimunol and
2) in vitro stimulation of THP-1 cells.
Results: Copaxone significantly modulated many genes and pathways in mouse splenocytes. Consistent with well-documented Copaxone mechanisms, these effects included key anti-inflammatory genes Il10 (FC=2.7, adj p< 2.3x10-24) and Foxp3 (FC=1.9, adj p< 3.4x10-23). Polimunol also upregulated Il10 (FC=3.0, adj p< 1.3x10-13) and Foxp3 (FC=2.0, adj p< 3.7x10-12) among thousands of genes modulated similarly by Polimunol and Copaxone.
Using a strict threshold of FC ≥1.4, differences were observed between Copaxone and Polimunol. 70 probesets were significantly differentially expressed (adj. p < 0.05) between Copaxone and Polimunol, and enriched for biologically relevant pathways including immune response
(adj p< 6.8x10-9), response to virus (adj p< 2.3x10-8), RIG-I-like receptor signaling (adj p< 9.2x10-5), cytokine activity (adj p< 0.03), and cytokine-cytokine receptor interaction (adj p< 0.04). Cytokine-cytokine receptor interaction (adj p< 1.9x10-5) and immune response (adj p < 1.5-5) pathways were also enriched comparing Polimunol to Copaxone in THP-1 cells at a threshold of FC ≥ 1.1.
Conclusions: While the gene expression profiles of Copaxone and Polimunol share many similarities, Polimunol induces pro-inflammatory genes and pathways to a greater extent than Copaxone. These consistent and biologically relevant observations suggest a need for further study in the interest of MS patient safety.
Disclosure:
DL, TH, AK, SB, IG and MRH are employees of Teva Pharmaceutical Industries, Israel.
SK, KF, and BZ are employees of Immuneering Corporation which is partially owned by Teva Pharmaceutical Industries, Israel.