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Peer-reviewedCC BY-NC-NDJHEP Reports

Bepirovirsen induces innate immune activation in the liver potentially through TLR8 signaling

  • Megan E. Ermler1
  • Jared L. Delahaye2
  • William T. Jordan3
  • Usha Nivarthi2
  • Anne DeHart2
  • Kristen Jones2
  • Amitabh Das2
  • Nicholas W. Galwey4
  • Bao Q. Hoang5
  • Rebecca L. Terry6
  • Jimmy Tarrant7
  • Valeriia Sherina8
6 more authors
  • Avijit Ray2
  • Daren J. Austin9
  • Jennifer M. Singh10
  • Dickens Theodore11
  • Melanie T. Paff12
  • Shihyun You13
13 affiliations
  1. 1Vaccines and Infectious Disease Research Unit, GSK, Collegeville, PA, USA. Electronic address: [email protected]
  2. 2Vaccines and Infectious Disease Research Unit, GSK, Collegeville, PA, USA
  3. 3Computational biology GSK, Collegeville, PA, USA
  4. 4BioStatistics, GSK, Stevenage, UK
  5. 5Non-Clinical Histology, GSK, Collegeville, PA, USA
  6. 6Non-Clinical Safety Pathology, GSK, Stevenage, UK
  7. 7Non-Clinical Safety Pathology, GSK, Collegeville, PA, USA
  8. 8BioStatistics, GSK, Collegeville, PA, USA
  9. 9Clinical Pharmacology, GSK, London, UK
  10. 10Clinical Biomarkers, GSK, Collegeville, PA, USA
  11. 11Clinical Development, GSK, Durham, NC, USA
  12. 12Medical Development, GSK, Collegeville, PA, USA
  13. 13Vaccines and Infectious Disease Research Unit, GSK, Collegeville, PA, USA. Electronic address: [email protected]
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Abstract

BACKGROUND & AIMS: Bepirovirsen is an unconjugated antisense oligonucleotide in phase III trials for chronic hepatitis B virus (HBV) infection. Post hoc analyses from a phase IIa study in participants with chronic HBV indicated immediate cytokine production following dosing with bepirovirsen, leading to the hypothesis that bepirovirsen may have innate immune stimulatory activity via pattern recognition receptors (PRRs) in hepatic non-parenchymal cells, alongside its known direct antiviral mechanism in hepatocytes. METHODS: Cytokine production was evaluated in phase IIa serum and plasma samples using Myriad RBM, Olink, or MSD panels. Preclinical studies used peripheral blood mononuclear cells (PBMCs) from healthy donors (MSD, flow cytometry) and PRR-overexpressing HEK or THP-1 cells to assess innate immune activation by bepirovirsen. Cytokine protein levels were measured using Luminex or MSD assays in wild-type (WT) and human Toll-like receptor 8 (hTLR8) transgenic mice, while gene expression (reverse-transcription quantitative PCR, RNAscope) was assessed in vivo exclusively in hTLR8 transgenic mice from the Shanghai Model Organisms Center. RESULTS: Multiple pro-inflammatory cytokines involved in immune cell recruitment and activation were upregulated in bepirovirsen-treated participants. Similar findings were observed preclinically in PBMCs from healthy donors following in vitro exposure to bepirovirsen. Analysis of innate immune activation in PRR-overexpressing cells revealed a weak but statistically significant (p = 0.00085) induction only in the presence of human Toll-like receptor 8 (TLR8). In hTLR8 transgenic mice - but not wild-type mice - bepirovirsen treatment induced pro-inflammatory cytokines, similar to the TLR8 agonist selgantolimod. Kupffer cells and macrophages were identified as the primary responders to bepirovirsen in the livers of hTLR8 mice. CONCLUSIONS: Clinical and preclinical data demonstrate that bepirovirsen elicits an innate immune response, evidenced by induction of inflammatory cytokines. This effect is mediated at least in part by TLR8 activation, complementing its established antiviral mechanism. IMPACT AND IMPLICATIONS: The aim of this study was to characterize additional mechanisms of action for bepirovirsen, including immune activation through pattern recognition receptors, based on the hypothesis that bepirovirsen may elicit an innate immune response in addition to its antiviral mechanism. Using phase IIa study samples we show that bepirovirsen induces IFN-γ, TNF, and other cytokines, while in vitro we demonstrate that bepirovirsen harbors innate immune stimulatory activity, potentially through human TLR8. Furthermore, we show that the innate immune activation induced by bepirovirsen is distinct from that of other antisense oligonucleotides. This study demonstrates that bepirovirsen can induce an innate immune response, likely through TLR8 agonism, in addition to its known antiviral mechanism; however, the clinical impact of this immunomodulatory effect remains unclear and requires further investigation.

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Cite

BibTeXRIS
BibTeX
@article{ermler2026bepirovirsen,
  title = {{Bepirovirsen induces innate immune activation in the liver potentially through TLR8 signaling}},
  author = {Megan E. Ermler and Jared L. Delahaye and William T. Jordan and Usha Nivarthi and Anne DeHart and Kristen Jones and Amitabh Das and Nicholas W. Galwey and Bao Q. Hoang and Rebecca L. Terry and Jimmy Tarrant and Valeriia Sherina and Avijit Ray and Daren J. Austin and Jennifer M. Singh and Dickens Theodore and Melanie T. Paff and Shihyun You},
  journal = {JHEP Reports},
  year = {2026},
  month = jun,
  doi = {10.1016/j.jhepr.2026.101923},
  url = {https://doi.org/10.1016/j.jhepr.2026.101923},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Bepirovirsen induces innate immune activation in the liver potentially through TLR8 signaling
AU  - Megan E. Ermler
AU  - Jared L. Delahaye
AU  - William T. Jordan
AU  - Usha Nivarthi
AU  - Anne DeHart
AU  - Kristen Jones
AU  - Amitabh Das
AU  - Nicholas W. Galwey
AU  - Bao Q. Hoang
AU  - Rebecca L. Terry
AU  - Jimmy Tarrant
AU  - Valeriia Sherina
AU  - Avijit Ray
AU  - Daren J. Austin
AU  - Jennifer M. Singh
AU  - Dickens Theodore
AU  - Melanie T. Paff
AU  - Shihyun You
PY  - 2026
DA  - 2026/06/09
JO  - JHEP Reports
DO  - 10.1016/j.jhepr.2026.101923
UR  - https://doi.org/10.1016/j.jhepr.2026.101923
AB  - BACKGROUND & AIMS: Bepirovirsen is an unconjugated antisense oligonucleotide in phase III trials for chronic hepatitis B virus (HBV) infection. Post hoc analyses from a phase IIa study in participants with chronic HBV indicated immediate cytokine production following dosing with bepirovirsen, leading to the hypothesis that bepirovirsen may have innate immune stimulatory activity via pattern recognition receptors (PRRs) in hepatic non-parenchymal cells, alongside its known direct antiviral mechanism in hepatocytes. METHODS: Cytokine production was evaluated in phase IIa serum and plasma samples using Myriad RBM, Olink, or MSD panels. Preclinical studies used peripheral blood mononuclear cells (PBMCs) from healthy donors (MSD, flow cytometry) and PRR-overexpressing HEK or THP-1 cells to assess innate immune activation by bepirovirsen. Cytokine protein levels were measured using Luminex or MSD assays in wild-type (WT) and human Toll-like receptor 8 (hTLR8) transgenic mice, while gene expression (reverse-transcription quantitative PCR, RNAscope) was assessed in vivo exclusively in hTLR8 transgenic mice from the Shanghai Model Organisms Center. RESULTS: Multiple pro-inflammatory cytokines involved in immune cell recruitment and activation were upregulated in bepirovirsen-treated participants. Similar findings were observed preclinically in PBMCs from healthy donors following in vitro exposure to bepirovirsen. Analysis of innate immune activation in PRR-overexpressing cells revealed a weak but statistically significant (p = 0.00085) induction only in the presence of human Toll-like receptor 8 (TLR8). In hTLR8 transgenic mice - but not wild-type mice - bepirovirsen treatment induced pro-inflammatory cytokines, similar to the TLR8 agonist selgantolimod. Kupffer cells and macrophages were identified as the primary responders to bepirovirsen in the livers of hTLR8 mice. CONCLUSIONS: Clinical and preclinical data demonstrate that bepirovirsen elicits an innate immune response, evidenced by induction of inflammatory cytokines. This effect is mediated at least in part by TLR8 activation, complementing its established antiviral mechanism. IMPACT AND IMPLICATIONS: The aim of this study was to characterize additional mechanisms of action for bepirovirsen, including immune activation through pattern recognition receptors, based on the hypothesis that bepirovirsen may elicit an innate immune response in addition to its antiviral mechanism. Using phase IIa study samples we show that bepirovirsen induces IFN-γ, TNF, and other cytokines, while in vitro we demonstrate that bepirovirsen harbors innate immune stimulatory activity, potentially through human TLR8. Furthermore, we show that the innate immune activation induced by bepirovirsen is distinct from that of other antisense oligonucleotides. This study demonstrates that bepirovirsen can induce an innate immune response, likely through TLR8 agonism, in addition to its known antiviral mechanism; however, the clinical impact of this immunomodulatory effect remains unclear and requires further investigation.
SN  - 2589-5559
ER  -