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

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Τίτλος: Bepirovirsen induces innate immune activation in the liver potentially through TLR8 signaling.
Συγγραφείς: Ermler ME; Vaccines and Infectious Disease Research Unit, GSK, Collegeville, PA, USA. Electronic address: megan.x.ermler@gsk.com., Delahaye JL; Vaccines and Infectious Disease Research Unit, GSK, Collegeville, PA, USA., Jordan W; Computational biology GSK, Collegeville, PA, USA., Nivarthi U; Vaccines and Infectious Disease Research Unit, GSK, Collegeville, PA, USA., DeHart A; Vaccines and Infectious Disease Research Unit, GSK, Collegeville, PA, USA., Jones K; Vaccines and Infectious Disease Research Unit, GSK, Collegeville, PA, USA., Das A; Vaccines and Infectious Disease Research Unit, GSK, Collegeville, PA, USA., Galwey N; BioStatistics, GSK, Stevenage, UK., Hoang B; Non-Clinical Histology, GSK, Collegeville, PA, USA., Terry RL; Non-Clinical Safety Pathology, GSK, Stevenage, UK., Tarrant J; Non-Clinical Safety Pathology, GSK, Collegeville, PA, USA., Sherina V; BioStatistics, GSK, Collegeville, PA, USA., Ray A; Vaccines and Infectious Disease Research Unit, GSK, Collegeville, PA, USA., Austin D; Clinical Pharmacology, GSK, London, UK., Singh JM; Clinical Biomarkers, GSK, Collegeville, PA, USA., Theodore D; Clinical Development, GSK, Durham, NC, USA., Paff M; Medical Development, GSK, Collegeville, PA, USA., You S; Vaccines and Infectious Disease Research Unit, GSK, Collegeville, PA, USA. Electronic address: shihyun.k.you@gsk.com.
Πηγή: JHEP reports : innovation in hepatology [JHEP Rep] 2026 Sep; Vol. 8 (9), pp. 101923. Date of Electronic Publication: 2026 Jun 09.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Elsevier B.V Country of Publication: Netherlands NLM ID: 101761237 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2589-5559 (Electronic) Linking ISSN: 25895559 NLM ISO Abbreviation: JHEP Rep Subsets: MEDLINE
Imprint Name(s): Original Publication: [Amsterdam] : Elsevier B.V., [2019]-
Ιατρικοί όροι (MeSH): Immunity, Innate*/drug effects , Toll-Like Receptor 8*/metabolism , Liver*/immunology , Liver*/drug effects , Hepatitis B, Chronic*/drug therapy , Hepatitis B, Chronic*/immunology , Antiviral Agents*/pharmacology, Signal Transduction/drug effects ; Cytokines/metabolism ; Leukocytes, Mononuclear/drug effects ; Humans ; Animals ; Mice ; Mice, Transgenic ; Toll-Like Receptor Agonists ; Female ; Innate Immunity Recognition ; Hexanols ; Pyrimidines
Περίληψη: 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.
(Copyright © 2026 GSK PLC. Published by Elsevier B.V. All rights reserved.)
Competing Interests: Conflicts of interest RNAscope is a registered trademark of Advanced Cell Diagnostics (ACD). FlowJo is a registered trademark of BD Life Sciences. Cyto-Fast is a registered trademark of BioLegend. SIMOA is a registered trademark of Quanterix Corporation. COBAS is a trademark of Roche Diagnostics Operations, Inc. DiscoveryMAP is a trademark of Myriad RBM. Usha Nivarthi, Anne DeHart, and Kristen Jones, are employed by GSK. Megan E. Ermler, William Jordan, Amitabh Das, Nicholas Galwey, Valeriia Sherina, Avijit Ray, Melanie Paff, Daren Austin, Jennifer M. Singh, Bao Hoang, Rebecca L. Terry, and Jimmy Tarrant are employed by GSK and hold financial equities in GSK. Jared L. Delahaye, Shihyun You, and Dickens Theodore are employed by GSK, have financial equities in GSK, and have patent applications with GSK. Please refer to the accompanying ICMJE disclosure forms for further details.
Contributed Indexing: Keywords: Antisense oligonucleotide; Bepirovirsen; HBV; Hepatitis B virus; Innate immunity; TLR8; Toll-like receptor 8
Substance Nomenclature: 0 (Toll-Like Receptor 8)
0 (Cytokines)
0 (TLR8 protein, human)
RM4GJT3SMQ (selgantolimod)
0 (Antiviral Agents)
0 (Toll-Like Receptor Agonists)
0 (Hexanols)
0 (Pyrimidines)
Entry Date(s): Date Created: 20260609 Date Completed: 20260827 Latest Revision: 20260827
Update Code: 20260828
PubMed Central ID: PMC13482607
DOI: 10.1016/j.jhepr.2026.101923
PMID: 42264034
Βάση Δεδομένων: MEDLINE
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  Data: Bepirovirsen induces innate immune activation in the liver potentially through TLR8 signaling.
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  Data: <searchLink fieldCode="AU" term="%22Ermler+ME%22">Ermler ME</searchLink>; Vaccines and Infectious Disease Research Unit, GSK, Collegeville, PA, USA. Electronic address: megan.x.ermler@gsk.com.<br /><searchLink fieldCode="AU" term="%22Delahaye+JL%22">Delahaye JL</searchLink>; Vaccines and Infectious Disease Research Unit, GSK, Collegeville, PA, USA.<br /><searchLink fieldCode="AU" term="%22Jordan+W%22">Jordan W</searchLink>; Computational biology GSK, Collegeville, PA, USA.<br /><searchLink fieldCode="AU" term="%22Nivarthi+U%22">Nivarthi U</searchLink>; Vaccines and Infectious Disease Research Unit, GSK, Collegeville, PA, USA.<br /><searchLink fieldCode="AU" term="%22DeHart+A%22">DeHart A</searchLink>; Vaccines and Infectious Disease Research Unit, GSK, Collegeville, PA, USA.<br /><searchLink fieldCode="AU" term="%22Jones+K%22">Jones K</searchLink>; Vaccines and Infectious Disease Research Unit, GSK, Collegeville, PA, USA.<br /><searchLink fieldCode="AU" term="%22Das+A%22">Das A</searchLink>; Vaccines and Infectious Disease Research Unit, GSK, Collegeville, PA, USA.<br /><searchLink fieldCode="AU" term="%22Galwey+N%22">Galwey N</searchLink>; BioStatistics, GSK, Stevenage, UK.<br /><searchLink fieldCode="AU" term="%22Hoang+B%22">Hoang B</searchLink>; Non-Clinical Histology, GSK, Collegeville, PA, USA.<br /><searchLink fieldCode="AU" term="%22Terry+RL%22">Terry RL</searchLink>; Non-Clinical Safety Pathology, GSK, Stevenage, UK.<br /><searchLink fieldCode="AU" term="%22Tarrant+J%22">Tarrant J</searchLink>; Non-Clinical Safety Pathology, GSK, Collegeville, PA, USA.<br /><searchLink fieldCode="AU" term="%22Sherina+V%22">Sherina V</searchLink>; BioStatistics, GSK, Collegeville, PA, USA.<br /><searchLink fieldCode="AU" term="%22Ray+A%22">Ray A</searchLink>; Vaccines and Infectious Disease Research Unit, GSK, Collegeville, PA, USA.<br /><searchLink fieldCode="AU" term="%22Austin+D%22">Austin D</searchLink>; Clinical Pharmacology, GSK, London, UK.<br /><searchLink fieldCode="AU" term="%22Singh+JM%22">Singh JM</searchLink>; Clinical Biomarkers, GSK, Collegeville, PA, USA.<br /><searchLink fieldCode="AU" term="%22Theodore+D%22">Theodore D</searchLink>; Clinical Development, GSK, Durham, NC, USA.<br /><searchLink fieldCode="AU" term="%22Paff+M%22">Paff M</searchLink>; Medical Development, GSK, Collegeville, PA, USA.<br /><searchLink fieldCode="AU" term="%22You+S%22">You S</searchLink>; Vaccines and Infectious Disease Research Unit, GSK, Collegeville, PA, USA. Electronic address: shihyun.k.you@gsk.com.
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  Data: 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.<br />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.<br />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.<br />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.<br />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.<br /> (Copyright © 2026 GSK PLC. Published by Elsevier B.V. All rights reserved.)
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  Data: Conflicts of interest RNAscope is a registered trademark of Advanced Cell Diagnostics (ACD). FlowJo is a registered trademark of BD Life Sciences. Cyto-Fast is a registered trademark of BioLegend. SIMOA is a registered trademark of Quanterix Corporation. COBAS is a trademark of Roche Diagnostics Operations, Inc. DiscoveryMAP is a trademark of Myriad RBM. Usha Nivarthi, Anne DeHart, and Kristen Jones, are employed by GSK. Megan E. Ermler, William Jordan, Amitabh Das, Nicholas Galwey, Valeriia Sherina, Avijit Ray, Melanie Paff, Daren Austin, Jennifer M. Singh, Bao Hoang, Rebecca L. Terry, and Jimmy Tarrant are employed by GSK and hold financial equities in GSK. Jared L. Delahaye, Shihyun You, and Dickens Theodore are employed by GSK, have financial equities in GSK, and have patent applications with GSK. Please refer to the accompanying ICMJE disclosure forms for further details.
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