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Conference Paper: Inhibition of hepatitis B surface antigen in chronic hepatitis B subjects by RNA interference therapeutic AB-729 is accompanied by upregulation of HBV-specific T cell activation markers

TitleInhibition of hepatitis B surface antigen in chronic hepatitis B subjects by RNA interference therapeutic AB-729 is accompanied by upregulation of HBV-specific T cell activation markers
Authors
Issue Date2021
PublisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep
Citation
The International Liver Congress 2021 (ILC 2021): Beating Liver Disease Together, Virtual Conference, 23-26 June 2021. In Journal of Hepatology, 2021, v. 75 n. Suppl. 2, p. S761 How to Cite?
AbstractBackground and aims: Therapeutic strategies aimed at reducing antigenemia, particularly hepatitis B surface antigen (HBsAg), may potentiate HBV-specific immune restoration in chronic hepatitis B (CHB). AB-729 is a single trigger N-Acetylgalactosamine (GalNAc)-conjugated siRNA targeting all HBV transcripts, currently in clinical development in combination with other agents for the treatment of CHB. Here we report immunological assessments in nucleos (t)ide analog-suppressed CHB subjects receiving single or repeat doses of AB-729. Method: Longitudinal plasma samples from subjects receiving a single injection of AB-729 (60–180 mg, n = 16) were assessed for cytokines/chemokines using a multiplex Luminex assay. Longitudinal plasma or peripheral blood mononuclear cell samples from subjects (n = 6 or 5) undergoing repeat dosing of 60 mg AB-729 every 4 weeks (Q4W) for 6 doses were assessed using Luminex, interferon gamma (IFNg) T-cell fluorospot, T-cell proliferation assay and flow cytometry. Results: Following a single dose of AB-729, transient elevation of 2 to 6-fold over pre-dose baseline levels in plasma IFNg, IL-17a, CD163, CXCL9 and CXCL13 were observed in some subjects (60 mg, 90 mg n = 3/6 each). In one subject receiving AB-729 60 mg Q4W, a 1.7 log10 reduction in HBsAg preceded a 9-fold elevation in IFNg at Week 28, which coincided with increase in IFNg-producing HBV-specific Tcells (Figure). This was preceded by mild elevations in serum alanine aminotransferase (ALT, Grade 1), which resolved by Week 28. In 3/5 subjects, elevated HBV-specific T-cell proliferation was observed by Week 8 and increases in IFNg-producing HBV-specific T-cells coincided with ≥1.7 log10 HBsAg reduction. Mild to moderate ALT elevations (n = 2/5 Grade 1, 2/5 Grade 2) preceded or coincided with IFNg-producing HBV-specific T-cells. No changes were observed in any subjects for inflammatory cytokine IP-10, or other liver safety markers. Conclusion: We believe this represents the first immunological assessment of CHB subjects with prolonged HBsAg suppression ollowing repeat doses of an HBV-targeting GalNAc-siRNA. Our findings suggest that AB-729-induced reductions in HBsAg results in increased HBV-specific immune responses in a subset of CHB subjects, accompanied by mild to moderate ALT elevations. These results strengthen the hypothesis that long-term HBV antigen suppression can promote immune reawakening in CHB and suggest AB-729 combinations with immunomodulatory agents may be beneficial.
DescriptionLate breaker posters: Poster presentation: PO-2823
Persistent Identifierhttp://hdl.handle.net/10722/305976
ISSN
2023 Impact Factor: 26.8
2023 SCImago Journal Rankings: 9.857

 

DC FieldValueLanguage
dc.contributor.authorParatala, B-
dc.contributor.authorPark, J-J-
dc.contributor.authorGanchua, SC-
dc.contributor.authorGane, E-
dc.contributor.authorYuen, RMF-
dc.contributor.authorLee, ACH-
dc.contributor.authorMoore, C-
dc.contributor.authorLam, AM-
dc.contributor.authorSevinsky, H-
dc.contributor.authorSims, K-
dc.contributor.authorAntoniello, D-
dc.contributor.authorSofia, MJ-
dc.contributor.authorPicchio, G-
dc.contributor.authorThi, EP-
dc.date.accessioned2021-10-20T10:17:02Z-
dc.date.available2021-10-20T10:17:02Z-
dc.date.issued2021-
dc.identifier.citationThe International Liver Congress 2021 (ILC 2021): Beating Liver Disease Together, Virtual Conference, 23-26 June 2021. In Journal of Hepatology, 2021, v. 75 n. Suppl. 2, p. S761-
dc.identifier.issn0168-8278-
dc.identifier.urihttp://hdl.handle.net/10722/305976-
dc.descriptionLate breaker posters: Poster presentation: PO-2823-
dc.description.abstractBackground and aims: Therapeutic strategies aimed at reducing antigenemia, particularly hepatitis B surface antigen (HBsAg), may potentiate HBV-specific immune restoration in chronic hepatitis B (CHB). AB-729 is a single trigger N-Acetylgalactosamine (GalNAc)-conjugated siRNA targeting all HBV transcripts, currently in clinical development in combination with other agents for the treatment of CHB. Here we report immunological assessments in nucleos (t)ide analog-suppressed CHB subjects receiving single or repeat doses of AB-729. Method: Longitudinal plasma samples from subjects receiving a single injection of AB-729 (60–180 mg, n = 16) were assessed for cytokines/chemokines using a multiplex Luminex assay. Longitudinal plasma or peripheral blood mononuclear cell samples from subjects (n = 6 or 5) undergoing repeat dosing of 60 mg AB-729 every 4 weeks (Q4W) for 6 doses were assessed using Luminex, interferon gamma (IFNg) T-cell fluorospot, T-cell proliferation assay and flow cytometry. Results: Following a single dose of AB-729, transient elevation of 2 to 6-fold over pre-dose baseline levels in plasma IFNg, IL-17a, CD163, CXCL9 and CXCL13 were observed in some subjects (60 mg, 90 mg n = 3/6 each). In one subject receiving AB-729 60 mg Q4W, a 1.7 log10 reduction in HBsAg preceded a 9-fold elevation in IFNg at Week 28, which coincided with increase in IFNg-producing HBV-specific Tcells (Figure). This was preceded by mild elevations in serum alanine aminotransferase (ALT, Grade 1), which resolved by Week 28. In 3/5 subjects, elevated HBV-specific T-cell proliferation was observed by Week 8 and increases in IFNg-producing HBV-specific T-cells coincided with ≥1.7 log10 HBsAg reduction. Mild to moderate ALT elevations (n = 2/5 Grade 1, 2/5 Grade 2) preceded or coincided with IFNg-producing HBV-specific T-cells. No changes were observed in any subjects for inflammatory cytokine IP-10, or other liver safety markers. Conclusion: We believe this represents the first immunological assessment of CHB subjects with prolonged HBsAg suppression ollowing repeat doses of an HBV-targeting GalNAc-siRNA. Our findings suggest that AB-729-induced reductions in HBsAg results in increased HBV-specific immune responses in a subset of CHB subjects, accompanied by mild to moderate ALT elevations. These results strengthen the hypothesis that long-term HBV antigen suppression can promote immune reawakening in CHB and suggest AB-729 combinations with immunomodulatory agents may be beneficial.-
dc.languageeng-
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/jhep-
dc.relation.ispartofJournal of Hepatology-
dc.relation.ispartofThe International Liver Congress 2021 (ILC 2021)-
dc.titleInhibition of hepatitis B surface antigen in chronic hepatitis B subjects by RNA interference therapeutic AB-729 is accompanied by upregulation of HBV-specific T cell activation markers-
dc.typeConference_Paper-
dc.identifier.emailYuen, RMF: mfyuen@hku.hk-
dc.identifier.authorityYuen, RMF=rp00479-
dc.description.natureabstract-
dc.identifier.hkuros326620-
dc.identifier.volume75-
dc.identifier.issueSuppl. 2-
dc.identifier.spageS761-
dc.identifier.epageS761-
dc.publisher.placeNetherlands-
dc.identifier.partofdoi10.1016/S0168-8278(21)01843-2-

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