JNJ-64794964 (AL-034/TQ-A3334), a TLR7 agonist, induces sustained anti-HBV activity in AAV/HBV mice via non-cytolytic mechanisms

• Published in: Antiviral research Vol. 196; p. 105196
• Main Authors: Herschke, Florence, Li, Chris, Zhu, Ren, Han, Qinglin, Wu, Qun, Lu, Qing, Barale-Thomas, Erio, De Jonghe, Sandra, Lin, Tse-I., De Creus, An
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2021
• Subjects: AAV/HBV mice; Animals; anti-HBs antibodies; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Cytokine-mediated; Cytokines - blood; Cytokines - immunology; Drug Evaluation, Preclinical; Drugs, Investigational - therapeutic use; Hepatitis B - drug therapy; Hepatitis B - immunology; Hepatitis B Antibodies - blood; Hepatitis B virus - drug effects; Hepatitis B virus - immunology; JNJ-64794964; Male; Mice; Mice, Inbred C57BL; Non-cytolytic; TLR7 agonist; Toll-Like Receptor 7 - agonists; AAV/HBV mice; anti-HBs antibodies; TLR7 agonist; Non-cytolytic; Cytokine-mediated; JNJ-64794964
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2021.105196

JNJ-64794964 (JNJ-4964/AL-034/TQ-A3334), an oral toll-like receptor 7 agonist, is being investigated for the treatment of chronic hepatitis B (CHB), a condition with a high unmet medical need. The anti–hepatitis B (HBV) activity of JNJ-4964 was assessed preclinically in an adeno-associated virus vector expressing HBV (AAV/HBV) mouse model. Mice were treated orally with 2, 6 or 20 mg/kg of JNJ-4964 once-per-week for 12 weeks and then followed up for 4 weeks. At 6 mg/kg, a partial decrease in plasma HBV-DNA and plasma hepatitis B surface antigen (HBsAg) was observed, and anti-HBs antibodies and HBsAg-specific T cells were observed in 1/8 animals. At 20 mg/kg, plasma HBV-DNA and HBsAg levels were undetectable for all animals 3 weeks after start of treatment, with no rebound observed 4 weeks after JNJ-4964 treatment was stopped. High anti-HBs antibody levels were observed until 4 weeks after JNJ-4964 treatment was stopped. In parallel, HBsAg-specific immunoglobulin G–producing B cells and interferon-γ–producing CD4+ T cells were detected in the spleen. In 2/4 animals, liver HBV-DNA and HBV-RNA levels and liver hepatitis B core antigen expression dropped 4 weeks after JNJ-4964 treatment-stop. In these animals, HBsAg-specific CD8+ T cells were detectable. Throughout the study, normal levels of alanine aminotransferase were observed, with no hepatocyte cell death (end of treatment and 4 weeks later) and minimal infiltrations of B and T cells into the liver, suggesting induction of cytokine-mediated, non-cytolytic mechanisms. [Display omitted] •The TLR7 agonist JNJ-4964 at 2, 6 or 20 mg/kg QW was evaluated in an AAV/HBV mouse model.•Dose-dependent systemic cytokine, B and T cell induction and anti-HBV activity was seen.•Throughout the study, normal ALT levels and no hepatocyte cell death was observed.•JNJ-4964 anti-HBV effect seems to be via cytokine-mediated, non-cytolytic mechanisms.