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

Antiviral Res. 2021 Dec:196:105196. doi: 10.1016/j.antiviral.2021.105196. Epub 2021 Oct 28.

Abstract

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.

Keywords: AAV/HBV mice; Cytokine-mediated; JNJ-64794964; Non-cytolytic; TLR7 agonist; anti-HBs antibodies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use*
  • 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
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Toll-Like Receptor 7 / agonists*

Substances

  • Antiviral Agents
  • Cytokines
  • Drugs, Investigational
  • Hepatitis B Antibodies
  • Toll-Like Receptor 7