JNJ-64794964 (AL-034/TQ-A3334) 是一种 TLR7 激动剂，通过非细胞溶解

StephenW

JNJ-64794964 (AL-034/TQ-A3334) 是一种 TLR7 激动剂，通过非细胞溶解机制在 AAV/HBV 小鼠中诱导持续的抗 HBV 活性
Florence Herschke 1 , Chris Li 2 , Ren Zhu 2 , Jinglin Han 2 , Qun Wu 2 , Qing Lu 2 , Erio Barale-Thomas 3 , Sandra De Jonghe 3 , Tse-I Lin 4 , An De Creus 3
隶属关系
隶属关系

    1
    Janssen Pharmaceutica NV, 2340, Turnhoutseweg 30, 2340, Beerse, Belgium。电子地址：[email protected]。
    2
    杨森中国研发中心，Discovery，上海，中国。
    3
    Janssen Pharmaceutica NV, 2340, Turnhoutseweg 30, 2340, Beerse, Belgium。
    4
    Janssen Biopharma, 260 E Grand Ave., South San Francisco, CA, 94080, United States。

    PMID：34718044 DOI：10.1016/j.antiviral.2021.105196

抽象的

JNJ-64794964 (JNJ-4964/AL-034/TQ-A3334) 是一种口服 toll 样受体 7 激动剂，正在研究用于治疗慢性乙型肝炎 (CHB)，这是一种医疗需求未得到满足的疾病。 JNJ-4964 的抗乙型肝炎 (HBV) 活性在表达 HBV (AAV/HBV) 小鼠模型的腺相关病毒载体中进行了临床前评估。小鼠每周一次口服 2、6 或 20 mg/kg JNJ-4964，持续 12 周，然后随访 4 周。在 6 mg/kg 时，观察到血浆 HBV-DNA 和血浆乙型肝炎表面抗原 (HBsAg) 部分降低，并且在 1/8 动物中观察到抗 HBs 抗体和 HBsAg 特异性 T 细胞。在 20 mg/kg 时，治疗开始 3 周后所有动物的血浆 HBV-DNA 和 HBsAg 水平均检测不到，JNJ-4964 治疗停止后 4 周未观察到反弹。在 JNJ-4964 治疗停止后 4 周，一直观察到高抗 HBs 抗体水平。同时，在脾脏中检测到产生 HBsAg 特异性免疫球蛋白 G 的 B 细胞和产生干扰素-γ 的 CD4+ T 细胞。在 2/4 动物中，JNJ-4964 治疗停止后 4 周，肝脏 HBV-DNA 和 HBV-RNA 水平以及肝脏乙型肝炎核心抗原表达下降。在这些动物中，可检测到 HBsAg 特异性 CD8+ T 细胞。在整个研究过程中，观察到丙氨酸氨基转移酶水平正常，没有肝细胞死亡（治疗结束和 4 周后），B 和 T 细胞很少浸润到肝脏，这表明诱导了细胞因子介导的非细胞溶解机制。

关键词：AAV/HBV 小鼠；细胞因子介导的； JNJ-64794964；非细胞溶解性； TLR7 激动剂；抗 HBs 抗体。

版权所有 © 2021。Elsevier B.V. 出版

StephenW

JNJ-64794964 (AL-034/TQ-A3334), a TLR7 agonist, induces sustained anti-HBV activity in AAV/HBV mice via non-cytolytic mechanisms
Florence Herschke  1 , Chris Li  2 , Ren Zhu  2 , Qinglin Han  2 , Qun Wu  2 , Qing Lu  2 , Erio Barale-Thomas  3 , Sandra De Jonghe  3 , Tse-I Lin  4 , An De Creus  3
Affiliations
Affiliations

    1
    Janssen Pharmaceutica NV, 2340, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: [email protected].
    2
    Janssen China R&D, Discovery, Shanghai, China.
    3
    Janssen Pharmaceutica NV, 2340, Turnhoutseweg 30, 2340, Beerse, Belgium.
    4
    Janssen Biopharma, 260 E Grand Ave., South San Francisco, CA, 94080, United States.

    PMID: 34718044 DOI: 10.1016/j.antiviral.2021.105196

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) were 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.

Copyright © 2021. Published by Elsevier B.V.