Zheng Shuquan, Cao Huiqing, Zhang Min, Guo Chun, Yan Xu, Sun Qi, Zhang Hongyan, Liang Zicai, Gao Shan, Gan Li-Ming
Suzhou Ribo Life Science Co. Ltd., Jiangsu 215300, China.
Ribocure Pharmaceuticals AB, Gothenburg, Sweden.
Mol Ther Nucleic Acids. 2025 Jul 17;36(3):102627. doi: 10.1016/j.omtn.2025.102627. eCollection 2025 Sep 9.
Potent small interfering RNA (siRNA) drugs that could achieve hepatitis B surface antigen (HBsAg) seroconversion and functional cure are currently lacking. The purpose of this study is to evaluate the therapeutic potential of RBD1016, a novel GalNAc-conjugated siRNA drug targeting transcripts of hepatitis B virus (HBV), in animal models. RBD1016 was designed to target X gene of HBV (HBx) and showed strong activities on HBV DNA and HBsAg for multiple HBV genotypes and nucleoside-resistant viral strains in studies. Through single and repeated administration of RBD1016 in two different HBV animal models, a robust reduction of both serum HBsAg and HBV DNA (maximum reduction 3.7 log) was demonstrated. The durable anti-HBV effects of RBD1016 could still be observed on day 169. Importantly, repeated or single administration of RBD1016 caused production of hepatitis B surface antibody (HBsAb), i.e., seroconversion in animals, which is an important hallmark of immune response induction. Furthermore, the combination of RBD1016 and entecavir (ETV) demonstrated an enhanced effect on serum HBV DNA inhibition. A strong and durable anti-HBV effect of RBD1016, both alone and in combination with nucleoside analogues (NAs), indicates significant therapeutic potential for chronic hepatitis B (CHB) patients.
目前缺乏能够实现乙肝表面抗原（HBsAg）血清学转换和功能性治愈的强效小干扰RNA（siRNA）药物。本研究的目的是在动物模型中评估RBD1016的治疗潜力，RBD1016是一种新型的、与N-乙酰半乳糖胺（GalNAc）偶联的siRNA药物，靶向乙型肝炎病毒（HBV）转录本。RBD1016被设计用于靶向HBV的X基因（HBx），并且在研究中对多种HBV基因型和核苷耐药病毒株的HBV DNA和HBsAg显示出强大的活性。通过在两种不同的HBV动物模型中单次和重复给药RBD1016，结果表明血清HBsAg和HBV DNA均显著降低（最大降低3.7 log）。在第169天时仍可观察到RBD1016持久的抗HBV作用。重要的是，重复或单次给药RBD1016可导致动物产生乙肝表面抗体（HBsAb），即血清学转换，这是诱导免疫反应的一个重要标志。此外，RBD1016与恩替卡韦（ETV）联合使用对血清HBV DNA抑制作用增强。RBD1016单独使用或与核苷类似物（NAs）联合使用时均具有强大且持久的抗HBV作用，这表明其对慢性乙型肝炎（CHB）患者具有显著的治疗潜力。
