IMAB362/Zolbetuximab 是一种针对癌症相关胃谱系标记物 CLDN18.2 的一流 IgG1 抗体，最近据报道在两项 3 期试验中作为一线治疗药物与CLDN18.2 阳性 Her2 阴性晚期胃癌的护理标准化疗。在这里，我们描述了 BNT141 的临床前药理学特征，BNT141 是一种编码 IMAB362/Zolbetuximab 序列的核苷修饰 RNA 治疗剂，配制在脂质纳米颗粒 (LNP) 中以供肝脏摄取。我们发现，mRNA 编码的抗体在临床前动物模型中表现出稳定的药代动力学特征，介导与 IMAB362 重组蛋白相当的 CLDN18.2 限制性细胞毒性，并抑制免疫功能低下小鼠中的人肿瘤异种移植物生长。在动物研究中，BNT141 给药并未导致死亡、临床毒性症状或胃部病理变化。 BNT141 mRNA-LNP 的 1/2 期临床试验已在表达 CLDN18.2 的晚期实体癌中启动 (NCT04683939)。© 2023 作者。经泰勒许可出版

IMAB362/Zolbetuximab, a first-in-class IgG1 antibody directed against the cancer-associated gastric-lineage marker CLDN18.2, has recently been reported to have met its primary endpoint in two phase 3 trials as a first-line treatment in combination with standard of care chemotherapy in CLDN18.2-positive Her2 negative advanced gastric cancer. Here we characterize the preclinical pharmacology of BNT141, a nucleoside-modified RNA therapeutic encoding the sequence of IMAB362/Zolbetuximab, formulated in lipid nanoparticles (LNP) for liver uptake. We show that the mRNA-encoded antibody displays a stable pharmacokinetic profile in preclinical animal models, mediates CLDN18.2-restricted cytotoxicity comparable to IMAB362 recombinant protein and inhibits human tumor xenograft growth in immunocompromised mice. BNT141 administration did not perpetrate mortality, clinical signs of toxicity, or gastric pathology in animal studies. A phase 1/2 clinical trial with BNT141 mRNA-LNP has been initiated in advanced CLDN18.2-expressing solid cancers (NCT04683939).© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.