Wang Yuchen, Liu Xiao, Zou Xiaowen, Wang Shuting, Luo Lijun, Liu Yuke, Dong Kai, Yao Xiaoqing, Li Yan, Chen Xiaoguang, Sheng Li
Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China.
Pharmaceutics. 2021 Apr 21;13(5):598. doi: 10.3390/pharmaceutics13050598.
IMMH-010 is an ester prodrug of YPD-29B, a potent programmed cell death ligand 1 (PD-L1) inhibitor. The metabolism of IMMH-010 was investigated and compared in various species. Four metabolites of IMMH-010 were identified, and the major metabolite was the parent compound, YPD-29B, which was mainly catalyzed by carboxylesterase 1 (CES1). We observed IMMH-010 metabolism in the plasma of various species. IMMH-010 was rapidly metabolized to YPD-29B in rat and mouse plasma, whereas it remained stable in human and monkey plasma. In the liver S9 fractions of human, monkey, dog, and rat, IMMH-010 was quickly transformed to YPD-29B with no obvious differences among species. In addition, the transformation ratio of IMMH-010 to YPD-29B was low in rat and human intestines, which indicated that the intestine was not an important site for IMMH-010 hydrolysis. Moreover, we demonstrated the remarkable antitumor efficacy of IMMH-010 in B16F10 melanoma and MC38 colon carcinoma xenograft mouse models. We also compared the pharmacokinetic profiles of IMMH-010 in rodents and primates. After oral administration of IMMH-010, the general exposure of active metabolite YPD-29B was slightly lower in primates than in rodents, suggesting that data should be extrapolated cautiously from rodents to humans.
IMMH-010是强效程序性细胞死亡配体1（PD-L1）抑制剂YPD-29B的酯前药。研究并比较了IMMH-010在不同物种中的代谢情况。鉴定出了IMMH-010的四种代谢产物，主要代谢产物是母体化合物YPD-29B，其主要由羧酸酯酶1（CES1）催化。我们观察到了IMMH-010在不同物种血浆中的代谢情况。IMMH-010在大鼠和小鼠血浆中迅速代谢为YPD-29B，而在人血浆和猴血浆中保持稳定。在人、猴、狗和大鼠的肝脏S9组分中，IMMH-010迅速转化为YPD-29B，不同物种之间无明显差异。此外，IMMH-010在大鼠和人肠道中向YPD-29B的转化率较低，这表明肠道不是IMMH-010水解的重要部位。此外，我们证明了IMMH-010在B16F10黑色素瘤和MC38结肠癌异种移植小鼠模型中具有显著的抗肿瘤疗效。我们还比较了IMMH-010在啮齿动物和灵长类动物中的药代动力学特征。口服IMMH-010后，活性代谢产物YPD-29B在灵长类动物中的总体暴露量略低于啮齿动物，这表明从啮齿动物向人类外推数据时应谨慎。
