Pognan François, Buono Chiara, Couttet Philippe, Galarneau Jean-René, Timsit Yoav, Wolf Armin
Novartis Institute for Biomedical Research, Basel, Switzerland.
Novartis Institute for Biomedical Research, Cambridge, MA, USA.
Curr Res Toxicol. 2022 Oct 29;3:100091. doi: 10.1016/j.crtox.2022.100091. eCollection 2022.
Sotuletinib (BLZ945), a CSF1-R specific kinase inhibitor developed for the treatment of Amyotrophic Lateral Sclerosis, induced liver enzyme elevation in absence of hepatocellular lesions in preclinical rat and monkey studies. The monocytic cell family, including Kupffer cells, e.g., the liver-resident macrophages, are dependent upon CSF1 pathway activation for their survival, proliferation, and differentiation. Kupffer cells act as the main body compartment responsible for elimination of some blood-borne proteins, like ALT, AST, and few others. The depletion of Kupffer cells through CSF1 pathway inhibition has already been hypothesized as responsible for apparent liver enzyme elevation without detectable corresponding liver damage. However, a release of these biomarkers from unseen hepatic lesions or from other organs cannot be excluded. In order to eliminate a potential contribution of ALT elevation from an internal organ source, we injected recombinant his-Tagged ALT1 into rats pretreated with Sotuletinib. The elimination rate of the exogenous ALT1 was significantly lower in treated animals, demonstrating a delayed clearance independently of any potential organ lesions.
索图替尼（BLZ945）是一种开发用于治疗肌萎缩侧索硬化症的CSF1-R特异性激酶抑制剂，在临床前大鼠和猴子研究中，它在没有肝细胞损伤的情况下导致肝酶升高。单核细胞家族，包括库普弗细胞，例如肝脏驻留巨噬细胞，其存活、增殖和分化依赖于CSF1途径的激活。库普弗细胞是负责清除一些血源性蛋白质（如ALT、AST等少数几种）的主要细胞成分。通过CSF1途径抑制使库普弗细胞耗竭已被推测是导致肝酶明显升高而无相应肝损伤的原因。然而，不能排除这些生物标志物从未见的肝脏病变或其他器官释放的可能性。为了排除内源性器官来源导致ALT升高的潜在影响，我们将重组His标签的ALT1注射到用索图替尼预处理的大鼠体内。在治疗的动物中，外源性ALT1的清除率显著降低，表明清除延迟，与任何潜在的器官病变无关。
