Global Drug Discovery, Novo Nordisk A/S, 2760 Måløv, Denmark.
Global Research Technologies, Novo Nordisk A/S, 2760 Måløv, Denmark.
Int J Mol Sci. 2020 Feb 11;21(4):1181. doi: 10.3390/ijms21041181.
Somapacitan is a long-acting, once-weekly, albumin-binding growth hormone (GH) derivative. The reversible albumin-binding properties leads to prolonged circulation half-life. Here, we investigated and compared somapacitan with human GH on downstream receptor signaling in primary hepatocytes and hepatocellular models and using isothermal titration calorimetry to characterize receptor binding of somapacitan in the presence or absence of human serum albumin (HSA). With non-invasive fluorescence imaging we quantitatively visualize and compare the temporal distribution and examine the tissue-specific growth hormone receptor (GHR) activation at distribution sites. We found that signaling kinetics were slightly more rapid and intense for GH compared with somapacitan. Receptor binding isotherms were characterized by a high and a low affinity interaction site with or without HSA. Using in vivo optical imaging we found prolonged systemically biodistribution of somapacitan compared with GH, which correlated with plasma pharmacokinetics. Ex vivo mouse organ analysis revealed that the temporal fluorescent intensity in livers dosed with somapacitan was significantly increased compared with GH-dosed livers and correlated with the degree of downstream GHR activation. Finally, we show that fluorescent-labeled analogs distributed to the hypertrophic zone in the epiphysis of proximal tibia of hypophysectomized rats and that somapacitan and GH activate the GHR signaling in epiphyseal tissues.
索马帕肽是一种长效、每周一次、白蛋白结合型生长激素（GH）衍生物。其可逆的白蛋白结合特性导致其循环半衰期延长。在这里，我们研究并比较了索马帕肽和人 GH 对原代肝细胞和肝细胞模型下游受体信号的影响，并使用等温滴定量热法来表征索马帕肽在存在或不存在人血清白蛋白（HSA）时与受体的结合。我们通过非侵入性荧光成像技术定量可视化和比较了时空分布，并检查了在分布部位的组织特异性生长激素受体（GHR）的激活情况。我们发现，与索马帕肽相比，GH 的信号转导动力学稍快且强度更高。受体结合等温线的特征是存在或不存在 HSA 时具有高亲和力和低亲和力相互作用位点。使用体内光学成像，我们发现与 GH 相比，索马帕肽在体内的系统生物分布时间更长，这与血浆药代动力学相关。离体小鼠器官分析显示，与 GH 处理的肝脏相比，索马帕肽处理的肝脏中荧光强度在时间上显著增加，并且与下游 GHR 激活的程度相关。最后，我们表明，荧光标记的类似物分布到去垂体大鼠近端胫骨骺板的肥大区，并且索马帕肽和 GH 激活骺板组织中的 GHR 信号。
