Capacity limits of asialoglycoprotein receptor-mediated liver targeting
Capacity limits of asialoglycoprotein receptor-mediated liver targeting
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DOI：
10.1080/19420862.2017.1373924
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发表时间：
2017-01-01
期刊：
影响因子：
5.3
通讯作者：
Krippendorff, Ben-Fillippo
中科院分区：
文献类型：
--
作者：
Bon, Charlotte;Hofer, Thomas;Krippendorff, Ben-Fillippo
富含asialalglycoprotein receptor （ASGPR）的细胞表面asialalglycoprotein receptor （ASGPR）是一种在肝细胞上发现的高选择性受体，可能被利用作为一种选择性的递送载体。多种结合ASGPR的核酸疗法已经在临床开发中，但这种受体介导的递送机制可能饱和，这可能导致肝脏的选择性降低，从而增加全身不良反应的可能性。因此，在利用这一机制时，优化给药方案和分子性质是很重要的。我们利用一种新的ASGPR靶向抗体来评估小鼠体内ASGPR的表达、周转和内化率。利用药代动力学数据（静脉和皮下给药）和计算机靶标介导的药物处置（TMDD）模型，我们估计ASGPR在每个肝细胞中的表达水平为180万分子。发现受体降解的半衰期为15小时，形成的配体-受体复合物被内化，半衰期为5天。进行了生物分布研究并证实了TMDD模型预测的准确性。ASGPR的动力学表明，在治疗浓度下梭体达到饱和是可能的；然而，模拟允许对剂量计划进行优化。所开发的TMDD模型可用于支持利用ASGPR作为进入肝细胞的通道的治疗方法的开发。
The abundant cell surface asialoglycoprotein receptor (ASGPR) is a highly selective receptor found on hepatocytes that potentially can be exploited as a selective shuttle for delivery. Various nucleic acid therapeutics that bind ASGPR are already in clinical development, but this receptor-mediated delivery mechanism can be saturated, which will likely result in reduced selectivity for the liver and therefore increase the likelihood for systemic adverse effects. Therefore, when aiming to utilize this mechanism, it is important to optimize both the administration protocol and the molecular properties. We here present a study using a novel ASGPR-targeted antibody to estimate ASGPR expression, turnover and internalization rates in vivo in mice. Using pharmacokinetic data (intravenous and subcutaneous dosing) and an in-silico target-mediated drug disposition (TMDD) model, we estimate an ASGPR expression level of 1.8 million molecules per hepatocyte. The half-life of the degradation of the receptor was found to be equal to 15 hours and the formed ligand-receptor complex is internalized with a half-life of 5 days. A biodistribution study was performed and confirmed the accuracy of the TMDD model predictions. The kinetics of the ASGPR shows that saturation of the shuttle at therapeutic concentrations is possible; however, simulation allows the dosing schedule to be optimized. The developed TMDD model can be used to support the development of therapies that use the ASGPR as a shuttle into hepatocytes.