Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, 100 Shih-Chuan First Road, Kaohsiung 80708, Taiwan.
Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, 100 Shih-Chuan First Road, Kaohsiung 80708, Taiwan.
Theranostics. 2018 May 9;8(11):3164-3175. doi: 10.7150/thno.22164. eCollection 2018.
Increasing frequency of human exposure to PEG-related products means that healthy people are likely to have pre-existing anti-PEG antibodies (pre-αPEG Ab). However, the influence of pre-αPEG Abs on the pharmacokinetics (PK) and therapeutic efficacy of LipoDox is unknown. We generated two pre-αPEG Ab mouse models. First, naïve mice were immunized with PEGylated protein to generate an endogenous αPEG Ab titer (endo αPEG). Second, monoclonal αPEG Abs were passively transferred (αPEG-PT) into naïve mice to establish a αPEG titer. The naïve, endo αPEG and αPEG-PT mice were intravenously injected with in-labeled LipoDox to evaluate its PK. Tumor-bearing naïve, endo αPEG and αPEG-PT mice were intravenously injected with in-labeled LipoDox to evaluate its biodistribution. The therapeutic efficacy of LipoDox was estimated in the tumor-bearing mice. The areas under the curve (AUC) of LipoDox in endo αPEG and αPEG-PT mice were 11.5- and 15.6- fold less, respectively, than that of the naïve group. The biodistribution results suggested that pre-αPEG Ab can significantly reduce tumor accumulation and accelerate blood clearance of In-labeled LipoDox from the spleen. The tumor volumes of the tumor-bearing endo αPEG and αPEG-PT mice after treatment with LipoDox were significantly increased as compared with that of the tumor-bearing naïve mice. Pre-αPEG Abs were found to dramatically alter the PK and reduce the tumor accumulation and therapeutic efficacy of LipoDox. Pre-αPEG may have potential as a marker to aid development of personalized therapy using LipoDox and achieve optimal therapeutic efficacy.
越来越多的人接触到含有聚乙二醇（PEG）的产品，这意味着健康人群可能预先存在针对 PEG 的抗体（预-αPEG Ab）。然而，预-αPEG Abs 对 LipoDox 的药代动力学（PK）和治疗效果的影响尚不清楚。我们生成了两种预-αPEG Ab 小鼠模型。首先，用 PEG 化蛋白免疫新生小鼠以产生内源性 αPEG Ab 滴度（endo αPEG）。其次，将单克隆 αPEG Ab 被动转移（αPEG-PT）到新生小鼠中以建立 αPEG 滴度。将新生、endo αPEG 和 αPEG-PT 小鼠静脉注射放射性标记的 LipoDox 以评估其 PK。将放射性标记的 LipoDox 静脉注射到荷瘤新生、endo αPEG 和 αPEG-PT 小鼠中以评估其生物分布。在荷瘤小鼠中评估 LipoDox 的治疗效果。endo αPEG 和 αPEG-PT 小鼠中 LipoDox 的曲线下面积（AUC）分别比新生组低 11.5 倍和 15.6 倍。生物分布结果表明，预-αPEG Ab 可显著减少肿瘤积累并加速从脾脏清除放射性标记的 LipoDox。与荷瘤新生小鼠相比，经 LipoDox 治疗后荷瘤 endo αPEG 和 αPEG-PT 小鼠的肿瘤体积明显增加。预-αPEG Ab 可显著改变 PK，降低 LipoDox 的肿瘤积累和治疗效果。预-αPEG Ab 可能有潜力作为一种标志物，有助于开发使用 LipoDox 的个体化治疗并实现最佳治疗效果。
