Background/Objectives: Antibody-based therapies often exhibit limited distribution within solid tumors due to the “binding-site barrier” (BSB). Our group has developed and validated the use of anti-idiotypic distribution enhancers (AIDEs), which transiently block antibody binding, improving intra-tumoral distribution and efficacy. This study evaluated 1HE and LG1, model anti-trastuzumab AIDEs, in combination with trastuzumab–PE24, a highly potent immunotoxin. Methods: The effects of 1HE on the whole-body disposition of radiolabeled trastuzumab were assessed in NCI-N87 tumor-bearing mice. Mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modeling was employed to explore how AIDE binding kinetics influence antibody intra-tumoral distribution and immunotoxin potency. Trastuzumab–PE24 was developed by site-specific conjugation, enabled by self-splicing split intein, with cytotoxicity tested on various cell lines in vitro. The impact of 1HE and LG1 coadministration on trastuzumab–PE24 efficacy was evaluated in NCI-N87 xenograft-bearing mice. Results: 1HE coadministration decreased trastuzumab tumor maximum concentration, reducing tumor terminal slope by 8% and overall tumor exposure by 2.6%, without negatively affecting selectivity. Modeling predicted the optimal AIDE dissociation rate constant for trastuzumab–PE24 to be between 0.015 and 0.3 h−1. The coadministration of trastuzumab–PE24 with 1HE and LG1 improved anti-tumor efficacy and extended median survival to 60 days (p= 0.0002). Conclusions: AIDE coadministration led to minimal negative impacts on overall tumor exposure, consistent with model simulations. AIDE coadministration improved the efficacy of trastuzumab–PE24 in NCI-N87 xenografts. Modeling further predicted that repeated AIDE administration with trastuzumab–PE24 could induce complete tumor regression. These findings highlight the advantages of the AIDE strategy, particularly when coadministered with highly potent immunotoxins.
背景/目的：基于抗体的疗法常因“结合位点屏障”效应而在实体瘤内分布受限。本研究团队开发并验证了抗独特型分布增强剂的应用，该制剂通过暂时阻断抗体结合，改善抗体在肿瘤内的分布与疗效。本研究评估了模型抗曲妥珠单抗AIDEs（1HE与LG1）与高效免疫毒素曲妥珠单抗-PE24的联合治疗效果。方法：在NCI-N87荷瘤小鼠模型中评估1HE对放射性标记曲妥珠单抗全身分布的影响，并采用机制性药代动力学/药效学模型探究AIDE结合动力学如何影响抗体瘤内分布及免疫毒素效力。通过自剪切分裂内含肽介导的定点偶联技术构建曲妥珠单抗-PE24，并在多种细胞系中测试其体外细胞毒性。在NCI-N87移植瘤小鼠模型中评估1HE与LG1联合给药对曲妥珠单抗-PE24疗效的影响。结果：1HE联合给药降低了曲妥珠单抗在肿瘤中的最大浓度，使肿瘤终末斜率降低8%，总体肿瘤暴露量减少2.6%，且未对选择性产生负面影响。模型预测显示，曲妥珠单抗-PE24的最佳AIDE解离速率常数应在0.015至0.3 h−1之间。曲妥珠单抗-PE24与1HE及LG1联合用药显著提升抗肿瘤疗效，中位生存期延长至60天（p=0.0002）。结论：AIDE联合给药对总体肿瘤暴露量的负面影响极小，与模型模拟结果一致。在NCI-N87移植瘤模型中，AIDE联合用药显著增强曲妥珠单抗-PE24疗效。模型进一步预测，曲妥珠单抗-PE24与AIDE的重复联合给药可能实现肿瘤完全消退。这些发现凸显了AIDE策略的优越性，尤其在与高效免疫毒素联合应用时更具价值。
肿瘤(癌症)患者之家