Chen Ping, Zhang Yu, Bordeau Brandon M, Balthasar Joseph P
Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14214, USA.
Cancers (Basel). 2025 Apr 27;17(9):1468. doi: 10.3390/cancers17091468.
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.
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.
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. The coadministration of trastuzumab-PE24 with 1HE and LG1 improved anti-tumor efficacy and extended median survival to 60 days ( = 0.0002).
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：由于“结合位点屏障”（BSB），基于抗体的疗法在实体瘤内的分布往往有限。我们团队已开发并验证了抗独特型分布增强剂（AIDE）的使用，其可短暂阻断抗体结合，改善肿瘤内分布和疗效。本研究评估了1HE和LG1这两种抗曲妥珠单抗AIDE模型与高效免疫毒素曲妥珠单抗-PE24联合使用的情况。
在荷NCI-N87肿瘤的小鼠中评估1HE对放射性标记曲妥珠单抗全身处置的影响。采用机制性药代动力学/药效学（PK/PD）模型来探究AIDE结合动力学如何影响抗体在肿瘤内的分布和免疫毒素效力。曲妥珠单抗-PE24通过自剪接分裂内含肽实现位点特异性偶联而开发，并在多种体外细胞系上测试了其细胞毒性。在荷NCI-N87异种移植瘤的小鼠中评估1HE和LG1联合给药对曲妥珠单抗-PE24疗效的影响。
联合给予1HE可降低曲妥珠单抗在肿瘤中的最大浓度，使肿瘤终末斜率降低8%，肿瘤总体暴露量降低2.6%，且对选择性无负面影响。模型预测曲妥珠单抗-PE24的最佳AIDE解离速率常数在0.015至0.3小时之间。曲妥珠单抗-PE24与1HE和LG1联合给药提高了抗肿瘤疗效，并将中位生存期延长至60天（P = 0.0002））。
AIDE联合给药对肿瘤总体暴露的负面影响最小，与模型模拟结果一致。AIDE联合给药提高了曲妥珠单抗-PE24在NCI-N87异种移植瘤中的疗效。模型进一步预测，曲妥珠单抗-PE24重复给予AIDE可诱导肿瘤完全消退。这些发现突出了AIDE策略的优势，特别是与高效免疫毒素联合使用时。
