Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York.
Mol Cancer Ther. 2022 Oct 7;21(10):1573-1582. doi: 10.1158/1535-7163.MCT-22-0192.
We have recently shown that coadministration of mAbs with anti-idiotypic distribution enhancers (AIDE) that inhibit mAb binding to tumor antigens enabled increased intratumoral mAb distribution and increased efficacy of an antibody-drug conjugate (trastuzumab emtansine, T-DM1). In this article, a pharmacokinetic/pharmacodynamic (PK/PD) model was applied to predict the impact of this optimization strategy on the within-tumor distribution and antitumor efficacy of trastuzumab-gelonin, where the released payload (gelonin) is expected to exhibit negligible bystander activity. Immunofluorescence histology was used to investigate trastuzumab-gelonin distribution in solid tumors following dosing with or without coadministration of anti-trastuzumab AIDEs. Antitumor efficacy of trastuzumab-gelonin, with or without coadministration of AIDEs, was also evaluated in tumor-bearing mice. Trastuzumab-gelonin efficiently induced cytotoxicity when applied to NCI-N87 cells in culture (IC50: 0.224 ± 0.079 nmol/L). PK/PD simulations predicted that anti-idiotypic single-domain antibodies AIDEs with dissociation rate constants between 0.03 and 0.2 per hour would provide optimal enhancement of trastuzumab-gelonin efficacy. LE8 and 1HE, anti-trastuzumab AIDEs, were selected for evaluation in vivo. Coadministration of trastuzumab-gelonin with the inhibitors increased the portion of tumor area that stained positive for trastuzumab-gelonin by 58% (P = 0.0059). In addition, LE8 or 1HE coadministration improved trastuzumab-gelonin efficacy in NCI-N87 xenograft-bearing mice by increasing the percent increase in life span (%ILS) from 27.8% (for trastuzumab-gelonin administered alone) to 62.5% when administered with LE8 (P = 0.0007) or 83.3% (P = 0.0007) when administered with 1HE. These findings support the hypothesis that transient, competitive inhibition of mAb-tumor binding can improve the intratumoral distribution and efficacy of immunotoxins when applied for treatment of solid tumors.
我们最近发现，与抑制 mAb 与肿瘤抗原结合的抗独特型分布增强剂（AIDE）联合给药，可以增加肿瘤内 mAb 的分布，并提高抗体药物偶联物（曲妥珠单抗-美坦新，T-DM1）的疗效。在本文中，应用药代动力学/药效学（PK/PD）模型来预测这种优化策略对曲妥珠单抗-蓖麻毒素的肿瘤内分布和抗肿瘤疗效的影响，其中释放的有效载荷（蓖麻毒素）预计不会表现出明显的旁观者活性。免疫荧光组织化学用于研究在给予或不给予抗曲妥珠单抗 AIDE 的情况下，曲妥珠单抗-蓖麻毒素在实体瘤中的分布。还在荷瘤小鼠中评价了曲妥珠单抗-蓖麻毒素联合或不联合 AIDE 的抗肿瘤疗效。曲妥珠单抗-蓖麻毒素在体外培养的 NCI-N87 细胞中有效地诱导了细胞毒性（IC50：0.224±0.079 nmol/L）。PK/PD 模拟预测，具有 0.03 至 0.2 每小时解离速率常数的抗独特型单域抗体 AIDE 将为曲妥珠单抗-蓖麻毒素的疗效提供最佳增强。选择 LE8 和 1HE 作为抗曲妥珠单抗 AIDE 进行体内评估。与抑制剂联合给予曲妥珠单抗-蓖麻毒素可使肿瘤区域内曲妥珠单抗-蓖麻毒素染色阳性的比例增加 58%（P=0.0059）。此外，LE8 或 1HE 联合给药可提高曲妥珠单抗-蓖麻毒素在荷 NCI-N87 异种移植瘤小鼠中的疗效，使生命延长率（%ILS）从单独给予曲妥珠单抗-蓖麻毒素时的 27.8%增加到给予 LE8 时的 62.5%（P=0.0007）或给予 1HE 时的 83.3%（P=0.0007）。这些发现支持这样一种假说，即瞬时、竞争性抑制 mAb 与肿瘤的结合，可以改善免疫毒素在治疗实体瘤时的肿瘤内分布和疗效。
