Transient Inhibition of Trastuzumab-Tumor Binding to Overcome the "Binding-Site Barrier" and Improve the Efficacy of a Trastuzumab-Gelonin Immunotoxin.
Transient Inhibition of Trastuzumab-Tumor Binding to Overcome the "Binding-Site Barrier" and Improve the Efficacy of a Trastuzumab-Gelonin Immunotoxin.
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DOI：
10.1158/1535-7163.mct-22-0192
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发表时间：
2022-10-07
影响因子：
5.7
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中科院分区：
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我们最近表明，单克隆抗体（mAb）与抑制mAb与肿瘤抗原结合的抗独特型分布增强剂（AIDE）共同给药能够增加肿瘤内mAb分布，并增加抗体-药物偶联物（曲妥珠单抗-美坦新偶联物，T-DM 1）的疗效。在本研究中，应用PK/PD模型预测该优化策略对曲妥珠单抗-白树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（白树素）预期表现出可忽略的旁观者活性。使用免疫荧光组织学研究在与或不与抗曲妥珠单抗AIDE联合给药后实体瘤中曲妥珠单抗-gelonin的分布。还在荷瘤小鼠中评价了曲妥珠单抗-白树素（与或不与AIDE联合给药）的抗肿瘤疗效。当曲妥珠单抗-白树素应用于培养的NCI-N87细胞时，可有效诱导细胞毒性（IC 50：0.224±0.079 nM）。PK/PD模拟预测，解离速率常数在0.03-0.2小时-1之间的抗独特型单域抗体AIDE将提供最佳的曲妥珠单抗-白树素疗效增强。选择LE 8和1HE（抗曲妥珠单抗AIDE）进行体内评价。曲妥珠单抗-白树素与抑制剂联合给药使曲妥珠单抗-白树素染色阳性的肿瘤区域部分增加了58%（p=0.0059）。此外，LE 8或1HE联合给药通过将寿命增加百分比（%ILS）从27.8%（曲妥珠单抗-白树素单独给药）增加至与LE 8联合给药时的62.5%（p=0.0007）或与1HE联合给药时的83.3%（p = 0.0007）来改善曲妥珠单抗-白树素在荷NCI-N87异种移植物小鼠中的疗效。这些发现支持以下假设：当应用于实体瘤治疗时，mAb-肿瘤结合的瞬时竞争性抑制可以改善免疫毒素的肿瘤内分布和功效。
We have recently shown that co-administration of monoclonal antibodies (mAb) with anti-idiotypic distribution enhancers (AIDEs) that inhibit mAb binding to tumor antigens enabled increased intra-tumoral mAb distribution and increased efficacy of an antibody-drug conjugate (trastuzumab emtansine, T-DM1). In the present work, a PK/PD model was applied to predict the impact of this optimization strategy on the within-tumor distribution and anti-tumor 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 co-administration of anti-trastuzumab AIDEs. Anti-tumor efficacy of trastuzumab-gelonin, with or without co-administration 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 nM). PK/PD simulations predicted that anti-idiotypic single-domain antibodies AIDEs with dissociation rate constants between 0.03-0.2 hour−1 would provide optimal enhancement of trastuzumab-gelonin efficacy. LE8 and 1HE, anti-trastuzumab AIDEs, were selected for evaluation in vivo. Co-administration of trastuzumab-gelonin with the inhibitors increased the portion of tumor area that stained positive for trastuzumab-gelonin by 58% (p=0.0059). Additionally, LE8 or 1HE co-administration 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 intra-tumoral distribution and efficacy of immunotoxins when applied for treatment of solid tumors.
DOI：
10.1208/s12248-022-00698-x
发表时间：
2022-03-25
期刊：
The AAPS journal
影响因子：
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