Transient Competitive Inhibition Bypasses the Binding Site Barrier to Improve Tumor Penetration of Trastuzumab and Enhance T-DM1 Efficacy.
Transient Competitive Inhibition Bypasses the Binding Site Barrier to Improve Tumor Penetration of Trastuzumab and Enhance T-DM1 Efficacy.
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DOI：
10.1158/0008-5472.can-20-3822
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发表时间：
2021-08-01
期刊：
影响因子：
11.2
通讯作者：
Balthasar JP
中科院分区：
文献类型：
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作者：
Bordeau BM;Yang Y;Balthasar JP
单克隆抗体 (mAb) 在实体瘤中渗透性差的部分原因是结合位点屏障假说。外渗后，单克隆抗体迅速结合细胞抗原，从而观察到，在亚饱和剂量下，实体瘤中的治疗性抗体位于肿瘤脉管系统周围。在这里，我们报告了一种独特的策略，通过抗体-抗原结合的瞬时竞争性抑制来克服结合位点障碍。通过体外结合测定，抗曲妥珠单抗单域抗体 1HE 被鉴定为模型抑制剂。 1HE 的共同给药不会改变曲妥珠单抗或 ado-曲妥珠单抗 emtansine (T-DM1) 体内的血浆药代动力学。单独给予 1HE 后可迅速消除，终末血浆半衰期为 1.2 小时，而 1HE 与曲妥珠单抗联合给药的终末半衰期为 56 小时。在携带 SKOV3 异种移植物的小鼠中，1HE 与曲妥珠单抗联合给药导致曲妥珠单抗从脉管系统的渗透以及曲妥珠单抗染色呈阳性的肿瘤区域百分比显着增加。 1HE 与单剂量 T-DM1 共同给予 NCI-N87 异种移植小鼠显着增强 T-DM1 功效，增加中位生存期。这些结果支持这样的假设：瞬时竞争性抑制可以改善治疗性抗体在实体瘤中的分布并增强抗体功效。
Poor penetration of monoclonal antibodies (mAb) in solid tumors is explained in part by the binding site barrier hypothesis. Following extravasation, mAbs rapidly bind cellular antigens, leading to the observation that, at sub-saturating doses, therapeutic antibody in solid tumors localizes around tumor vasculature. Here we report a unique strategy to overcome the binding site barrier through transient competitive inhibition of antibody-antigen binding. The anti-trastuzumab single domain antibody 1HE was identified through in vitro binding assays as a model inhibitor. Co-administration of 1HE did not alter the plasma pharmacokinetics of trastuzumab or ado-trastuzumab emtansine (T-DM1) in vivo. Administration of 1HE alone was rapidly eliminated with a terminal plasma half-life of 1.2 hours, while co-administrations of 1HE with trastuzumab had a terminal half-life of 56 hours. In mice harboring SKOV3 xenografts, co-administration of 1HE with trastuzumab led to significant increases in both penetration of trastuzumab from vasculature and the percent of tumor area that stained positive for trastuzumab. 1HE co-administered with a single dose of T-DM1 to NCI-N87 xenograft bearing mice significantly enhanced T-DM1 efficacy, increasing median survival. These results support the hypothesis that transient competitive inhibition can improve therapeutic antibody distribution in solid tumors and enhance antibody efficacy.