Tumor-specific delivery of cytotoxic agents remains a challenge in cancer therapy. Antibody-drug conjugates (ADC) deliver their payloads to tumor cells that overexpress specific tumor-associated antigens-but the multi-day half-life of ADC leads to high exposure even of normal, antigen-free, tissues and thus contributes to dose-limiting toxicity. Here, we present Adnectin-drug conjugates, an alternative platform for tumor-specific delivery of cytotoxic payloads. Due to their small size (10 kDa), renal filtration eliminates Adnectins from the bloodstream within minutes to hours, ensuring low exposure to normal tissues. We used an engineered cysteine to conjugate an Adnectin that binds Glypican-3, a membrane protein overexpressed in hepatocellular carcinoma, to a cytotoxic derivative of tubulysin, with the drug-to-Adnectin ratio of 1. We demonstrate specific, nanomolar binding of this Adnectin-drug conjugate to human and murine Glypican-3; its high thermostability; its localization to target-expressing tumor cells in vitro and in vivo, its fast clearance from normal tissues and its efficacy against Glypican-3-positive mouse xenograft models.

中文翻译：

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Adnectin-药物缀合物用于将细胞毒性有效负载特异性地递送至肿瘤的 Glypican-3。


细胞毒性药物的肿瘤特异性递送仍然是癌症治疗中的一个挑战。抗体-药物偶联物 (ADC) 将其有效负载传递给过度表达特定肿瘤相关抗原的肿瘤细胞，但 ADC 的多天半衰期甚至会导致正常、无抗原的组织的高暴露，从而导致剂量-限制毒性。在这里，我们提出了 Adnectin-药物缀合物，这是一种用于肿瘤特异性递送细胞毒性有效负载的替代平台。由于 Adnectin 体积小 (10 kDa)，肾过滤可在几分钟到几小时内将 Adnectin 从血流中消除，从而确保正常组织的接触量较低。我们使用工程化的半胱氨酸将 Adnectin 与 Glypican-3（一种在肝细胞癌中过度表达的膜蛋白）结合到微管蛋白抑制剂的细胞毒性衍生物上，药物与 Adnectin 的比例为 1。我们证明了该 Adnectin 的特异性、纳摩尔结合[0100]-人和鼠Glypican-3的药物缀合物；其高热稳定性；它在体外和体内定位于表达靶标的肿瘤细胞，从正常组织中快速清除，以及对 Glypican-3 阳性小鼠异种移植模型的功效。