Vascular Biology Program, Boston Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, United States.
Department of Surgery, Harvard Medical School and Boston Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, United States.
ACS Biomater Sci Eng. 2020 May 11;6(5):2563-2569. doi: 10.1021/acsbiomaterials.9b01060. Epub 2019 Oct 1.
The promise of antiangiogenic therapy for the treatment of breast cancer has been limited by the inability to selectively disrupt the established tumor vasculature. Here, we report the development of rationally designed antibody drug conjugates (ADCs) that can selectively recognize and attack breast tumor-associated endothelial cells (BTECs), while sparing normal endothelial cells (NECs). We first performed a quantitative and unbiased screening of a panel of cancer-related antigens on human BTECs and identified CD105 as the optimal ADC target on these cells. We then used clinically approved ADC linkers and cytotoxic drugs to engineer two CD105-targeted ADCs: CD105-DM1 and CD105-MMAE and evaluated their in vitro efficacy in human BTECs and NECs. We found that both CD105-DM1 and CD105-MMAE exhibited highly potent and selective cytotoxicity against BTECs with IC values of 3.2 and 3.7 nM, respectively, significantly lower than their IC values on NECs (8-13 fold). Our proof-of-principle study suggests that CD105-targeted ADCs are promising antiangiogenic agents that have the potential to be used to inhibit the established tumor vasculature of breast tumors in a safe and precise manner.
抗血管生成治疗乳腺癌的前景受到限制，原因是无法选择性地破坏已建立的肿瘤血管。在这里，我们报告了合理设计的抗体药物偶联物（ADC）的开发，这些 ADC 可以选择性地识别和攻击乳腺癌相关的内皮细胞（BTEC），同时避免正常的内皮细胞（NEC）受到影响。我们首先在人 BTEC 上进行了定量和无偏见的癌症相关抗原筛选，并鉴定出 CD105 是这些细胞上的最佳 ADC 靶标。然后，我们使用临床批准的 ADC 接头和细胞毒性药物来设计两种针对 CD105 的 ADC：CD105-DM1 和 CD105-MMAE，并评估它们在人 BTEC 和 NEC 中的体外功效。我们发现，CD105-DM1 和 CD105-MMAE 对 BTEC 均表现出高度有效且选择性的细胞毒性，IC 值分别为 3.2 和 3.7 nM，明显低于它们在 NEC 上的 IC 值（8-13 倍）。我们的原理验证研究表明，CD105 靶向 ADC 是有前途的抗血管生成剂，具有以安全和精确的方式抑制乳腺癌中已建立的肿瘤血管的潜力。
