Rationally Designed Antibody Drug Conjugates Targeting the Breast Cancer-Associated Endothelium.

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.