Abstract
The oncofetal antigen 5T4 is expressed in many solid tumors, making it an attractive antitumor target. XB010 is a novel, 5T4-targeted, antibody-drug conjugate developed using the SMARTag platform to optimize tolerability. We describe the development, design, and preclinical characterization of XB010. In vitro and in vivo efficacy of XB010 was assessed in cell-derived xenograft breast cancer cell lines (MCF-7 and MDA-MB-468) and in patient-derived xenograft tumor models (squamous cell carcinoma of the head and neck, non-small cell lung cancer, and breast cancer). Additionally, the in vivo combinatorial efficacy of XB010 + anti-PD-1 antibody was assessed in an MC38-h5T4 syngeneic colon cancer xenograft model. The toxicity profile of XB010 was evaluated in both Sprague-Dawley rats and cynomolgus monkeys. XB010 demonstrated in vitro cytotoxic effects with sub-nanomolar potency in the MCF-7 and MDA-MB-468 breast cancer cell lines and in vivo tumor growth inhibition (80%-99%) compared with vehicle-treated animals in xenograft and patient-derived xenograft models at doses of 5 to 10 mg/kg XB010. In the syngeneic MC38-h5T4-expressing colon cancer xenograft model, XB010 + anti-PD-1 showed improved efficacy compared with either agent administered alone. XB010 safety assessments demonstrated tolerability of doses up to 60 mg/kg in rats and up to 25 mg/kg in nonhuman primates. XB010 is a novel anti-5T4 antibody-drug conjugate that exhibits potent antitumor activity, inhibiting cancer cell growth in vitro and tumor growth in various in vivo models, with an acceptable toxicity profile. These findings support the evaluation of XB010 in clinical studies.