Preclinical Characterization of XB002, an Anti-Tissue Factor Antibody-Drug Conjugate for the Treatment of Solid...

Tissue factor (TF) is overexpressed in various cancers and is typically associated with poor clinical outcomes. XB002 is an anti-TF antibody-drug conjugate designed to selectively deliver a cytotoxic payload to TF-expressing tumors while minimizing TF-related adverse events, particularly bleeding. The conjugate consists of a zovodotin linker-payload attached to a mAb (clone 25A3) that binds TF with high affinity (KD = 0.86 nmol/L). In vitro coagulation assays confirmed that 25A3 does not interfere with the clotting cascade; even at a concentration of 100 nmol/L, it did not affect the activation of coagulation factor X or thrombin generation. XB002 demonstrated efficient internalization in TF-expressing cancer cell lines, exhibiting potent cytotoxicity at subnanomolar concentrations. In the HPAF-II xenograft model, a regimen of XB002 (1.5 mg/kg, i.v.) administered once weekly for two weeks achieved complete tumor regression, with no detectable tumor growth up to five weeks after the second dose. In murine patient-derived xenograft models, a single dose of XB002 (10 mg/kg, i.v.) inhibited tumor growth across multiple cancer models, including bladder, cervical, gastric, head and neck squamous cell carcinoma, and non-small cell lung cancers. Remarkably, complete tumor regression was observed in the cervical cancer and head and neck squamous cell carcinoma models within 30 days of treatment. In nonhuman primate studies, XB002 demonstrated favorable pharmacokinetics with exposure in the desired therapeutic range and no signs of bleeding or neutropenia. Collectively, these data highlight XB002's broad-spectrum antitumor activity and strongly support its further clinical development.