靶向组织因子(tissue factor)用于治疗实体瘤的抗体药物偶联物XNW28012的临床前开发

Tissue factor (TF) is a transmembrane protein that serves as the primary initiator of physiological hemostasis. TF binds coagulation factor VII (FVII), promotes its activation, and enhances the proteolytic activity of FVIIa to initiate the extrinsic pathway of blood coagulation. To prevent any improper coagulation cascade activation, TF is normally not expressed by cells exposed to flowing blood such as endothelial cells. Elevated TF expression has been reported in multiple solid cancers, such as cervical cancer, esophageal cancer, and pancreatic cancer. TF is well-internalized into lysosomes and given these various features, represents a favorable target for an antibody-drug conjugate (ADC) modality.XNW28012 is a TF-targeting ADC comprised of a humanized IgG1 antibody conjugated with a potent DNA topoisomerase I inhibitor via a protease-cleavable linker with a drug-antibody ratio (DAR) of 8. The tripeptide linker is highly stable in blood and cleavable in the tumor microenvironment and in tumor cell lysosomes. In preclinical studies, XNW28012 can bind to TF on cell surface, enter the cell through internalization effect, and then exhibits similar efficacy with toxin, such as inhibition of cell proliferation, cell cycle arrest, DNA damage response and apoptosis. XNW28012 also exhibits significant antitumor efficacy in multiple tumor xenograft models, including cervical cancer (CaSki), ovarian cancer (OVCAR8), pancreatic cancer (HPAF-II), etc. In vivo efficacy is dose-dependent and test dosages are well-tolerated, with minimum effective dose at 1 mg/kg/dose weekly. At the well-tolerated 3 or 10 mg/kg dosage, XNW28012 achieves partial tumor regression (PR) and complete tumor regression (CR) in most xenograft models. XNW28012 combined with SOC showed synergistic effect in multiple xenograft models. The antibody has minimal effect on blood coagulation through antibody screening and therefore no bleeding adverse effect (AE) is observed in toxicity studies.In pharmacokinetic studies, the ADME characteristics of XNW28012 confirmed the designed attributes of the ADC that directs toward the target antigen expressed on the cancer cell surface, and has excellent stability in the bloodstream and the exposure of payload was very low, leading to reduced toxicity. In toxicity studies, XNW28012 displays good tolerability with wide therapeutic windows in Cynomolgus monkeys. It is particularly important to note that XNW28012 has no toxic effect on the lungs and eyes, and no bleeding risk was observed in monkeys.Taken together, preclinical data suggest that XNW28012 could be a promising new antitumor agent for further investigation in clinical trials. Clinical activity of XNW28012 is currently under evaluation in a Phase I/II clinical trial (CTR20233056) and a Phase III clinical trial (CTR20252545).