Abstract Tissue factor (TF) protein is involved in activating the extrinsic blood coagulation cascade. TF expression is normally anatomically limited to the perivascular space, but TF is overexpressed in many malignancies, including pancreatic, cervical, prostate, and head and neck cancer, which makes TF an ideal antibody-drug conjugate (ADC) target. The TF-ADC tisotumab vedotin is approved for cervical cancer treatment but induces substantial side effects including ocular toxicities, peripheral neuropathy, and bleeding, limiting its further clinical development and warranting optimized ADC design to improve the therapeutic window. ADCE-T02 is a novel TF-ADC comprising the monoclonal antibody Ab-T02 conjugated via a self-immolative linker to the Topoisomerase-1 inhibitor Exatecan at an average drug-to-antibody ratio of 4.5. In contrast to tisotumab, Ab-T02 does not inhibit Coagulation Factor X activation. ADCE-T02 binds TF with high affinity inducing ADC internalization, exatecan release, cancer cell death and bystander cytotoxicity in vitro. In vivo, ADCE-T02 is highly efficacious across a range of cell-line and patient-derived xenograft models including hard to treat models with large tumors, resistance to standard of care, low and/or heterogeneous expression of TF, and multi-drug resistance. Importantly, ADCE-T02 demonstrates favorable pharmacokinetic properties and is well tolerated in non-human primates and in contrast to tisotumab vedotin and other auristatin based ADCs shows no evidence of ocular, skin and lung toxicity, peripheral nerve damage, or bleeding. In summary, ADCE-T02 constitutes a novel TF ADC with a much improved preclinical therapeutic window. Phase I clinical development of ADCE-T02 in patients with advanced solid tumors is ongoing (ClinicalTrials-ID NCT06597721).
Poulsen et al. (Fri,) studied this question.