TUB-040, a homogenous and hydrophilic NaPi2b-targeting ADC with stably linked exatecan, exhibits long-lasting anti-tumor activity and a well-tolerated safety profile.

Abstract

TUB-040 is a highly homogenous and hydrophilic antibody-drug conjugate (ADC) targeting NaPi2b, a surface receptor overexpressed in ovarian cancer and non-small cell lung adenocarcinoma. Previous NaPi2b-directed therapies have shown target-mediated and expression-dependent clinical activity. However, none of the previous tubulin inhibitor-based ADCs has been able to leverage the full therapeutic potential of the target. TUB-040 was constructed with a drug-to-antibody ratio (DAR) of 8 using the Tubutecan linker-payload technology based on ethynylphosphonamidates (P5 conjugation chemistry), a protease cleavage site and exatecan, a potent topoisomerase 1 (TOP1) inhibitor. TUB-040 induces potent antigen-specific cytotoxicity against NaPi2b-expressing cancer cells and demonstrates strong bystander activity. It displays a favorable pharmacokinetic behavior, showing dose-proportionality and superimposable total antibody and intact ADC curves and low free payload levels, reflecting the high stability of TUB-040 enabled by the P5 conjugation platform. This specific feature also ensures sustained delivery of exatecan to tumor sites which translates into excellent in vivo efficacy and tolerability. In cell line- and patient-derived xenograft models, including those with low target expression, single-dose TUB-040 administration leads to prolonged tumor growth inhibition and significant rates of complete remission, with a minimally effective dose (MED) level of 1 mg/kg in the OVCAR-3 model. Repeated-dose toxicological assessment in rats indicates that TUB-040 is well-tolerated, with no evidence of lung toxicity or thrombocytopenia. Taken together, TUB-040 is designed to enable long-lasting, durable tumor responses and to optimize both efficacy and tolerability, supporting the advancement of TUB-040 into clinical trials.