The Trop-2-targeting antibody drug conjugate DB-1305 has higher antitumor activity and a potentially better safety profile compared with DS-1062

Background: Trop-2 is a well validated oncology therapeutic target. DB-1305 an antibody drug conjugate designed by conjugating anti-Trop-2 with novel topoisomerase I inhibitor P1021 via enzymatically cleavable tetrapeptide linker. Material and Methods: To characterize the payload P1021, thorough studies were performed including in vitro functional assays, vivo efficacy PK/PD murine CDX models, as PK/TK GLP toxicity monkeys rats. Results: The results show that vitro, selectively bound to Trop-2-positive cells was endocytosed into their lysosomes. led Trop-2-dependent cytotoxicity Trop-2-expressing but not Trop-2-negative concentration-dependent manner. demonstrated tumor cell proliferation inhibition activities comparable or stronger than DS-1062 produced in-house, intriguingly displayed bystander killing effect. vivo, showed strong anti-tumor activity mouse models of MDA-MB-468, COLO205 DMS-53, significantly higher compared DS-1062. In negative SHP77 model, did suppress growth, indicating dependence on expression. study treatment MDA-MB-468 model substantially increased ratios exposure (AUC) DB-1305-total DB-1305-ADC serum, suggesting effectively released tumor. pharmacokinetics parameters (total antibody, ADC, payload) obtained from monkeys. profile assessed rats addition levels had no obvious gender difference apparent accumulation systemic AUC0-last Cmax ADC similar values those total both approximately dose proportionally 1 mg/kg 10 mg/kg. Particularly, monkeys, peak concentration group reduced 1/171 0.14 (equivalent molar mass DB-1305), while t1/2 prolonged 0.651 h 194 h. tolerated Cynomolgus highest non-severely toxic (HNSTD) 80 mg/kg, which HNSTD 30 for Conclusions: Taken together, this has potentially better safety DS-1062, supporting further clinical development great potential cancers. No conflict interest.