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