DB-1303, a HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising safety profile and anti-tumor efficacy with differentiation from DS-8201a

Background: DB-1303 is a novel antibody-drug conjugate comprised of trastuzumab biosimilar, enzymatically cleavable peptide-linker, and a proprietary topoisomerase I inhibitor P1003. It is designed to have high plasma stability, low free payload in circulation and wide therapeutic index. Herein, we describe the preclinical profile of DB-1303, including efficacy, pharmacokinetics, and safety. Material and Methods: In vitro cell growth inhibition and in vivo antitumor activities of DB-1303 were evaluated in several Her2-low tumor cell lines and xenograft models. Tumor-bearing mice were used to assess pharmacokinetic and pharmacodynamic characteristic of DB-1303. The mechanism of action for the efficacy was also evaluated. Plasma stability of DB-1303 was determined with rat, monkey, and human plasma. Pharmacokinetic and safety profiles of DB-1303 were evaluated in cynomolgus monkeys. Results: In vitro, DB-1303 selectively binds to and is endocytosed into the lysosome of HER2-positive cells. DB-1303 causes G2/M cell cycle arrest, induces DNA damage, and inhibits cell proliferation in HER2-expressing cells. Importantly, DB-1303 showed inhibitory activity to Her2 low-expressing CAPAN-1 (pancreatic cancer) and Ishikawa (endometrial cancer) cell lines. Under a coculture condition of HER2-positive KPL-4 cells and HER2-negative MDA-MB-468 cells in vitro, DB-1314 inhibited the proliferation of both cells, demonstrating its bystander effect. In vivo, DB-1303 induced dose-dependent tumor growth inhibition and tumor regression in T-DM1-resistant JIMT-1 xenograft model, HER2 low-expressing Ishikawa xenograft and two HER2-low breast cancer PDX models. A single dosing of DB-1303 in NCI-N87 tumor-bearing mice induced significant DNA damage in tumors, and the Cmax of payload in tumor tissues was about 45-fold higher than that in peripheral blood. Pharmacokinetics and safety profiles of DB-1303 were favorable and the highest non-severely toxic dose was 80 mg/kg in cynomolgus monkey study with Q3W dosing of 3 repeated doses. It’s worth noting that, unlike DS-8201a, no interstitial pneumonia was observed in monkeys during the dosing period and recovery period. The payload P1003 poses very low risk of drug-drug interaction. Following administration of DB-1303, systemic P1003 exposure was low and P1003 was cleared rapidly. Conclusions: DB-1303 exhibited potent antitumor activity in both HER2 positive and HER2 low tumor models with a wide therapeutic window. The stable linker in circulation and fast clearance of P1003 may contribute to the superior safety profile of DB-1303. These studies suggest the potential of DB-1303 to address unmet medical needs in HER2 expressing cancers, especially in HER2 low cancers. At the time of presentation, a first-in-human phase 1/2 study in patients with advanced solid tumors is in progress (NCT05150691). No conflict of interest.