Abstract
Purpose:
We developed a bifunctional B7-H3 × PD-L1-targeting bispecific antibody-drug conjugate (named DB-1419) conjugated with a novel topoisomerase I inhibitor, P1003 (drug-to-antibody ratio, 8), and assessed its preclinical profiles.
Experimental design:
The pharmacologic activities of DB-1419 were assessed in multiple cancer cell lines and immunodeficient and immunocompetent cell line-/patient-derived xenograft (PDX) models. The mechanisms of action behind the efficacy, pharmacokinetics in cynomolgus monkeys, and the safety profiles in vitro and in cynomolgus monkeys were also explored.
Results:
With high stability in circulation, DB-1419 displayed efficient cellular internalization and trafficked to the lysosome within 48 hours to release the payload P1003. In vitro, we observed inhibitory effects on the proliferation of lung cancer cell lines and beyond, mechanically by P1003-mediated direct cytotoxicity, antibody-mediated antibody-dependent cellular cytotoxicity, and bystander effects. Excellent tumor growth inhibition of DB-1419 was revealed in liver cancer cell line-derived xenografts and lung cancer PDX, along with the verification of DNA damage and apoptosis induced by P1003 using tumor tissues. Furthermore, DB-1419 has driven a robust antitumor response in immunocompetent PDX; the blockade of the interaction between PD-1 and PD-L1 and significant induction of markers of immunogenic cell death were also found, suggesting the activation of tumor-specific immunity. DB-1419 was well tolerated in cynomolgus monkeys (highest nonseverely toxic dose, 120 mg/kg) and did not elicit the production of inflammatory cytokines in vitro.
Conclusions:
DB-1419 demonstrated potent antitumor activity against multiple tumors, with favorable pharmacokinetic and safety profiles. These preclinical data potentially position DB-1419 as a promising treatment approach, currently in the ongoing phase I/IIa study in advanced tumors (NCT06554795).