hIMB1636-LDM, a novel anti-TROP2 ADC, exerts potent antitumor efficacy in pancreatic cancer via direct cytotoxicity and immune activation.
TL;DR
HIMB1636-LDM exerts potent antitumor activity through a dual mechanism combining targeted cytotoxicity and ICD induction, and was for the first time found to possess the ability to trigger immunogenic cell death (ICD).
Abstract
Pancreatic cancer remains a lethal malignancy with limited treatment options. Trophoblast cell surface antigen 2 (TROP2), which is frequently overexpressed in pancreatic tumors and closely associated with poor prognosis, represents a promising therapeutic target. hIMB1636-LDM is a novel antibody-drug conjugate (ADC) developed by our laboratory, comprising the anti-TROP2 antibody hIMB1636 covalently linked to cytotoxic payload lidamycin (LDM) via an uncleavable linker. In this study, we systematically evaluated the antitumor efficacy and underlying mechanism of action of hIMB1636-LDM in pancreatic cancer. The results showed that hIMB1636-LDM exhibited TROP2-dependent binding and internalization, as well as potent cytotoxicity (Half maximal inhibitory concentration (IC50): 0.27-0.5 nM) against pancreatic cancer cells. Mechanistically, beyond inducing cell cycle arrest and apoptosis, it was for the first time found to possess the ability to trigger immunogenic cell death (ICD). In vivo, hIMB1636-LDM at a dose of 0.8 mg/kg significantly suppressed tumor growth in both T3M4 and BxPC3 models, with no obvious toxic reactions observed. hIMB1636-LDM exerts potent antitumor activity through a dual mechanism combining targeted cytotoxicity and ICD induction. Its favorable safety profile, potent efficacy, and unprecedented ICD-inducing property highlight its potential as a promising therapeutic candidate for TROP2-positive pancreatic cancer.