HLX91-048

HLX91-048 is a novel, first-in-class small molecule antibody-drug conjugate (ADC) payload developed by Shanghai Henlius Biotech. Chemically featuring a 3-(4-hydroxyphenyl) indoline-2 scaffold, HLX91-048 is designed to overcome ADC resistance and synergize with existing therapies. It exerts its potent antitumor activity through a highly differentiated mechanism of action involving the sustained activation of the unfolded protein response (UPR), leading to cell death. Preclinically, HLX91-048 has demonstrated sub-nanomolar to nanomolar cytotoxicity across various tumor cell types, showing a greater than 10-fold increase in potency compared to the UPR activator ErSO. When conjugated to a HER2-targeting antibody via a cleavable GGFG linker (forming the ADC HLX-91), it has shown robust, dose-dependent antitumor efficacy and bystander killing in breast and gastric cancer models, including those resistant to trastuzumab deruxtecan (DS-8201).