Antibody-drug conjugates (ADCs) have reshaped targeted cancer therapy by selectively delivering cytotoxic agents to malignant cells. Nevertheless, the clinical landscape of Trop2-directed ADCs is dominated by topoisomerase I inhibitors, a limited payload class associated with cumulative toxicity and emerging resistance. Degrader-antibody conjugates (DACs) combine antigen-specific targeting with targeted protein degradation, thereby expanding mechanistic diversity beyond conventional cytotoxic payloads. Here, we report the development and preclinical evaluation of DAC-1522, a Trop2-targeting DAC designed to address therapeutic resistance and broaden treatment options for Trop2-positive tumors.

A panel of bromodomain and extra-terminal (BET) degraders was screened in MDA-MB-231 and BT-474 cells using cell viability assays, followed by confirmation of target degradation by Western blot analysis. Lead molecules were engineered into linker-compatible intermediates and conjugated to an anti-Trop2 monoclonal antibody. Drug-to-antibody ratio (DAR) and aggregation were assessed by reversed-phase liquid chromatography and size-exclusion chromatography. Antigen dependency and antiproliferative activity were assessed across various cancer cell lines. Activity in a trastuzumab deruxtecan (Enhertu)-resistant NCI-N87 model was examined. In vivo efficacy following intravenous administration was evaluated in BXPC-3, HCC-827 and MDA-MB-231 xenografts.

In screening models, selected novel BET degraders induced specific and marked target protein degradation, accompanied by proliferation inhibition. The resulting conjugates achieved predefined DAR specifications with minimal aggregation, supporting favorable developability. DAC-1522 demonstrated potent Trop2-dependent antiproliferative effects across multiple tumor types. In vivo, a single dose of DAC-1522 induced complete tumor regression without body weight loss in the BXPC-3 xenograft model, with consistent antitumor activity confirmed in additional models. Notably, DAC-1522 retained activity in an Enhertu-resistant NCI-N87 model, whereas SKB264 showed markedly reduced efficacy, suggesting its potential to overcome resistance associated with conventional ADCs utilizing topoisomerase I inhibitor payloads. Furthermore, DAC-1522 significantly reduced hematological toxicity compared to its unconjugated payload, indicating a promising safety profile.

By integrating antigen targeting with selective protein degradation, DAC-1522 demonstrates superior antitumor efficacy and a differentiated therapeutic profile compared to currently approved Trop2-directed ADCs, highlighting its significant potential for further development.