Antibody-drug conjugates (ADCs) have revolutionized cancer therapies by enabling the targeted delivery of cytotoxic payloads to tumor cells. However, their efficacy and safety are constrained by the limited repertoire of payloads. Notably, all FDA-approved Trop2-targeting ADCs currently rely on topoisomerase inhibitors as payloads, which may lead to both intrinsic and acquired drug resistance. Degrader-antibody conjugates (DACs) have emerged as a next-generation approach, combining the precision targeting of ADCs with the diverse options of protein degraders to overcome these challenges. Our study aimed to develop a Trop-2 targeting DAC with the potential to surpass the limitations of traditional ADCs.

We screened a library of BET degraders using MDA-MB-231 and BT-474 cell lines using the CCK8 assay and confirmed their degradation efficacy via Western blot analysis. The selected payload candidates were subsequently converted into linker-drug conjugates and attached to antibodies to generate DACs. The drug-to-antibody ratio (DAR) and aggregation levels were characterized using reversed-phase liquid chromatography (RPLC) and size-exclusion chromatography (SEC). The in vitro potency and selectivity of representative DACs were assessed across a panel of cancer cell lines, including MDA-MB-231, JIMT-1, BXPC-3, KP-4, and NCI-N87. Additionally, their in vivo anticancer efficacy was investigated in JIMT-1, MIA PaCA-2, and BXPC-3 cell-derived xenograft (CDX) models.

Several BET degraders demonstrated significantly enhanced cytotoxicity and degradation efficacy. The corresponding DACs achieved the designated DAR without aggregation. In vitro studies showed that DAC-1522 exhibits potent antiproliferative activity against multiple human cancer cell lines. Its efficacy is strongly correlated with Trop2 expression, ensuring selective cytotoxicity in Trop2-positive cells while sparing Trop2-negative cells, thereby offering a favorable therapeutic window. Notably, DAC-1522 retains uncompromised antiproliferative activity in an ADC-induced acquired drug resistance model, underscoring its potential to overcome resistance following ADC treatments. In vivo, a single intravenous injection of DAC-1522 achieves complete tumor regression in a human pancreatic cancer BXPC-3 xenograft model, significantly outperforming Trodelvy® in efficacy. No obvious safety concerns were observed.

Our findings strongly support the further development of DAC-1522 as a highly promising therapeutic candidate for Trop2-expressing cancers.