DAC-1522: A novel Trop2-targeting degrader-antibody conjugate for precision oncology

Background 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 diversity of cytotoxic payloads. Notably, all FDA-approved Trop2-targeting ADCs employ topoisomerase I inhibitors as payloads, which may lead to both intrinsic and acquired drug resistance. Degrader-antibody conjugates (DACs) have emerged as a next-generation modality that integrates the selective targeting of ADCs with the mechanistic versatility of protein degraders, thereby offering a means to overcome these limitations. In this study, we sought to develop a TROP2-directed DAC capable of addressing the constraints of conventional ADCs and enhancing therapeutic outcomes. Methods A library of BET degraders was screened in MDA-MB-231 and BT-474 cells using CCK8 assays, and their degradation efficacy was subsequently confirmed by Western blot analysis. The selected payload candidates were converted into linker-drug precursors and conjugated to antibodies to generate the corresponding DACs. The drug-to-antibody ratio (DAR) and aggregation profiles were characterized using reversed-phase liquid chromatography (RPLC) and size-exclusion chromatography (SEC), respectively. In vitro cytotoxicity and selectivity were evaluated across multiple cancer cell lines, including MDA-MB-231, JIMT-1, BXPC-3, and KP-4. Furthermore, the DACs were evaluated in an Enhertu-resistant NCI-N87 model. In vivo anticancer efficacy was investigated in JIMT-1, MIA PaCA-2, and BXPC-3 cell-derived xenograft (CDX) models. Results Several BET degraders demonstrated potent cytotoxic and degradation activities. The corresponding DACs achieved the designated DAR without detectable aggregation. In vitro , DAC-1522 exhibited potent and Trop-2 dependent antiproliferative effects across multiple human cancer cell lines. Notably, DAC-1522 maintained robust activity in an Enhertu-acquired drug resistance model, whereas Enhertu and SKB264 showed markedly compromised efficacy, highlighting its potential to overcome resistance associated with conventional ADC therapies. In vivo , a single intravenous dose of DAC-1522 induced complete tumor regression in the BXPC-3 xenograft model without body weight loss. Conclusion DAC-1522 represents a novel Trop2-targeting DAC that demonstrates superior in vivo antitumor efficacy and the ability to overcome drug resistance, underscoring its promise as a therapeutic candidate for TROP2-positive malignancies.