DB-1326, a novel dual-payload TA-MUC1-directed antibody-drug conjugate, shows potent antitumor efficacy in pre-clinical tumor model

Introduction: Tumor-associated mucin-1 (TA-MUC1) is a glycoform of the MUC1 protein that is aberrantly glycosylated and is highly specific expressed by cancer cells. TA-MUC1 is highly expressed in various human epithelial cancers, making it an attractive target for cancer therapies. Several antibody-drug conjugates (ADCs) targeting TA-MUC1 are in development in clinical and preclinical stage, such as DS-3939a, CAT-09-833. However, their application remains limited by inadequate efficacy, highlighting the unmet clinical need for improving the efficacy of single payload ADCs. This study presents the preclinical evaluation of a novel dual-payload TA-MUC1-targeting ADC, DB-1326, composed of a fully human IgG1 antibody specific recognize TA-MUC1 which is conjugated to a topoisomerase I inhibitor and a novel ecteinascidin derivative. The dual mechanism of DB-1326 results in potent anti-tumor effect across different tumor types with a range of MUC1 expression levels. Methods: Binding activity of DB-1326 to TA-MUC1 was evaluated by ELISA. The tumor selectivity between tumor cell and normal cell was evaluated via FACS analysis. The internalization of DB-1326 to tumor cell was tested by Incucyte. CTG assay was used to evaluate the cancer cell killing of DB-1326 on multiple target positive cell lines. Both cell line-derived xenograft (CDX) models and patient-derived xenograft (PDX) models were established to evaluate the in vivo efficacy of DB-1326 monotherapy. Results: The naked antibody of DB-1326 showed strong binding ability to TA-MUC1 but not MUC1 peptide without glycosylation and significant higher tumor selectivity than traditional MUC1 antibody. Internalization assays demonstrated that unconjugated DB-1326 was endocytosed in tumor cells expressing TA-MUC1. DB-1326 exhibited strong cytotoxicity in vitro against several tumor cell lines. DB-1326 exhibited dose-dependent tumor growth inhibition and demonstrated superior anti-tumor activity compared to the single payload ADC in both CDX and PDX models across a range of target expression. Conclusions: DB-1326 is a novel dual-payload ADC with a TA-MUC1 antibody. It displayed high tumor cell selectivity and superior anti-tumor effects in preclinical studies. These findings support the potential of DB-1326 as a promising advanced therapeutic candidate for tumors.