Abstract Introduction: Epidermal growth factor receptor (EGFR) is a well-known and validated target for anti-tumor therapies. However, anti-EGFR therapy in clinical showed obvious safety concerns because of broad EGFR expression in normal tissue, and such adverse effects limit the efficacy of these products. Mucin 1 (MUC1) is highly co-expressed with EGFR in multiple tumor types including esophageal squamous cell carcinoma (ESCC), non-small cell lung cancer (NSCLC), breast cancer (BC), colorectal cancer (CRC) and others. Dual targeting of both EGFR and MUC1 is a promising therapeutic strategy to enhance tumor-selective targeting and avoid undesired toxicity observed with anti-EGFR therapeutics. DB-1421 is a bispecific ADC comprised of a fully human EGFR/MUC1 bispecific antibody conjugated to a novel DNA topoisomerase I inhibitor via a cleavable linker. The naked antibody of DB-1421 is constructed by an affinity reduced EGFR binding arm and a tumor-associated MUC1 (TA-MUC1) specific binding arm. Based to this optimized format, DB-1421 showed both high tumor cell selectivity and high tolerable in preclinical models. Methods: The tumor selectivity of DB-1421 between tumor cell and normal cell was evaluated via FACS analysis. The internalization of DB-1421 to tumor cell was tested by Incucyte. CTG assay was used to evaluate the cancer cell killing of DB-1421 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-1421 monotherapy. The safety and PK of DB-1421 were evaluated by in vivo monkey studies. Results: The naked antibody of DB-1421 showed significant higher tumor selectivity than EGFR antibody. Internalization assays demonstrated that unconjugated DB-1421 was endocytosed in tumor cells co-expressing EGFR and TA-MUC1. DB-1421 exhibited strong cytotoxicity in vitro against several tumor cell lines across a range of target expression. DB-1421 inhibited tumor growth in vivo in CDX and PDX models by dose dependent manner. Additionally, it was well tolerated with repeat dose administration up to 80 mg/kg in monkeys. Conclusions: DB-1421 is an EGFR/MUC1 bispecific ADC with a common light chain bispecific antibody and a DNA topoisomerase I inhibitor. Through rational design and engineer of EGFR and MUC1 binding arm, DB-1421 showed improved tumor selectivity, efficacy and very good safety. The promising efficacy and safety profile warrants further clinical development of DB-1421. Citation Format: Chenggang Li, Jun Yao, Yongsheng Nie, Yang Qiu, Haiqing Hua. DB-1421, an optimized EGFR/MUC1 bispecific ADC, exhibits improved tumor selectivity, promising efficacy and safety in preclinical studies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2654.
Li et al. (Fri,) studied this question.