Dual Targeting of EGFR and HER2 by a Bispecific Antibody-Drug Conjugate Demonstrates Broad Antitumor Activity in Multiple Solid Tumors.
While HER2-directed antibody-drug conjugates (ADCs), such as ENHERTU® (DS-8201), represent a major therapeutic advance, treatment options for tumors with low HER2 expression remain limited, and acquired resistance continues to pose a significant clinical challenge. Given the frequent co-expression of EGFR and HER2 across multiple tumor types, we hypothesized that dual targeting could improve therapeutic efficacy and overcome resistance mechanisms. This approach may achieve broader tumor coverage, synergistic enhancement of binding and internalization, and concurrent blockade of two key oncogenic pathways. To test this, we developed GenSci139, an EGFR×HER2 bispecific ADC (BsADC). It is conjugated via a novel, proprietary hydrophilic peptide-cleavable linker to a potent topoisomerase I inhibitor payload. In preclinical studies, GenSci139 exhibited remarkable plasma stability and favorable pharmacokinetics, enabling efficient tumor-specific payload delivery. Compared to monospecific ADCs, it demonstrated superior binding affinity and enhanced internalization across a panel of cancer cell lines with diverse EGFR/HER2 expression profiles. In vitro, GenSci139 mediated potent cytotoxic activity and induced a robust bystander-killing effect. Furthermore, its parental bispecific antibody effectively inhibited both EGF-induced signaling and cell proliferation. In vivo, GenSci139 demonstrated superior antitumor efficacy over DS-8201 in multiple cell-line-derived xenograft and patient-derived xenograft models. Mechanistic studies revealed that GenSci139 induced DNA damage, apoptosis, and hallmarks of immunogenic cell death, suggesting potential for synergistic combination with immunotherapies. Collectively, our preclinical data position GenSci139 as a promising novel therapeutic candidate with the potential to address the unmet medical need in a broad spectrum of solid tumors, including those of the lung, breast and stomach.