EGFR- and HER3-targeted bispecific antibody-drug conjugate demonstrates antitumor activity in metastatic castration-resistant prostate cancer

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Abstract

Metastatic castration-resistant prostate cancer (mCRPC) remains lethal with limited treatment options. Antibody–drug conjugates (ADCs) have emerged as a transformative class across multiple solid tumors, yet their clinical application in prostate cancer has been limited. Izalontamab brengitecan (Iza-bren; BL-B01D1) is a bispecific ADC-targeting EGFR and HER3 that has demonstrated activity in other malignancies. Here, we evaluated its therapeutic potential in the treatment of prostate cancer. Multi-omics analyses revealed frequent EGFR and HER3 expression in CRPC adenocarcinoma but not in neuroendocrine subtypes. BL-B01D1 exerted potent, target-dependent cytotoxicity in prostate cancer cell lines, xenografts, and patient-derived organoids (PDOs). We highlight a representative patient with mCRPC with high EGFR/HER3 expression whose disease rapidly and durably mounted a clinical and radiologic response to BL-B01D1, concordant with matched PDO sensitivity. Mechanistic studies identified ABCG2 upregulation as a driver of acquired resistance, with genetic or pharmacologic inhibition restoring BL-B01D1 sensitivity. Importantly, tumor tissue obtained at progression after BL-B01D1 treatment confirmed ABCG2 upregulation, validating a clinically relevant resistance mechanism. These findings support BL-B01D1 as a promising therapeutic strategy in mCRPC and indicate ABCG2 may be a rational target for overcoming resistance.

Authors

Bangwei Fang, Xiaomeng Li, Ying Lu, Weiwei Ma, Hualei Gan, Tingwei Zhang, Qi Liu, Beihe Wang, Zixian Wang, Yi Zhu, Hai Zhu, Sa Xiao, Xiaojie Bian, Gonghong Wei, Dingwei Ye, Yao Zhu