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

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

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

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Figure 3

Antitumor activity of BL-B01D1 in human prostate cancer cell line models in vitro.

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Antitumor activity of BL-B01D1 in human prostate cancer cell line models...
(A) Immunoblot of EGFR, HER3, and AR in prostate cancer cell lines. (B) Flow cytometry of EGFR/HER3 expression in prostate cancer cell lines. Max, maximum. (C) Immunoblot of downstream signaling pathways and AR in C4-2 cells treated with PBS, BL-B01D1, SI-B001, or isotype IgG ADC ± EGF or NRG-1. (D) Cell viability assays comparing BL-B01D1, SI-B001, and isotype IgG ADC (n = 3). (E) Colony formation assays after BL-B01D1 treatment with quantification (n = 3). Ref, reference. (F) Cell viability and Western blots in PC-3 cells overexpressing EGFR, HER3, or both, after BL-B01D1 treatment (n = 3). EV, empty vector. (G and H) Cell viability assays after BL-B01D1 treatment in DU145 cells with EGFR knockdown (G) and 22Rv1 cells with HER3 knockdown (H) (n = 3), with corresponding Western blots. Data are presented as mean ± SD (D–H). Statistical significance was determined by 1-way ANOVA with Dunnett’s multiple comparisons (E).