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 2

Distinct expression patterns of EGFR and HER3 across CRPC subtypes and their association with AR signaling.

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Distinct expression patterns of EGFR and HER3 across CRPC subtypes and t...
(A) Schematic overview of specimen sources from 70 patients with CRPC, stratified by CRPC-Ad (n = 54) and CRPC-NE (n = 16). (B) Representative IHC staining of AR, EGFR, HER3, and synaptophysin (SYN) in CRPC-Ad (n = 54) and CRPC-NE (n = 16) tumors. Scale bar, 100 μm. (C) Quantification of EGFR and HER3 protein levels (H-scores) in CRPC-Ad (n = 54) and CRPC-NE (n = 16) subgroups. (D) Distribution of EGFR and HER3 co-expression patterns among CRPC-Ad cases. (E) Comparison of EGFR and ERBB3 mRNA expression between CRPC-Ad and CRPC-NE tumors in the SU2C cohort. (F) Pearson correlations analysis between AR and EGFR (left panel) or ERBB3 (right panel) mRNA expression in the TCGA-PRAD dataset. (G) ChIP-Seq tracks showing AR binding peaks and active histone marks (H3K27ac and H3K4me2) at the EGFR (upper panel) and ERBB3 (lower panels) loci. (H) Uniform manifold approximation and projection (UMAP) plot of luminal and neuroendocrine cell clusters in an NEPC mouse model scRNA-Seq dataset. (I) Feature plots showing mutually exclusive expression of AR markers (Ar, Hoxb13), NE markers (Chga, Ascl1), and Egfr/Erbb3 in scRNA-Seq data of the NEPC mouse model. The box plot represents the IQR divided by the median (C and E). Statistical significance was determined by Mann-Whitney U test (C and E) or Pearson correlation test (F).