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 1

Genomic alterations and mRNA expression pattern of EGFR and ERBB3 in prostate cancer.

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Genomic alterations and mRNA expression pattern of EGFR and ERBB3 in pro...
(A) Frequency of genomic gain and amplification of ErbB family genes (EGFR, ERBB2, ERBB3, ERBB4) across 4 prostate cancer cohorts, including localized prostate cancer (TCGA and CPGEA) and mCRPC (SU2C and FHCRC). CNV, copy number variation. (B) Relative mRNA expression ranking of EGFR family members in 4 prostate cancer cohorts. (C) Proportion of tumor samples with high or low EGFR and ERBB3 expression in TCGA and CPGEA datasets. Com, combined. (D) Uniform manifold approximation and projection (UMAP) visualization of cell-type clusters from a published scRNA-Seq dataset of 13 patients with prostate cancer. Data were obtained from the GEO dataset GSE141445 (ref. 34) and re-analyzed in this study. (E) Dot plot showing the RNA expression levels of representative marker genes and ErbB family genes in annotated cell clusters. Avg. Expr., average expression. % Expr., percentage of expression. (F) Feature plots displaying the spatial distribution and relative expression levels of EGFR and ERBB3 across all the cell clusters. (G) Proportional distribution of luminal tumor cells classified by EGFR and ERBB3 expression levels.