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 4

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

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Antitumor activity of BL-B01D1 in human prostate cancer cell line models...
(A) Xenograft study schematic. (B) Representative tumor images in C4-2 and LNCaP xenografts (n = 8/group for C4-2 xenograft; n = 9/group for LNCaP xenograft here and for remaining panels). (C and D) Tumor growth curves (C) and final tumor weights (D) in mice treated with BL-B01D1 or isotype IgG ADC. (E) Representative H&E and IHC staining of EGFR, HER3, and Ki-67 in C4-2 and LNCaP xenografts. Scale bar, 50 μm. (F) Quantification of Ki-67–positive tumor cells in C4-2 and LNCaP xenografts. Data are reported as mean ± SEM (C and D). The box plot represents the IQR divided by the median (F). Statistical significance was determined by 2-tailed unpaired t test (C, D, and F).