B7-H3 as a Therapeutic Target in Advanced Prostate Cancer

作者：Christina W. Guo, Inês Ferreira Figueiredo, Bora Gürel, Antje Neeb, George Seed, Mateus Crespo, Suzanne Carreira, Jan Rekowski, Lorenzo Buroni, Jon C. Welti, Denisa Bogdan, Lewis Gallagher, Adam Sharp, Maria D. Fenor de la Maza, Pasquale Rescigno, Daniel Westaby, Khobe Chandran, Ruth Riisnaes, Ana Ferreira, Susana Miranda, Bianca Calì, Andrea Alimonti, Silvia Bressan, Alana H.T. Nguyen, Michael M. Shen, Jessica E. Hawley, Aleksandar Obradović, Charles G. Drake, Claudia Maria Bertan, Chloe Baker, Nina Tunariu, Wei Yuan, Johann Sebastian De Bono · 发表于：European Urology · 年份：2022 · DOI：10.1016/j.eururo.2022.09.004 · 被引用次数：99 · 研究领域：Cancer Immunotherapy and Biomarkers、Prostate Cancer Treatment and Research、Immunotherapy and Immune Responses

BACKGROUND: B7-H3 is a cell surface immunomodulatory glycoprotein overexpressed in prostate cancers (PCs). Understanding its longitudinal expression at emergence of castration resistance and association with tumour genomics are critical to the development of and patient selection for B7-H3 targeted therapies. OBJECTIVE: To characterise B7-H3 expression in same-patient hormone-sensitive (HSPC) and castration-resistant (CRPC) PC biopsies, associating this with PC genomics, and to evaluate the antitumour activity of an anti-B7-H3 antibody-drug conjugate (ADC) in human CRPC in vitro and in vivo. DESIGN, SETTING, AND PARTICIPANTS: We performed immunohistochemistry and next-generation sequencing on a cohort of 98 clinically annotated CRPC biopsies, including 72 patients who also had HSPC biopsies for analyses. We analysed two CRPC transcriptome and exome datasets, and PC scRNASeq datasets. PC organoids (patient-derived xenograft [PDX]-derived organoids [PDX-Os]) were derived from PDXs generated from human CRPC biopsies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We evaluated B7-H3 mRNA expression in relation to a panel of 770 immune-related genes, compared B7-H3 protein expression between same-patient HSPC and CRPC biopsies, determined associations with PC genomic alterations, and evaluated the antitumour activity of DS-7300a, a topoisomerase-1 inhibitor payload anti-B7-H3 ADC, in human PC cell lines, organoids (PDX-Os), and xenografts (PDXs) of different histologies, B7-H3 exp...