Oncology Research, Amgen Research, Amgen Inc., South San Francisco, California.
Oncology Research, Amgen Research, Amgen Inc., Thousand Oaks, California.
Cancer Discov. 2024 Jan 12;14(1):90-103. doi: 10.1158/2159-8290.CD-23-0984.
The tumor-associated antigen STEAP1 is a potential therapeutic target that is expressed in most prostate tumors and at increased levels in metastatic castration-resistant prostate cancer (mCRPC). We developed a STEAP1-targeted XmAb 2+1 T-cell engager (TCE) molecule, AMG 509 (also designated xaluritamig), that is designed to redirect T cells to kill prostate cancer cells that express STEAP1. AMG 509 mediates potent T cell-dependent cytotoxicity of prostate cancer cell lines in vitro and promotes tumor regression in xenograft and syngeneic mouse models of prostate cancer in vivo. The avidity-driven activity of AMG 509 enables selectivity for tumor cells with high STEAP1 expression compared with normal cells. AMG 509 is the first STEAP1 TCE to advance to clinical testing, and we report a case study of a patient with mCRPC who achieved an objective response on AMG 509 treatment.
Immunotherapy in prostate cancer has met with limited success due to the immunosuppressive microenvironment and lack of tumor-specific targets. AMG 509 provides a targeted immunotherapy approach to engage a patient's T cells to kill STEAP1-expressing tumor cells and represents a new treatment option for mCRPC and potentially more broadly for prostate cancer. See related commentary by Hage Chehade et al., p. 20. See related article by Kelly et al., p. 76. This article is featured in Selected Articles from This Issue, p. 5.
肿瘤相关抗原 STEAP1 是一个潜在的治疗靶点，在大多数前列腺肿瘤中表达，并在转移性去势抵抗性前列腺癌（mCRPC）中表达水平增加。我们开发了一种针对 STEAP1 的 XmAb 2+1 T 细胞衔接器（TCE）分子 AMG 509（也称为 xaluritamig），旨在将 T 细胞重新定向杀死表达 STEAP1 的前列腺癌细胞。AMG 509 在体外介导前列腺癌细胞系的强烈依赖 T 细胞的细胞毒性，并促进体内前列腺癌异种移植和同基因小鼠模型中的肿瘤消退。AMG 509 的亲和力驱动活性使它能够选择性地针对高表达 STEAP1 的肿瘤细胞，而不是正常细胞。AMG 509 是第一个进入临床测试的 STEAP1 TCE，我们报告了一例 mCRPC 患者在 AMG 509 治疗后获得客观缓解的病例研究。
由于免疫抑制微环境和缺乏肿瘤特异性靶点，前列腺癌的免疫疗法取得的成功有限。AMG 509 提供了一种针对免疫疗法的方法，使患者的 T 细胞能够杀死表达 STEAP1 的肿瘤细胞，这代表了 mCRPC 以及潜在地更广泛的前列腺癌的一种新的治疗选择。请参阅 Hage Chehade 等人的相关评论，第 20 页。请参阅 Kelly 等人的相关文章，第 76 页。本文是本期精选文章的特色文章，第 5 页。
