PO.TB04.02 · 肿瘤生物学
靶向STEAP1的双特异性T细胞衔接器临床前评估的一站式解决方案
One-stop solution for preclinical evaluation of bispecific T-cell engagers targeting STEAP1
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
STEAP1（前列腺六次跨膜上皮抗原1）是一种在前列腺癌和其他上皮性癌症中高表达的膜蛋白，使其成为基于免疫的治疗药物极具吸引力的靶点。为支持STEAP1定向药物的开发，集萃药康（GemPharmatech）建立了一个全面的体外-体内评估平台，旨在表征STEAP1表达、功能相关性以及T细胞衔接器（TCE）介导的药理学。AMG509（Xaluritamig），一种目前处于临床开发中的III期STEAP1×CD3 TCE，被用作基准分子以验证平台性能。方法：开发了体外实验，利用流式细胞术定量前列腺癌细胞系（如LNCaP、22Rv1）中的内源性STEAP1表达，随后利用基于荧光素酶和基于流式的读数评估T细胞依赖性细胞毒性（TDCC）。分析T细胞活化标志物（CD69、CD25）和细胞偶联频率，以表征T细胞招募至STEAP1阳性肿瘤细胞的效率。通过流式微球阵列（CBA）进行细胞因子分析（IL-2、IFN-gamma、TNF-alpha、IL-6），以监测T细胞活化和细胞因子释放潜能。此外，集萃药康构建了22Rv1-hSTEAP1和RM-1-hSTEAP1细胞系，以扩展STEAP1平台在人类和小鼠肿瘤背景中的转化适用范围。在体内，采用了一组人源化免疫小鼠模型（PBMC-NCG、NCG-MHC-dKO和HSC-NCG），以在不同的免疫环境下评估STEAP1靶向TCE的药理学。AMG509治疗在STEAP1阳性异种移植物中引起了强效、抗原依赖性的肿瘤抑制，实现了>90%的肿瘤生长抑制，并在多个病例中实现完全消退。肿瘤分析显示人CD3+ T细胞的稳健浸润和局部IFN-gamma表达的增加，与有效的STEAP1定向免疫结合一致。接受治疗的小鼠维持稳定的体重，且未显示细胞因子释放综合征（CRS）或移植物抗宿主病（GVHD）的迹象，证实了这些模型适用于转化安全性评估。总之，这些结果证明了针对STEAP1靶向免疫疗法建立了稳健且模块化的评估工作流程。通过整合抗原定量、免疫功能实验和人源化体内系统，集萃药康的平台能够对新兴的TCE模式进行全面且可重复的评估。这项工作为STEAP1生物学提供了宝贵的临床前见解，并为未来靶向这一临床相关抗原的治疗项目奠定了实验基础。
查看英文原文 English abstract
STEAP1 (Six-Transmembrane Epithelial Antigen of the Prostate 1) is a membrane protein highly expressed in prostate and other epithelial cancers, making it an attractive target for immune-based therapeutics. To support the development of STEAP1-directed agents, GemPharmatech established a comprehensive in vitro-in vivo evaluation platform designed to characterize STEAP1 expression, functional relevance, and T-cell engager (TCE)-mediated pharmacology. AMG509 (Xaluritamig), a Phase III STEAP1×CD3 TCE currently in clinical development, was used as a benchmark molecule to validate platform performance. Methods: In vitro assays were developed to quantify endogenous STEAP1 expression across prostate cancer cell lines (e.g., LNCaP, 22Rv1) using flow cytometry, followed by evaluation of T-cell dependent cytotoxicity (TDCC) with both luciferase-based and flow-based readouts. T-cell activation markers (CD69, CD25) and cell conjugation frequency were analyzed to characterize the efficiency of T-cell recruitment to STEAP1-positive tumor cells. Cytokine profiling (IL-2, IFN-gamma, TNF-alpha, IL-6) was performed via Cytometric Bead Array (CBA) to monitor T-cell activation and cytokine release potential. Additionally, GemPharmatech engineered 22Rv1-hSTEAP1 and RM-1-hSTEAP1 cell lines to expand the translational scope of the STEAP1 platform across human and murine tumor contexts. In vivo, a panel of humanized immune mouse models (PBMC-NCG, NCG-MHC-dKO, and HSC-NCG) were employed to evaluate STEAP1-targeted TCE pharmacology under distinct immune settings. AMG509 treatment led to potent, antigen-dependent tumor suppression in STEAP1-positive xenografts, achieving >90% tumor growth inhibition and, in several cases, complete regression. Tumor analyses revealed robust infiltration of human CD3+ T-cells and increased local IFN-gamma expression, consistent with effective STEAP1-directed immune engagement. Treated mice maintained stable body weight and displayed no signs of cytokine release syndrome (CRS) or graft-versus-host disease (GVHD), confirming the models' suitability for translational safety assessment. Collectively, these results demonstrate the establishment of a robust and modular evaluation workflow for STEAP1-targeted immunotherapies. By integrating antigen quantification, immune functional assays, and humanized in vivo systems, GemPharmatech's platform enables comprehensive and reproducible assessment of emerging TCE modalities. This work provides valuable preclinical insight into STEAP1 biology and establishes an experimental foundation for future therapeutic programs targeting this clinically relevant antigen.
利益披露 Disclosure
H. Sun, None..
Y. Han, None..
F. Zhu, None..
Y. Zhang, None..
H. Yang, None..
X. Gao, None.