PO.ET02.14 · 实验与分子治疗
SCR-M030：一种创新的、潜在首创的靶向PSMA和STEAP1的三特异性T细胞衔接器用于mCRPC
SCR-M030, an innovative and potential first-in-class trispecific T cell engager targeting PSMA and STEAP1 for mCRPC
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
转移性去势抵抗性前列腺癌（mCRPC）是一种高度侵袭性且无法治愈的疾病，治疗选择有限，预后不良。在最有前景的分子靶点中，前列腺特异性膜抗原（PSMA）和前列腺六次跨膜上皮抗原1（STEAP1）在mCRPC中均显著过表达，且其表达水平与肿瘤侵袭性和对雄激素剥夺治疗的耐药性呈正相关。值得注意的是，PSMA表现出显著的肿瘤间和肿瘤内异质性，这一因素可能是PSMA导向药物观察到的异质性临床反应的基础。相比之下，STEAP1在恶性细胞中表现出更均匀的分布，其表达模式在一部分患者中部分补充了PSMA。利用STEAP1和PSMA的互补表达，我们生成了一种首创的三特异性T细胞衔接器（TCE）SCR-M030，它同时以高亲和力结合STEAP1、以中等亲和力结合PSMA、并以刻意减弱的亲和力结合CD3。这种亲合力优化的结构驱动其优先对接双阳性肿瘤细胞，相较于单靶点结合具有显著的结合优势。在功能上，SCR-M030在体外优于PSMA-CD3和STEAP1-CD3双特异性对照，对中低抗原表达肿瘤细胞引发更优的裂解，同时在靶点阴性条件下释放极少细胞因子，预示CRS风险降低。在PBMC重建的前列腺癌异种移植小鼠模型中，SCR-M030表现出特异性、剂量依赖性的抗肿瘤活性。值得注意的是，在22RV1模型中，SCR-M030表现出比AMG509类似物更强效的肿瘤抑制。最后，大鼠药代动力学分析揭示了较长的血浆半衰期以及与静脉和皮下给药途径的完全兼容性，支持灵活的临床给药。总之，新型三特异性TCE SCR-M030是一种经战略性设计的疗法，通过以差异化亲和力同时靶向PSMA和STEAP1，对具有挑战性的低表达肿瘤表现出强效疗效。其稳健的体内表现、良好的药代动力学以及优于相关对照品的表现，凸显了其作为下一代前列腺癌疗法的强大潜力。
查看英文原文 English abstract
Metastatic castration-resistant prostate cancer (mCRPC) represents a highly aggressive and incurable disease, with limited therapeutic options and a dismal prognosis. Among the most promising molecular targets, prostate-specific membrane antigen (PSMA) and six-transmembrane epithelial antigen of the prostate 1 (STEAP1) are both markedly overexpressed in mCRPC, and their expression levels correlate positively with tumor aggressiveness and resistance to androgen-deprivation therapy. Notably, PSMA exhibits significant inter- and intratumoral heterogeneity, a factor that may underlie the heterogeneous clinical responses observed with PSMA-directed agents. In contrast, STEAP1 demonstrates a more uniform distribution across malignant cells, and its expression pattern partially complements that of PSMA in a subset of patients. Leveraging the complementary expression of STEAP1 and PSMA, we generated a first-in-class trispecific T-cell engager (TCE), SCR-M030, that concomitantly binds STEAP1 with high affinity, PSMA with moderate affinity, and CD3 with deliberately attenuated affinity. This avidity-optimized architecture drives preferential docking to double-positive tumor cells, conferring a marked binding advantage over single-target engagement. Functionally, SCR-M030 outperformed PSMA-CD3 and STEAP1-CD3 bispecific controls in vitro, eliciting superior lysis of medium-to-low antigen-expressing tumor cells while releasing minimal cytokines in target-negative conditions, forecasting a reduced risk of CRS. In PBMC-reconstituted prostate cancer xenograft mouse models, SCR-M030 demonstrated specific, dose-dependent antitumor activity. Notably, in the 22RV1 model, SCR-M030 exhibited more potent tumor suppression than the AMG509 analog. Finally, rat pharmacokinetic profiling revealed a long plasma half-life and full compatibility with both intravenous and subcutaneous dosing routes, supporting flexible clinical administration. In conclusion, the novel trispecific TCE SCR-M030 is a strategically designed therapy that demonstrates potent efficacy against challenging low-expression tumors by simultaneously targeting PSMA and STEAP1 with differential affinity. Its robust in vivo performance, favorable pharmacokinetics, and superiority over a relevant comparator underscore its strong potential as a next-generation therapeutic for prostate cancer.
利益披露 Disclosure
C. Chen, None..
Y. Fu, None..
S. You, None..
M. Gao, None..
K. Wang, None..
Y. kuang, None..
C. Lu, None..
R. Tang, None.