肿瘤细胞治疗研究
英文原题：Proteomic Profiling Identifies CLDN3 as a Tumor-Selective Therapeutic Target in Small Cell Lung Cancer.
这些发现支持CLDN3靶向疗法的临床开发，并证明了整合蛋白质基因组学方法在实体瘤抗原发现中的实用性。
小细胞肺癌（SCLC）仍是一种高度致命的疾病，除delta样配体3（DLL3）外，可靶向的表面抗原十分有限。我们试图系统性地识别并验证复发SCLC中的肿瘤选择性细胞表面靶点。为此，我们开发了一套整合蛋白质基因组学流程，结合单细胞RNA测序、组合优化、基于质谱的蛋白质组学和免疫组织化学，系统性地绘制了25例复发SCLC患者共49个肿瘤的SCLC表面蛋白质组图谱。通过该方法，我们发现claudin-3（CLDN3）是一种持续表达且具有肿瘤选择性的抗原，其覆盖范围比当前临床基准DLL3更广。CLDN3在各种治疗状态下均高表达，同时在大多数非恶性组织中保持低表达。使用一种新型CLDN3特异性单克隆抗体（ABN501）进行的功能验证表明，其在体外可介导NK细胞杀伤作用，在体内可诱导肿瘤消退，并具有良好的安全性特征。这些发现支持CLDN3靶向疗法的临床开发，并证明了整合蛋白质基因组学方法在实体瘤抗原发现中的实用性。
Small cell lung cancer (SCLC) remains a highly lethal disease with limited targetable surface antigens beyond delta-like ligand 3 (DLL3). We sought to systematically identify and validate tumor-selective cell-surface targets in relapsed SCLC. To this end, we developed an integrated proteogenomic pipeline combining single-cell RNA sequencing, combinatorial optimization, mass spectrometry-based proteomics, and immunohistochemistry to systematically map the SCLC surfaceome of 49 tumors across 25 patients with relapsed SCLC. Using this approach we found claudin-3 ( CLDN3 ) to be a consistently expressed and tumor-selective antigen, with broader coverage than DLL3, which is the current clinical benchmark. CLDN3 was highly expressed across various treatment states, while maintaining low expression in most nonmalignant tissues. Functional validation using a novel CLDN3-specific monoclonal antibody (ABN501) demonstrated NK cell-mediated cytotoxicity in vitro and tumor regression in vivo , as well as a favorable safety profile. These findings support clinical development of CLDN3-directed therapies and demonstrate the utility of integrated proteogenomic approaches for antigen discovery in solid tumors.
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