Although tyrosine kinase inhibitor therapy and immunotherapy have significantly improved lung cancer management, many patients do not benefit or become resistant to treatment, highlighting the need for novel treatments. We found elevated CD73 expression to be prevalent in non–small cell lung cancer (NSCLC) including those harboring the RAS- or RTK (EGFR, EML4-ALK) oncogenes. CD73 expression is enriched closely with the transcriptome signature of epithelial–mesenchymal transition and the immune-tolerant tumor microenvironment, which are increasingly relevant for disease progression and therapy resistance. We developed two novel series of CD73 antibody, Ab001/Ab002 and humanized version Hu001/Hu002, which demonstrated high CD73 binding affinity, potent enzyme inhibition, and efficiently protected effector T lymphocyte function from adenosine/cancer-imposed toxicity. Hu001/Hu002 inhibited growth of RAS-mutant NSCLC tumors in mice via enhanced antibody-dependent cell-mediated cytotoxicity and multifaceted remodeling of the tumor immune environment, reflecting diminished levels of tumor-associated macrophages, myeloid-derived suppressor cells, and tumor vasculature. A novel MMAE-conjugated CD73-ADC (Hu001–MMAE) elicited potent cytotoxicity against CD73-high expressing tumor cells (IC50<0.1 nmol/L) and suppressed in vivo growth of multiple NSCLC and glioma tumors, including the RAS-mutant models [minimum effective dose <1 mg/kg]. Treatment with CD73–ADC triggered a robust intratumoral accumulation of proinflammatory macrophages and activated dendritic cells (DC), which were not observed with naked CD73 antibody or standard chemotherapy. Studies with human PBMC-derived systems confirmed CD73-ADC as fully functional in protecting effector T cells and stimulating DCs thus providing dual benefits in killing CD73-high tumors and improving cancer immunity response. These results warrant clinical investigation of CD73-targeted antibody and ADC for treating advanced lung cancer.

中文翻译：

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新型CD73靶向抗体和抗体-药物偶联物抑制肺肿瘤生长和促进抗肿瘤免疫效应功能的双重机制

尽管酪氨酸激酶抑制剂疗法和免疫疗法显着改善了肺癌的治疗，但许多患者没有受益或对治疗产生抗药性，这凸显了对新疗法的需求。我们发现 CD73 表达升高在非小细胞肺癌 (NSCLC) 中普遍存在，包括那些携带 RAS- 或 RTK (EGFR, EML4-ALK) 癌基因的肺癌。CD73 表达与上皮-间质转化的转录组特征和免疫耐受的肿瘤微环境密切相关，这与疾病进展和治疗耐药性越来越相关。我们开发了两个新系列的 CD73 抗体，Ab001/Ab002 和人源化版本 Hu001/Hu002，它们表现出高 CD73 结合亲和力，有效的酶抑制，并有效保护效应 T 淋巴细胞功能免受腺苷/癌症引起的毒性。Hu001/Hu002 通过增强抗体依赖性细胞介导的细胞毒性和肿瘤免疫环境的多方面重塑来抑制小鼠 RAS 突变 NSCLC 肿瘤的生长，这反映了肿瘤相关巨噬细胞、髓源性抑制细胞和肿瘤血管系统水平的降低。一种新型 MMAE 偶联 CD73-ADC (Hu001–MMAE) 对高表达 CD73 的肿瘤细胞具有有效的细胞毒性 (IC50<0.1 nmol/L)，并抑制了包括 RAS 突变模型在内的多种 NSCLC 和神经胶质瘤肿瘤的体内生长。最小有效剂量<1 mg/kg]。CD73-ADC 治疗引发了促炎性巨噬细胞和活化的树突状细胞 (DC) 的强烈肿瘤内积聚，用裸 CD73 抗体或标准化疗未观察到。对人类 PBMC 衍生系统的研究证实，CD73-ADC 在保护效应 T 细胞和刺激 DC 方面具有完全功能，因此在杀死 CD73 高肿瘤和改善癌症免疫反应方面具有双重益处。这些结果保证了 CD73 靶向抗体和 ADC 用于治疗晚期肺癌的临床研究。