Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.
Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Mol Cancer Ther. 2020 Nov;19(11):2340-2352. doi: 10.1158/1535-7163.MCT-20-0076. Epub 2020 Sep 17.
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 (IC<0.1 nmol/L) and suppressed 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.
尽管酪氨酸激酶抑制剂治疗和免疫疗法显著改善了肺癌的治疗效果，但许多患者并未从中受益或对治疗产生耐药性，这凸显了需要新的治疗方法。我们发现，CD73 的表达在非小细胞肺癌（NSCLC）中升高，包括那些携带 RAS 或 RTK（EGFR、EML4-ALK）癌基因的 NSCLC。CD73 的表达与上皮-间充质转化和免疫耐受肿瘤微环境的转录组特征密切相关，这些特征对于疾病进展和治疗耐药性越来越重要。我们开发了两种新型 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、强大的酶抑制作用，并能有效地保护效应 T 淋巴细胞免受腺苷/癌症施加的毒性。Hu001/Hu002 通过增强抗体依赖的细胞介导的细胞毒性和肿瘤免疫微环境的多方面重塑，抑制了 RAS 突变型 NSCLC 肿瘤在小鼠中的生长，反映出肿瘤相关巨噬细胞、髓源性抑制细胞和肿瘤血管的水平降低。一种新型 MMAE 缀合的 CD73-ADC（Hu001-MMAE）对 CD73 高表达的肿瘤细胞表现出强大的细胞毒性（IC<0.1 nmol/L），并抑制了多种 NSCLC 和神经胶质瘤肿瘤的生长，包括 RAS 突变模型[最小有效剂量<1mg/kg]。用 CD73-ADC 治疗可引发肿瘤内促炎巨噬细胞和激活的树突状细胞（DC）的大量积累，而用裸 CD73 抗体或标准化疗则观察不到这种现象。用人 PBMC 衍生系统进行的研究证实，CD73-ADC 可完全发挥功能，保护效应 T 细胞并刺激 DC，从而在杀伤 CD73 高表达肿瘤和改善癌症免疫反应方面具有双重益处。这些结果证明了 CD73 靶向抗体和 ADC 用于治疗晚期肺癌的临床研究价值。
