A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo.
A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo.
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DOI：
10.1126/scitranslmed.aac9459
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发表时间：
2015-08-26
影响因子：
17.1
通讯作者：
Dylla SJ
中科院分区：
文献类型：
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作者：
Saunders LR;Bankovich AJ;Anderson WC;Aujay MA;Bheddah S;Black K;Desai R;Escarpe PA;Hampl J;Laysang A;Liu D;Lopez-Molina J;Milton M;Park A;Pysz MA;Shao H;Slingerland B;Torgov M;Williams SA;Foord O;Howard P;Jassem J;Badzio A;Czapiewski P;Harpole DH;Dowlati A;Massion PP;Travis WD;Pietanza MC;Poirier JT;Rudin CM;Stull RA;Dylla SJ
高级别肺神经内分泌肿瘤，小细胞肺癌(SCLC)和大细胞神经内分泌癌(LCNEC)仍然是最致命的恶性肿瘤之一。有效靶向并杀死这些癌症中的肿瘤起始细胞(TIC)的治疗应该转化为提高患者的存活率。患者来源的异种移植瘤(PDX)是研究肿瘤生物学和表征TICS的良好模型。Delta样3(DLL3)在SCLC和LCNEC PDX肿瘤中表达增加，并在原发SCLC和LCNEC肿瘤中得到证实。DLL3蛋白在肿瘤细胞表面表达，但在正常成人组织中不表达。一种针对DLL3的抗体-药物结合物SC16LD6.5由人源化抗DLL3单抗与DNA损伤的吡咯苯二氮卓类(PBD)二聚体毒素结合而成，可在体内跨多种PDX模型诱导持久的肿瘤消退。在细胞稀释度有限的情况下进行的一系列移植实验提供了功能证据，证实SC16LD6.5暴露后肿瘤无复发是由于有效靶向表达DLL3的TIC。体内疗效与DLL3的表达有关，在PDX模型中观察到了反应，这些反应来自局限性和广泛期疾病患者，并与他们对标准护理化疗方案的敏感性无关。SC16LD6.5能有效靶向和根除SCLC和LCNEC PDX肿瘤中表达DLL3的TICS，是治疗高级别肺神经内分泌肿瘤的一种有前途的一流ADC。
The high-grade pulmonary neuroendocrine tumors, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), remain among the most deadly malignancies. Therapies that effectively target and kill tumor-initiating cells (TICs) in these cancers should translate to improved patient survival. Patient-derived xenograft (PDX) tumors serve as excellent models to study tumor biology and characterize TICs. Increased expression of delta-like 3 (DLL3) was discovered in SCLC and LCNEC PDX tumors and confirmed in primary SCLC and LCNEC tumors. DLL3 protein is expressed on the surface of tumor cells but not in normal adult tissues. A DLL3-targeted antibody-drug conjugate (ADC), SC16LD6.5, comprised of a humanized anti-DLL3 monoclonal antibody conjugated to a DNA-damaging pyrrolobenzodiazepine (PBD) dimer toxin, induced durable tumor regression in vivo across multiple PDX models. Serial transplantation experiments executed with limiting dilutions of cells provided functional evidence confirming that the lack of tumor recurrence after SC16LD6.5 exposure resulted from effective targeting of DLL3-expressing TICs. In vivo efficacy correlated with DLL3 expression, and responses were observed in PDX models initiated from patients with both limited and extensive-stage disease and were independent of their sensitivity to standard-of-care chemotherapy regimens. SC16LD6.5 effectively targets and eradicates DLL3-expressing TICs in SCLC and LCNEC PDX tumors and is a promising first-in-class ADC for the treatment of high-grade pulmonary neuroendocrine tumors.