An antibody-drug conjugate directed to the ALK receptor demonstrates efficacy in preclinical models of neuroblastoma.
An antibody-drug conjugate directed to the ALK receptor demonstrates efficacy in preclinical models of neuroblastoma.
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DOI：
10.1126/scitranslmed.aau9732
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发表时间：
2019-03-13
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
--
作者：
在过去几年中，在癌症治疗中使用抗体-药物缀合物（ADC）的热情有所上升。这种治疗方法的成功依赖于对肿瘤细胞上广泛和选择性表达的细胞表面抗原的鉴定。研究表明，天然ALK蛋白在大多数神经母细胞瘤细胞的表面表达，这为开发免疫靶向策略提供了机会。尚未开发针对该靶标的临床相关抗体。在这里，我们描述了一种ALK-ADC，CDX-0125-TEI的开发，它选择性地靶向野生型和突变的ALK表达神经母细胞瘤。CDX-0125-TEI在细胞表面ALK表达不同的细胞中表现出有效的抗原结合和内化，以及皮摩尔浓度的细胞毒性。体内研究表明，CDX-0125-TEI对ALK野生型和突变型患者来源的异种移植模型有效。这些数据表明，ALK是真正的免疫靶点，并为临床开发用于神经母细胞瘤和其他表达ALK的儿童癌症（如横纹肌肉瘤）的ALK-ADC方法提供了依据。
Enthusiasm for the use of antibody-drug conjugates (ADCs) in cancer therapy has risen over the past few years. The success of this therapeutic approach relies on the identification of cell surface antigens that are widely and selectively expressed on tumor cells. Studies have shown that native ALK protein is expressed on the surface of most neuroblastoma cells, providing an opportunity for development of immune-targeting strategies. Clinically relevant antibodies for this target have not yet been developed. Here, we describe the development of an ALK-ADC, CDX-0125-TEI, which selectively targets both wild-type and mutated ALK-expressing neuroblastomas. CDX-0125-TEI exhibited efficient antigen binding and internalization, and cytotoxicity at picomolar concentrations in cells with different expression of ALK on the cell surface. In vivo studies showed that CDX-0125-TEI is effective against ALK wild-type and mutant patient-derived xenograft models. These data demonstrate that ALK is a bona fide immunotherapeutic target and provide a rationale for clinical development of an ALK-ADC approach for neuroblastomas and other ALK-expressing childhood cancers such as rhabdomyosarcomas.
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DOI：
10.1016/s1470-2045(16)30030-4
发表时间：
2016-06
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Thomas A;Teicher BA;Hassan R
通讯作者：
Hassan R
影响因子：
28.2
作者：
Infarinato, Nicole R.;Park, Jin H.;Mosse, Yael P.
通讯作者：
Mosse, Yael P.
影响因子：
11.5
作者：
Teicher, Beverly A.;Chari, Ravi V. J.
通讯作者：
Chari, Ravi V. J.
DOI：
10.1056/nejmoa1407222
发表时间：
2014-10-16
期刊：
The New England journal of medicine
影响因子：
--
作者：
Maude SL;Frey N;Shaw PA;Aplenc R;Barrett DM;Bunin NJ;Chew A;Gonzalez VE;Zheng Z;Lacey SF;Mahnke YD;Melenhorst JJ;Rheingold SR;Shen A;Teachey DT;Levine BL;June CH;Porter DL;Grupp SA
通讯作者：
Grupp SA
影响因子：
3.7
作者：
Schneeberger VE;Allaj V;Gardner EE;Poirier JT;Rudin CM
通讯作者：
Rudin CM