Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Division of Oncology and Center for Biomedical Informatics (CBMi), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Sci Transl Med. 2019 Mar 13;11(483). doi: 10.1126/scitranslmed.aau9732.
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.
近年来，抗体药物偶联物（ADCs）在癌症治疗中的应用受到了广泛关注。这种治疗方法的成功依赖于识别广泛且选择性表达于肿瘤细胞表面的细胞表面抗原。研究表明，天然的 ALK 蛋白在大多数神经母细胞瘤细胞表面表达，为免疫靶向策略的开发提供了机会。目前尚未开发出针对这一靶点的临床相关抗体。在这里，我们描述了一种 ALK-ADC，CDX-0125-TEI 的开发，它可以选择性地靶向表达野生型和突变型 ALK 的神经母细胞瘤。CDX-0125-TEI 在细胞表面表达不同水平的 ALK 时，表现出高效的抗原结合、内化和在皮摩尔浓度下的细胞毒性。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均有效。这些数据表明 ALK 是一个真正的免疫治疗靶点，并为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 方法提供了理论依据。
