Antitumor activity of an anti-CD98 antibody.
Antitumor activity of an anti-CD98 antibody.
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DOI：
10.1002/ijc.29415
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发表时间：
2015-08-01
影响因子：
6.4
通讯作者：
H van der Horst E
中科院分区：
文献类型：
--
作者：
Hayes GM;Chinn L;Cantor JM;Cairns B;Levashova Z;Tran H;Velilla T;Duey D;Lippincott J;Zachwieja J;Ginsberg MH;H van der Horst E
CD 98在几种组织类型上表达，并且在经历克隆扩增的快速循环细胞上特异性上调。各种固体（例如，非小细胞肺癌）以及血液恶性肿瘤（例如，急性髓性白血病）过表达CD 98。我们已经确定了一种CD 98特异性小鼠单克隆抗体，其对已建立的淋巴瘤肿瘤异种移植物表现出有效的临床前抗肿瘤活性。此外，命名为IGN 523的人源化抗体在白血病细胞系来源的异种移植物模型中表现出稳健的肿瘤生长抑制，并且在患者来源的非小细胞肺癌异种移植物中与标准治疗卡铂一样有效。体外研究表明，IGN 523引发强烈的ADCC活性，诱导溶酶体膜透化并抑制必需氨基酸转运功能，最终导致caspase-3和caspase-7介导的肿瘤细胞凋亡。IGN 523目前正在急性髓性白血病的I期临床试验（NCT 02040506）中进行评估。此外，临床前数据支持IGN 523在实体瘤中的治疗潜力。有什么新消息吗？CD 98蛋白在多种癌症中过表达，其表达水平与肿瘤进展和转移呈正相关。CD 98的重链和轻链都具有治疗意义。本研究报告了抗CD 98人源化单克隆抗体IGN 523在白血病细胞系来源的异种移植物模型和患者来源的非小细胞肺癌异种移植物中的广泛和有效的抗肿瘤活性。IGN 523表现出多种作用机制，并在体外表现出抗体依赖性细胞毒性，阻断氨基酸转运，并通过caspase-3和caspase-7途径介导肿瘤细胞凋亡。
CD98 is expressed on several tissue types and specifically upregulated on fast‐cycling cells undergoing clonal expansion. Various solid (e.g., nonsmall cell lung carcinoma) as well as hematological malignancies (e.g., acute myeloid leukemia) overexpress CD98. We have identified a CD98‐specific mouse monoclonal antibody that exhibits potent preclinical antitumor activity against established lymphoma tumor xenografts. Additionally, the humanized antibody designated IGN523 demonstrated robust tumor growth inhibition in leukemic cell‐line derived xenograft models and was as efficacious as standard of care carboplatin in patient‐derived nonsmall lung cancer xenografts. In vitro studies revealed that IGN523 elicited strong ADCC activity, induced lysosomal membrane permeabilization and inhibited essential amino acid transport function, ultimately resulting in caspase‐3 and ‐7‐mediated apoptosis of tumor cells. IGN523 is currently being evaluated in a Phase I clinical trial for acute myeloid leukemia (NCT02040506). Furthermore, preclinical data support the therapeutic potential of IGN523 in solid tumors. What's new? The CD98 protein is overexpressed in a wide variety of cancers, and its expression levels show positive association with tumor progression and metastasis. Both the heavy and the light chains of CD98 are of therapeutic interest. The present study reports broad and potent anti‐tumor activity of the anti‐CD98 humanized monoclonal antibody IGN523 in leukemic cell‐line‐derived xenograft models and patient‐derived non‐small cell lung cancer xenografts. IGN523 exhibited multiple mechanisms of action, and in vitro demonstrated antibody‐dependent cellular cytotoxicity, blocked amino acid transport, and led to tumor cell apoptosis mediated via caspase‐3 and caspase‐7 pathways.
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