Antibody-Drug Conjugates for the Treatment of Non-Hodgkin's Lymphoma: Target and Linker-Drug Selection
Antibody-Drug Conjugates for the Treatment of Non-Hodgkin's Lymphoma: Target and Linker-Drug Selection
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DOI：
10.1158/0008-5472.can-08-2250
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发表时间：
2009-03-15
期刊：
影响因子：
11.2
通讯作者：
Ebens, Allen
中科院分区：
文献类型：
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作者：
Polson, Andrew G.;Calemine-Fenaux, Jill;Ebens, Allen
抗体-药物偶联物（ADC）是一种有效的细胞毒性药物，通过化学连接物与抗体共价连接，提供了一种通过将药物靶向肿瘤细胞而增加化疗有效性的方法，同时减少了副作用。在这里，我们系统地研究了可能为非霍奇金淋巴瘤治疗提供最佳ADC的潜在靶点和连接药物组合。我们确定了7种抗原（CD19, CD20, CD21, CD22, CD72， CD79b和CD180）用于非霍奇金淋巴瘤adc的潜在治疗。具有可切割连接体的adc通过所有这些靶点介导体内功效；具有不可切割连接体的adc仅在靶向CD22和CD79时有效。在针对大鼠的非靶向安全性研究中，不可切割的连接物adc显示出毒性降低，可能是由于它减少了游离药物或其他有毒代谢物进入循环的释放。因此，我们的数据表明，具有可切割连接体的adc可作用于广泛的靶标，对于特定靶标，具有不可切割连接体的adc为改善人类adc的治疗窗口提供了有希望的机会。[癌症研究2009；69 (6): 2358 - 64)
Antibody-drug conjugates (ADC), potent cytotoxic drugs covalently linked to antibodies via chemical linkers, provide a means to increase the effectiveness of chemotherapy by targeting the drug to neoplastic cells while reducing side effects. Here, we systematically examine the potential targets and linker-drug combinations that could provide an optimal ADC for the treatment for non-Hodgkin's lymphoma. We identified seven antigens (CD19, CD20, CD21, CD22, CD72, CD79b, and CD180) for potential treatment of non-Hodgkin's lymphoma with ADCs. ADCs with cleavable linkers mediated in vivo efficacy via all these targets; ADCs with uncleavable linkers were only effective when targeted to CD22 and CD79. In target-independent safety studies in rats, the uncleavable linker ADCs showed reduced toxicity, presumably due to I e reduced release of free drug or other toxic metabolites into the circulation. Thus, our data suggest that ADCs with cleavable linkers work on a broad range of targets, and for specific targets, ADCs with uncleavable linkers provide a promising opportunity to improve the therapeutic window for ADCs in humans. [Cancer Res 2009;69(6):2358-64]