Polson Andrew G, Calemine-Fenaux Jill, Chan Pamela, Chang Wesley, Christensen Erin, Clark Suzanna, de Sauvage Frederic J, Eaton Dan, Elkins Kristi, Elliott J Michael, Frantz Gretchen, Fuji Reina N, Gray Alane, Harden Kristin, Ingle Gladys S, Kljavin Noelyn M, Koeppen Hartmut, Nelson Christopher, Prabhu Saileta, Raab Helga, Ross Sarajane, Slaga Dion S, Stephan Jean-Philippe, Scales Suzie J, Spencer Susan D, Vandlen Richard, Wranik Bernd, Yu Shang-Fan, Zheng Bing, Ebens Allen
Genentech, Inc., South San Francisco, California, USA.
Cancer Res. 2009 Mar 15;69(6):2358-64. doi: 10.1158/0008-5472.CAN-08-2250. Epub 2009 Mar 3.
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 CD79b. In target-independent safety studies in rats, the uncleavable linker ADCs showed reduced toxicity, presumably due to the 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.
抗体药物偶联物（ADC）是通过化学连接子将强效细胞毒性药物与抗体共价连接而成的，它提供了一种通过将药物靶向肿瘤细胞来提高化疗效果同时减少副作用的方法。在此，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的潜在靶点以及连接子-药物组合。我们确定了七种抗原（CD19、CD20、CD21、CD22、CD72、CD79b和CD180）可用于ADC治疗非霍奇金淋巴瘤。具有可裂解连接子的ADC通过所有这些靶点介导体内疗效；具有不可裂解连接子的ADC仅在靶向CD22和CD79b时有效。在大鼠的非靶向安全性研究中，不可裂解连接子的ADC显示出较低的毒性，推测这是由于游离药物或其他有毒代谢物释放到循环中的量减少所致。因此，我们的数据表明，具有可裂解连接子的ADC作用于广泛的靶点，而对于特定靶点，具有不可裂解连接子的ADC为改善人类ADC的治疗窗口提供了一个有前景的机会。
