Combating non-Hodgkin lymphoma by targeting both CD20 and HLA-DR through CD20–243 CrossMab
Combating non-Hodgkin lymphoma by targeting both CD20 and HLA-DR through CD20–243 CrossMab
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DOI：
10.4161/mabs.28613
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发表时间：
2014-03
期刊：
影响因子：
5.3
通讯作者：
Lei Zhao;Feiyue Xie;Xin Tong;Huafei Li;Yalin Chen;Wei-zhu Qian;Shuyan Duan;Jui-Pin Zheng;Ziye Zhao;Bo-hua Li;Da-peng Zhang;Jian Zhao;Jianxin Dai;S. Hou;Ya-jun Guo
中科院分区：
文献类型：
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作者：
Lei Zhao;Feiyue Xie;Xin Tong;Huafei Li;Yalin Chen;Wei-zhu Qian;Shuyan Duan;Jui-Pin Zheng;Ziye Zhao;Bo-hua Li;Da-peng Zhang;Jian Zhao;Jianxin Dai;S. Hou;Ya-jun Guo
尽管利妥昔单抗已经彻底改变了血液系统恶性肿瘤的治疗，但获得性耐药是癌症治疗的主要障碍之一，迫切需要开发具有有效抗肿瘤活性和特异性的新型靶向cd20抗体。新的证据表明，溶酶体可以被认为是癌细胞的“阿喀琉斯之踵”，并可能作为一种有效的方法来杀死耐药的癌细胞。最近有报道称，HLA-DR抗体L243在淋巴瘤和白血病细胞中引发溶酶体介导的有效细胞死亡，这表明HLA-DR可能被用作治疗淋巴瘤的潜在靶点。在本研究中，我们通过CrossMab技术合成了一种靶向CD20和HLA-DR的双特异性免疫球蛋白g样抗体（CD20 - 243 CrossMab）。我们发现CrossMab可以诱导非常高水平的补体依赖性细胞毒性、抗体依赖性细胞介导的细胞毒性和抗增殖活性。值得注意的是，尽管HLA-DR在正常细胞和恶性细胞上表达，但CrossMab具有高度的抗肿瘤特异性，在体外和体内都能有效根除血液系统恶性肿瘤。我们的数据表明，联合靶向CD20和HLA-DR可能是一种有效的治疗恶性肿瘤的方法，这表明CD20 - 243 CrossMab可能是一种有前景的治疗淋巴瘤的药物。
Although rituximab has revolutionized the treatment of hematological malignancies, the acquired resistance is one of the prime obstacles for cancer treatment, and development of novel CD20-targeting antibodies with potent anti-tumor activities and specificities is urgently needed. Emerging evidence has indicated that lysosomes can be considered as an “Achilles heel” for cancer cells, and might serve as an effective way to kill resistant cancer cells. HLA-DR antibody L243 has been recently reported to elicit potent lysosome-mediated cell death in lymphoma and leukemia cells, suggesting that HLA-DR could be used as a potential target against lymphoma. In this study, we generated a bispecific immunoglobulin G-like antibody targeting both CD20 and HLA-DR (CD20–243 CrossMab) through CrossMab technology. We found that the CrossMab could induce remarkably high levels of complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity and anti-proliferative activity. Notably, although HLA-DR is expressed on normal and malignant cells, the CrossMab exhibited highly anti-tumor specificity, showing efficient eradication of hematological malignancies both in vitro and in vivo. Our data indicated that combined targeting of CD20 and HLA-DR could be an effective approach against malignancies, suggesting that CD20–243 CrossMab would be a promising therapeutic agent against lymphoma.