Involvement of neutrophils and natural killer cells in the anti-tumor activity of alemtuzumab in xenograft tumor models
Involvement of neutrophils and natural killer cells in the anti-tumor activity of alemtuzumab in xenograft tumor models
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DOI：
10.3109/10428191003777963
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发表时间：
2010-07-01
影响因子：
2.6
通讯作者：
Kaplan, Johanne M.
中科院分区：
文献类型：
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作者：
Siders, William M.;Shields, Jacqueline;Kaplan, Johanne M.
Alemtuzumab是一种针对CD52的重组人源化IgG1单抗，CD52是一种表达在正常和恶性B和T淋巴细胞表面的抗原。Alemtuzumab已被批准用于治疗B细胞慢性淋巴细胞白血病(B-CLL)，但该抗体在体内耗尽恶性淋巴细胞的确切机制尚不清楚。为了解决这个问题，我们在播散性和皮下移植瘤模型中研究了阿伦图珠单抗的抗肿瘤活性。肿瘤细胞表面CD52靶抗原的密度与阿仑珠单抗的抗肿瘤活性有关。阿仑珠单抗的脱糖作用在体外导致细胞毒性丧失，在体内被发现取消抗肿瘤活性。荷瘤小鼠体内效应机制的个体失活表明，阿仑珠单抗在体内的保护作用主要依赖于中性粒细胞介导的ADCC，其次是NK细胞。通过G-CSF处理增加循环中的中性粒细胞数量可增强抗体的抗肿瘤活性，从而为中性粒细胞作为效应细胞参与alemtuzumab的活性提供了进一步的证据。
Alemtuzumab is a recombinant humanized IgG1 monoclonal antibody directed against CD52, an antigen expressed on the surface of normal and malignant B and T lymphocytes. Alemtuzumab is approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL), but the exact mechanism by which the antibody depletes malignant lymphocytes in vivo is not clearly defined. To address this issue, the anti-tumor activity of alemtuzumab was studied in disseminated and subcutaneous xenograft tumor models. The density of CD52 target antigen on the surface of tumor cells appeared to correlate with the anti-tumor activity of alemtuzumab. Deglycosylation of alemtuzumab resulted in a loss of cytotoxicity in vitro and was found to abolish anti-tumor activity in vivo. Individual inactivation of effector mechanisms in tumor-bearing mice indicated that the protective activity of alemtuzumab in vivo was primarily dependent on ADCC mediated by neutrophils and to a lesser extent NK cells. Increasing the number of circulating neutrophils by treatment with G-CSF enhanced the anti-tumor activity of the antibody, thus providing further evidence for the involvement of neutrophils as effector cells in the activity of alemtuzumab.