Mapping of binding epitopes of a human decay-accelerating factor monoclonal antibody capable of enhancing rituximab-mediated complement-dependent cytotoxicity

被引：9

作者：

Guo, Bo ^{[2
]}

Ma, Zheng-wei ^{[3
,4
]}

Li, Hua ^{[2
]}

Xu, Gui-lian ^{[2
]}

Zheng, Ping ^{[2
]}

Zhu, Bo ^{[2
]}

Wu, Yu-Zhang ^{[2
]}

Zou, Qiang ^{[1
]}

机构：

[1] Chengdu Med Coll, Dept Immunol, Chengdu 610083, Peoples R China

[2] Third Mil Med Univ, Inst Immunol, Chongqing 400038, Peoples R China

[3] Third Mil Med Univ, Inst Hepatobiliary Surg, Chongqing 400038, Peoples R China

[4] Third Mil Med Univ, SW Hosp, Chongqing 400038, Peoples R China

来源：

CLINICAL IMMUNOLOGY | 2008年 / 128卷 / 02期

基金：

中国国家自然科学基金;

关键词：

decay-accelerating factor; monoclonal antibody; complement-dependent cytotoxicity (CDC); tumor; immunotherapy;

D O I：

10.1016/j.clim.2008.03.507

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Complement-dependent cytotoxicity (CDC) is thought to be one of the most important mechanisms of action of therapeutic monoclonal antibodies (mAbs). The decay-accelerating factor (DAF) overexpressed in certain tumors limits the CDC effect of the therapeutic anticancer antibodies. The use of DAF blocking antibodies targeted specifically at cancer cells in combination with immunotherapeutic mAbs of cancer may improve the therapeutic effect in cancer patients. In this study, the lysis of Raji cells mediated by CDC was determined after blocking DAF function by anti-DAF polyclonal antibody and 3 mAbs (DG3, DG9, DA11) prepared in our laboratory, respectively, in the presence of the anti-CD20 chimeric mAb rituximab. The binding domains of the three anti-DAF mAbs were identified using yeast surface display technique, and the mimic epitopes of mAb DG3 were screened from a random phage-display nonapeptide library. The results showed that blocking DAF function by anti-DAF polyclonal antibody enhanced complement-mediated killing of Raji cells. Among the 3 mAbs against DAF, only DG3 was found to be able to remarkably enhance the CDC effect of the therapeutic mAb rituximab. DG3 bound to the third short consensus repeat (SCR) of DAF Binding of DG3 to immobilized DAF was inhibited by mimic epitope peptides screened from the peptide library. Our results suggest that a higher level. of DAF expressed by certain tumor cells is significant to abolish the CDC effect of therapeutic anticancer antibodies, and mAbs binding to SCR3 can enhance the complement-mediated killing of Raji cells. It is of significance to identify the DAF epitopes required in inhibiting CDC not only for better understanding of the relationship between the structure and function of DAF, but also for designing and developing anti-DAF mAbs capable of enhancing CDC. (c) 2008 Elsevier Inc. All. rights reserved.

引用

页码：155 / 163

页数：9

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