Activation of complement by monoclonal antibodies that target cell-associated ¦Â2-microglobulin: Implications for cancer immunotherapy
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- 作者：Michael J. Pokrass ; Monica F. Liu ; Margaret A. Lindorfer ; Ronald P. Taylor
- 关键词：Al ; Alexa ; APC ; allophycocyanin ; ¦Â2M ; ¦Â2-microglobulin ; CDC ; complement dependent cytotoxicity ; HBMT ; Hepes buffered modified Tyrode's ; HI ; heat-inactivated ; mAb ; monoclonal antibody ; MESF ; molecules of equivalent soluble fluorochrome ; RT ; room temperat
- 刊名：Molecular Immunology
- 出版年：2013
- 出版时间：31 December, 2013
- 年：2013
- 卷：56
- 期：4
- 页码：549-560
- 全文大小：2185 K
文摘
¦Â2-Microglobulin (¦Â2M), the light chain of the class I major histocompatibilty complex (MHC-I), is a promising tumor target for monoclonal antibodies (mAbs) in cancer immunotherapy. Several reports indicate that chelation of cell-associated ¦Â2M by specific mouse mAbs promotes tumor cell destruction by inducing apoptosis or other cytotoxic signaling pathways. Human mAbs employed in cancer therapy are usually IgG1, which mediates cell-killing by effector mechanisms including complement dependent cytotoxicity (CDC). The analogous mouse IgG2a and IgG2b isotypes are similarly effective in activating complement. Therefore, we examined the complement-activating properties of anti-¦Â2M mouse mAbs 1B749 (IgG2a) and HB28 (IgG2b) when either mAb was bound to tumor cell lines or normal cells; we compared these ¦Â2M-specific mAbs with mouse mAb W6/32 (IgG2a), specific for human leukocyte antigens in the MHC-I heavy chain. All three mAbs bind to most human cell lines and normal cells in approximately equal amounts, consistent with a 1:1 stoichiometry for the HLA heavy chain in association with ¦Â2M. The three mAbs promote rapid C3b deposition and substantial CDC of human cell lines, and mAbs 1B749 and W6/32 have robust cytotoxic activity on reaction with normal mononuclear cells and platelets. Curiously, mAb HB28 induces modest C3b deposition and little CDC of normal cells, and its weaker complement-fixing activity was confirmed by ELISA. Based on these findings, we suggest that human IgG mAbs that target ¦Â2M for cancer immunotherapy be selected or engineered so as not to activate complement, thus eliminating the potential adverse effects of complement-mediated lysis of normal cells.