Fishelson Z, Donin N, Zell S, Schultz S, Kirschfink M
Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
Mol Immunol. 2003 Sep;40(2-4):109-23. doi: 10.1016/s0161-5890(03)00112-3.
Monoclonal antibodies (mAbs) are being increasingly used in cancer therapy owing to their ability to recognize specifically cancer cells and to activate complement- and cell-mediated cytotoxicity and/or to induce growth arrest or apoptosis. The therapeutic potential of anticancer antibodies is significantly limited due to the ability of cancer cells to block killing by complement. Of the multiple resistance strategies exploited by cancer cells, the expression of membrane complement regulatory proteins (mCRPs), such as CD46 (membrane cofactor protein (MCP)), CD55 (decay-accelerating factor (DAF)), CD35 (complement receptor type-1 (CR1)) and CD59, has received most attention. CD46, CD55 and CD35 block the complement cascade at the C3 activation stage and CD59 prevents assembly of the membrane attack complex of complement (MAC). These proteins protect normal tissues from accidental injury by activated complement, but also confer resistance on cancer cells, thereby limiting the effect of complement-fixing monoclonal antibodies. Expression of mCRPs on malignant cells is highly variable, yet there is clear indication that certain tumors express higher mCRP levels than the normal tissue from which they have evolved. mCRP level of expression and cellular location may also vary during malignant transformation and between differentiated and undifferentiated tumors. Neutralizing anti-mCRP mAbs have been used in vitro to elucidate the significance of mCRP expression to the tumor complement resistance phenotype. In general, CD59 appears to be the most effective mCRP protecting tumor cells from complement-mediated lysis. Nevertheless, it acts additively, and in certain tumors even synergistically, with CD55 and CD46. It is envisaged that treatment of cancer patients with mCRP blocking antibodies targeted specifically to cancer cells in combination with anticancer complement-fixing antibodies will improve the therapeutic efficacy.
单克隆抗体（mAb）因其能够特异性识别癌细胞并激活补体和细胞介导的细胞毒性和/或诱导生长停滞或凋亡，而越来越多地用于癌症治疗。由于癌细胞具有阻断补体杀伤的能力，抗癌抗体的治疗潜力受到显著限制。在癌细胞所采用的多种耐药策略中，膜补体调节蛋白（mCRP）的表达，如CD46（膜辅因子蛋白（MCP））、CD55（衰变加速因子（DAF））、CD35（补体受体1型（CR1））和CD59，受到了最多关注。CD46、CD55和CD35在C3激活阶段阻断补体级联反应，CD59则阻止补体膜攻击复合物（MAC）的组装。这些蛋白保护正常组织免受激活补体的意外损伤，但也赋予癌细胞抗性，从而限制了补体结合单克隆抗体的作用。mCRP在恶性细胞上的表达高度可变，但有明确迹象表明，某些肿瘤表达的mCRP水平高于其起源的正常组织。mCRP的表达水平和细胞定位在恶性转化过程中以及在分化和未分化肿瘤之间也可能有所不同。体外已使用中和性抗mCRP单克隆抗体来阐明mCRP表达对肿瘤补体抗性表型的意义。一般来说，CD59似乎是保护肿瘤细胞免受补体介导的裂解最有效的mCRP。然而，它与CD55和CD46协同作用，在某些肿瘤中甚至是协同作用。据设想，用特异性靶向癌细胞的mCRP阻断抗体联合抗癌补体结合抗体治疗癌症患者将提高治疗效果。
