Human monocytes expressing a CEA-specific chimeric CD64 receptor specifically target CEA-expressing tumour cells in vitro and in vivo
Human monocytes expressing a CEA-specific chimeric CD64 receptor specifically target CEA-expressing tumour cells in vitro and in vivo
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DOI：
10.1038/sj.gt.3302706
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发表时间：
2006-04-01
期刊：
影响因子：
5.1
通讯作者：
Gilham, DE
中科院分区：
文献类型：
--
作者：
Biglari, A;Southgate, TD;Gilham, DE
抗体依赖性细胞毒性（ADCC）是巨噬细胞（以及自然杀伤细胞和粒细胞）引发细胞毒性反应的一种手段。这是通过Fc-γ受体（CD 64）与结合靶细胞的抗体Fc部分相互作用实现的。我们已经创建了一个嵌合的CD 64分子，它包含一个单链Fv分子，靶向人类癌胚抗原（CEA），融合到跨膜和胞质结构域的人CD 64。在腺病毒转移到原代人单核细胞后，这种嵌合CD 64受体在固定化CEA蛋白或CEA表达肿瘤细胞上培养期间诱导抗原特异性细胞因子分泌。此外，CEA靶向，但不是控制，单核细胞有效地延缓CEA阳性肿瘤细胞的体外生长。重要的是，在异种移植研究中，靶向单核细胞培养物显著降低了体内肿瘤生长速率，导致存活率高于对照单核细胞培养物。这些数据表明，遗传指导单核细胞对肿瘤抗原可能是一个有用的手段，实现免疫应答。
Antibody-dependent cellular cytotoxicity ( ADCC) is one means by which macrophages ( as well as natural killer cells and granulocytes) elicit a cytotoxic response. This is achieved via interaction of the Fc-gamma-receptor (CD64) with the Fc portion of antibody bound to target cells. We have created a chimeric CD64 molecule that incorporates a single chain Fv molecule, targeted against human carcinoembryonic antigen (CEA), fused to the membrane spanning and cytosolic domains of human CD64. Following adenoviral transfer to primary human monocytes, this chimeric CD64 receptor induced antigen-specific cytokine secretion during culture on immobilised CEA protein or on CEA-expressing tumour cells. Moreover, CEA targeted, but not control, monocytes effectively retarded CEA-positive tumour cell growth in vitro. Importantly, targeted monocyte cultures significantly reduced in vivo tumour growth rates in xenograft studies resulting in improved survival rates over that of control monocyte cultures. These data suggest that genetically directing monocytes against tumour antigens may be a useful means of achieving an immunotherapeutic response.