Targeted cancer immunotherapy with oncolytic adenovirus coding for a fully human monoclonal antibody specific for CTLA-4
Targeted cancer immunotherapy with oncolytic adenovirus coding for a fully human monoclonal antibody specific for CTLA-4
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DOI：
10.1038/gt.2011.176
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发表时间：
2012-10-01
期刊：
影响因子：
5.1
通讯作者：
Hemminki, A.
中科院分区：
文献类型：
--
作者：
Dias, J. D.;Hemminki, O.;Hemminki, A.
用单克隆抗体（mAb）如伊匹单抗和曲美木单抗阻断细胞毒性T淋巴细胞相关抗原-4（CTLA-4，CD 152）已经实现了有希望的临床结果。然而，这些药物的全身给药也有可能发生严重的免疫相关不良事件。因此，当地生产可能会使目标浓度更高，同时减少全身副作用。我们产生了转导和转录靶向的溶瘤腺病毒Ad 5/3-Delta 24 aCTLA 4，表达对CTLA-4特异性的完整人mAb，并在体外、体内和正常供体和晚期实体瘤患者的外周血单核细胞（PBMC）中对其进行了测试。免疫印迹和免疫组化证实mAb表达。在来自癌症患者的T细胞系和PBMC中测定生物功能性。患者的T细胞，而不是健康供体的T细胞，被Ad 5/3-Delta 24 aCTLA 4产生的抗CTLA 4 mAb激活。除了免疫学效应之外，在体外和体内观察到直接的抗CTLA-4介导的促凋亡效应。本地生产导致43倍（P
Promising clinical results have been achieved with monoclonal antibodies (mAbs) such as ipilimumab and tremelimumab that block cytotoxic T lymphocyte-associated antigen-4 (CTLA-4, CD152). However, systemic administration of these agents also has the potential for severe immune-related adverse events. Thus, local production might allow higher concentrations at the target while reducing systemic side effects. We generated a transductionally and transcriptionally targeted oncolytic adenovirus Ad5/3-Delta 24aCTLA4 expressing complete human mAb specific for CTLA-4 and tested it in vitro, in vivo and in peripheral blood mononuclear cells (PBMCs) of normal donors and patients with advanced solid tumors. mAb expression was confirmed by western blotting and immunohistochemistry. Biological functionality was determined in a T-cell line and in PBMCs from cancer patients. T cells of patients, but not those of healthy donors, were activated by an anti-CTLA4mAb produced by Ad5/3-Delta 24aCTLA4. In addition to immunological effects, a direct anti-CTLA-4-mediated pro-apoptotic effect was observed in vitro and in vivo. Local production resulted in 43-fold higher (P