A novel human monoclonal antibody that binds with high affinity to mesothelin-expressing cells and kills them by antibody-dependent cell-mediated cytotoxicity.
A novel human monoclonal antibody that binds with high affinity to mesothelin-expressing cells and kills them by antibody-dependent cell-mediated cytotoxicity.
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DOI：
10.1158/1535-7163.mct-08-0945
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发表时间：
2009-05
影响因子：
5.7
通讯作者：
Dimitrov DS
中科院分区：
文献类型：
--
作者：
Feng Y;Xiao X;Zhu Z;Streaker E;Ho M;Pastan I;Dimitrov DS
间皮素仅在健康人胸膜、腹膜和心包膜的间皮细胞中含量相对较低，但在间皮瘤、卵巢癌、胰腺癌和肺癌等多种肿瘤中含量显著升高，是癌症免疫治疗的潜在新靶点。然而，目前所有针对间皮素的抗体都是小鼠或嵌合的，这可能限制了它们的使用，因为与完全的人抗体相比，免疫原性的可能性增加了。在这里，我们报道了一种新的全人源单克隆抗体m912的鉴定和特性，该抗体是从人源Fab文库中分离出来的，通过筛选来对抗重组间皮素。该抗体具有scFv、Fab和IgG1格式，与细胞表面相关的人间皮素和重组间皮素具有高亲和力（平衡解离常数在nM范围内）。它特异性地裂解癌细胞，使其在从健康供者分离的外周血单个核细胞存在下表达间皮素，这很可能是通过抗体依赖性细胞毒性（ADCC）。M912是首个报道的针对间皮素的全人源单克隆抗体，具有治疗和诊断癌症的潜力
Mesothelin is a potential new target for cancer immunotherapy because it is present at relatively low levels only in mesothelial cells of pleura, peritoneum and pericardium of healthy people but is significantly elevated in a number of tumors, including mesothelioma, ovarian, pancreatic and lung cancers. However, all currently available antibodies against mesothelin are either murine or chimeric which could limit their use because of increased likelihood of immunogenicity compared to fully human antibodies. Here we report the identification and characterization of a novel fully human monoclonal antibody, m912, which was isolated from a human Fab library by panning against recombinant mesothelin. This antibody in scFv, Fab and IgG1 formats bound specifically and with high affinity (equilibrium dissociation constant in the nM range) to cell surface-associated human mesothelin and to recombinant mesothelin. It specifically lysed cancer cells engineered to express mesothelin in the presence of peripheral blood mononuclear cells isolated from healthy donors most likely by antibody-dependent cellular cytotoxicity (ADCC). M912 is the first reported fully human monoclonal antibody to mesothelin, which has potential for cancer treatment and diagnosis