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A peptide inhibitor of antibody-dependent cell-mediated cytotoxicity against EGFR/folate receptor-α double positive cells†
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2018-02-26 00:00:00 , DOI: 10.1039/c8md00010g
Koichi Sasaki 1, 2, 3, 4, 5 , Yoshiki Miyashita 1, 2, 3, 4, 5 , Daisuke Asai 5, 6, 7, 8 , Daiki Funamoto 1, 2, 3, 4, 5 , Kazuki Sato 4, 5, 9, 10 , Yoko Yamaguchi 4, 5, 9, 10 , Yuji Mishima 5, 11, 12, 13, 14 , Tadafumi Iino 3, 4, 5, 15 , Shigeo Takaishi 3, 4, 5, 15 , Jun Nagano 3, 4, 5, 16 , Akihiro Kishimura 1, 2, 3, 4, 5 , Takeshi Mori 1, 2, 3, 4, 5 , Yoshiki Katayama 1, 2, 3, 4, 5
Affiliation  

Antibody-dependent cell-mediated cytotoxicity (ADCC) is caused by natural killer (NK) cells upon recognition of antigen-bound IgG via FcγRIIIa. This mechanism is crucial for cytolysis of pathogen-infected cells and monoclonal antibody (mAb)-mediated elimination of cancer cells. However, there is concern that mAb-based cancer therapy induces ADCC against non-target cells expressing antigens. To date, no strategy has been reported to enhance the selectivity of ADCC to protect non-target cells expressing antigens. Here, we introduce a model inhibitor which specifically blocks ADCC of anti-EGFR mAbs towards EGFR/folate receptor α (FRα) double positive cells. This inhibitor recruits mAbs on the FRα of the cell surface independent of Fab antigen recognition. The resulting ternary and/or quaternary complexes formed on the cell surface suppress signal transduction of FcγRIIIa in NK cells, consequently leading to more specific ADCC.

中文翻译:

一种针对EGFR /叶酸受体-α双阳性细胞的抗体依赖性细胞介导的细胞毒性肽抑制剂

抗体依赖性细胞介导的细胞毒性(ADCC)是通过自然杀伤引起的(NK)当识别抗原结合的IgG的细胞通过FcγRIIIa。该机制对于病原体感染细胞的细胞溶解以及单克隆抗体(mAb)介导的癌细胞消除至关重要。但是,基于mAb的癌症治疗引起针对表达抗原的非靶细胞的ADCC的关注。迄今为止,还没有任何报道可以增强ADCC的选择性来保护表达抗原的非靶细胞的策略。在这里,我们介绍了一种模型抑制剂,该抑制剂可特异性阻断针对EGFR /叶酸受体α(FRα)双阳性细胞的抗EGFR mAb的ADCC。该抑制剂在细胞表面的FRα上募集mAb,与Fab抗原识别无关。在细胞表面上形成的三元和/或四元复合物抑制了NK细胞中FcγRIIIa的信号转导,因此导致了更特异性的ADCC。
更新日期:2018-02-26
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