Anti-HER2 antibody therapy using gene-transduced adipocytes for HER2-positive breast cancer
Anti-HER2 antibody therapy using gene-transduced adipocytes for HER2-positive breast cancer
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使用基因转导脂肪细胞的抗 HER2 抗体疗法治疗 HER2 阳性乳腺癌
DOI：
10.1007/s10549-020-05581-x
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发表时间：
2020
影响因子：
3.8
通讯作者：
Masayuki Ohtsuka
中科院分区：
文献类型：
--
作者：
Takahito Masuda;Hiroshi Fujimoto;Ryotaro Teranaka;Masayuki Kuroda;Yasuyuki;Aoyagi;Takeshi Nagashima;Takafumi Sangai;Mamoru Takada;Ayako;Nakagawa;Yoshitaka Kubota;Koutaro Yokote;Masayuki Ohtsuka
目的虽然分子靶向治疗的最新进展提高了乳腺癌患者的生存率，但高昂的费用和频繁的住院治疗给社会和个人带来了负担。为了减少这些问题，有人提出在体内产生抗体。在这里，我们构建了分泌抗her2抗体（her2 - ccdpa）的基因转导的人天花板培养来源的增生性脂肪细胞，并评估了它们分泌抗体和介导抗肿瘤作用的能力。方法利用splasmid慢病毒作为抗her2抗体cDNA的受体，转染人增生性脂肪细胞。ELISA和western blot检测分泌抗体的表达。免疫荧光法检测分泌抗体对HER2的特异性结合。用BT474 （HER2+）和MDA-MB-231 （HER2−）乳腺癌细胞系评价了HER2- ccdpa上清液的直接和间接抗肿瘤作用。此外，利用不同细胞成熟状态收集的上清，研究脂肪细胞分化是否影响抗体分泌。结果在her2 - ccdpa细胞上清液中检测到抗her2抗体，并随着向成熟脂肪细胞的分化而增加。her2 - ccdpa上清液中的抗体与her2阳性乳腺癌细胞结合，类似于曲妥珠单抗。HER2-ccdPAs上清液抑制了BT474细胞的增殖，但抑制了MDA-MB-231细胞的增殖，与对照组相比，下调了BT474细胞中AKT的磷酸化水平。her2 - ccdpa的上清液也通过ADCC对BT474细胞具有间接的抗肿瘤作用。此外，单次接种HER2-ccdPAs在BT474异种移植瘤模型中显示出抗肿瘤作用。结论sher2 - ccdpa可能用于细胞基因治疗。该系统可作为多种抗体治疗的平台。
PurposeAlthough recent advances in molecular target therapy have improved the survival of breast cancer patients, high cost and frequent hospital visits result in both societal and individual burden. To reduce these problems, it has been proposed to produce antibodies in vivo. Here, we constructed gene-transduced human ceiling culture-derived proliferative adipocytes secreting anti-HER2 antibody (HER2-ccdPAs) and evaluated their ability to secrete antibody and mediate an anti-tumor effect.MethodsPlasmid lentivirus was used as a recipient for anti-HER2 antibody cDNA and transduced into human proliferative adipocyte. Secretory antibody expression was evaluated by ELISA and western blot. Specific binding of secretory antibody to HER2 was examined by immunofluorescence analysis. Direct and indirect anti-tumor effects of supernatants from HER2-ccdPAs were evaluated using BT474 (HER2+) and MDA-MB-231 (HER2−) breast cancer cell lines. Additionally, whether adipocyte differentiation affects antibody secretion was investigated using supernatant collected from different cell maturation states.ResultsAnti-HER2 antibody was identified in the supernatant from HER2-ccdPAs and its production increased with the differentiation into mature adipocyte. Antibodies in supernatants from HER2-ccdPAs bound to HER2-positive breast cancer cells similar to trastuzumab. Supernatant from HER2-ccdPAs inhibited the proliferation of BT474 but not MDA-MB-231 cells, and downregulated AKT phosphorylation in BT474 cells compared with controls. Supernatants from HER2-ccdPAs also had an indirect anti-tumor effect on BT474 cells through ADCC. Additionally, Single inoculation of HER2-ccdPAs showed an anti-tumor effect in BT474 xenograft model.ConclusionsHER2-ccdPAs might be useful for cell-based gene therapy. This system could be a platform for various antibody therapies.
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影响因子：
5.4
作者：
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通讯作者：
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影响因子：
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通讯作者：
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作者：
von Minckwitz, Gunter;Schweller, Kathrin;Loibl, Sibylle
通讯作者：
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