Therapeutic potential of an anti-HER2 single chain antibody-DM1 conjugates for the treatment of HER2-positive cancer.
Therapeutic potential of an anti-HER2 single chain antibody-DM1 conjugates for the treatment of HER2-positive cancer.
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抗 HER2 单链抗体与 DM1 缀合物治疗 HER2 阳性癌症的治疗潜力
DOI：
10.1038/sigtrans.2017.15
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发表时间：
2017
影响因子：
39.3
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Zhang H;Wang Y;Wu Y;Jiang X;Tao Y;Yao Y;Peng Y;Chen X;Fu Y;Yu L;Wang R;Lai Q;Lai W;Li W;Kang Y;Yi S;Lu Y;Gou L;Wu M;Yang J
抗体-药物偶联物（Antibody-drug conjugates，ADC）利用单克隆抗体的优势，选择性地将高效细胞毒药物递送至肿瘤细胞，近年来已成为肿瘤治疗的有力手段。为了开发用于人表皮生长因子受体2（HER 2）阳性癌症的更有效的疗法，我们探索了由抗HER 2 scFv-HSA融合抗体缀合物与强效细胞毒性药物DM 1组成的新型ADC。所得到的ADC T-SA 1-DM 1和T-SA 2-DM 1（药物与抗体的比例在3.2-3.5的范围内）在体外显示出对HER 2阳性肿瘤细胞系的生长的有效抑制，并且对SKBR-3和SKOV 3细胞的半最大抑制浓度均在纳摩尔水平。在HER 2阳性人卵巢癌异种移植模型中，T-SA 1-DM 1和T-SA 2-DM 1也显示出显著的抗肿瘤活性。重要的是，在T-SA 1-DM 1高剂量组中，6只小鼠中有3只表现出完全缓解，没有再生长。在发光成像分析的基础上，与曲妥珠单抗相比，抗HER 2 scFv-HSA融合抗体，尤其是T-SA 1，显示出强且快速的肿瘤组织穿透性和分布。总的来说，新型ADC对HER 2阳性癌症是有效和选择性的靶向，并且可能是进一步研究的有希望的抗肿瘤药物候选物。
Antibody–drug conjugates (ADCs) take the advantage of monoclonal antibodies to selectively deliver highly potent cytotoxic drugs to tumor cells, which have become a powerful measure for cancer treatment in recent years. To develop a more effective therapy for human epidermal growth factor receptor 2 (HER2)-positive cancer, we explored a novel ADCs composed of anti-HER2 scFv–HSA fusion antibodies conjugates with a potent cytotoxic drug DM1. The resulting ADCs, T-SA1–DM1 and T-SA2–DM1 (drug-to-antibody ratio in the range of 3.2–3.5) displayed efficient inhibition in the growth of HER2-positive tumor cell lines and the half-maximal inhibitory concentration on SKBR-3 and SKOV3 cells were both at the nanomolar levels in vitro. In HER2-positive human ovarian cancer xenograft models, T-SA1–DM1 and T-SA2–DM1 also showed remarkable antitumor activity. Importantly, three out of six mice exhibited complete remission without regrowth in the high-dose group of T-SA1–DM1. On the basis of the analysis of luminescence imaging, anti-HER2 scFv–HSA fusion antibodies, especially T-SA1, showed strong and rapid tumor tissue penetrability and distribution compared with trastuzumab. Collectively, the novel type of ADCs is effective and selective targeting to HER2-positive cancer, and may be a promising antitumor drug candidate for further studies.
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影响因子：
11.2
作者：
Erickson, HK;Park, PU;Blättler, WA
通讯作者：
Blättler, WA
影响因子：
5.7
作者：
Cao, Yu;Marks, James D.;Rosenblum, Michael G.
通讯作者：
Rosenblum, Michael G.
影响因子：
11.2
作者：
Cai Z;Fu T;Nagai Y;Lam L;Yee M;Zhu Z;Zhang H
通讯作者：
Zhang H
影响因子：
8
作者：
Cao Y;Marks JW;Liu Z;Cheung LH;Hittelman WN;Rosenblum MG
通讯作者：
Rosenblum MG
影响因子：
3.5
作者：
Arndt, MAE;Krauss, R;Rybak, SM
通讯作者：
Rybak, SM