An antibody-drug conjugate targeting a GSTA glycosite-signature epitope of MUC1 expressed by non-small cell lung cancer
文献类型：期刊论文
| 作者 | Pan, Deng1,2; Tang, Yubo3; Tong, Jiao1; Xie, Chengmei1; Chen, Jiaxi1; Feng, Chunchao1; Hwu, Patrick4; Huang, Wei3; Zhou, Dapeng1,2 |
| 刊名 | CANCER MEDICINE
 |
| 出版日期 | 2020-10-20 |
| 页码 | 12 |
| ISSN号 | 2045-7634 |
| DOI | 10.1002/cam4.3554 |
| 通讯作者 | Zhou, Dapeng(dapengzhoulab@tongji.edu.cn) |
| 英文摘要 | Antibodies targeting aberrantly glycosylated proteins are ineffective in treating cancer. Antibody-drug conjugates have emerged as effective alternatives, facilitating tumor-specific drug delivery. Previous studies have assessed the aberrantly glycosylated tandem repeat region of MUC1 glycoprotein as three site-specific glycosylated neoantigen peptide motifs (PDTR, GSTA, and GVTS) for binding with a monoclonal antibody. This study aimed to develop an antibody-drug conjugate for cancer treatment based on monoclonal antibodies against the aforementioned three neoantigen peptide motifs. Internalization of monoclonal antibodies was assessed via immunofluorescence staining and colocalization with lysosomal markers in live cells. Antibody positivity in tumor and peritumoral tissue samples was assessed via immunohistochemistry. The efficacy of anti-MUC1 ADCs was evaluated using various cancer cell lines and a mouse tumor xenograft model. An anti-MUC1 ADC was synthesized by conjugating GSTA neoantigen-specific 16A with monomethyl auristatin E (MMAE), which displayed potent antitumoral efficacy with an IC(50)ranging 0.2-49.4 nM toward various cancer cells. In vivo, 16A-MMAE inhibited tumor growth in a dose-dependent manner in a mouse xenograft model established using the NCI-H838 NSCLC cell line, at a minimum effective dose of 1 mg/kg. At 3 mg/kg, 16A-MMAE did not cause significant toxicity in a transgenic mouse expressing human MUC1. The high antitumoral efficacy of 16A-MMAE suggests that aberrant glycosylated MUC1 neoantigen is a potential target for the development of ADCs for treating various cancers. Personalized therapy may be achieved through such glycosite-specific ADCs. |
| WOS关键词 | TRASTUZUMAB EMTANSINE ; ANTITUMOR-ACTIVITY ; ADVANCED BREAST ; OVARIAN ; TUMOR ; AUTOANTIBODIES ; GLYCOPEPTIDES ; GLYCOPROTEIN ; VALIDATION ; THERAPY |
| 资助项目 | Outstanding Clinical Discipline Project of Shanghai Pudong[PWYgy2018-10] ; Fundamental Research Funds for Central Universities[22120200163] ; National Key Research and Development Plan grant[2017YFA0505901] ; National Natural Science Foundation of China[31870972] |
| WOS研究方向 | Oncology |
| 语种 | 英语 |
| WOS记录号 | WOS:000579635600001 |
| 出版者 | WILEY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/291441]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Zhou, Dapeng |
| 作者单位 | 1.Tongji Univ, Sch Med, Shanghai, Peoples R China 2.Tongji Univ, Sch Med, Shanghai Pudong New Area Mental Hlth Ctr, Shanghai, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Ctr Excellence Mol Cell Sci, CAS Key Lab Receptor Res, Shanghai, Peoples R China 4.Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA |
| 推荐引用方式 GB/T 7714 | Pan, Deng,Tang, Yubo,Tong, Jiao,et al. An antibody-drug conjugate targeting a GSTA glycosite-signature epitope of MUC1 expressed by non-small cell lung cancer[J]. CANCER MEDICINE,2020:12. |
| APA | Pan, Deng.,Tang, Yubo.,Tong, Jiao.,Xie, Chengmei.,Chen, Jiaxi.,...&Zhou, Dapeng.(2020).An antibody-drug conjugate targeting a GSTA glycosite-signature epitope of MUC1 expressed by non-small cell lung cancer.CANCER MEDICINE,12. |
| MLA | Pan, Deng,et al."An antibody-drug conjugate targeting a GSTA glycosite-signature epitope of MUC1 expressed by non-small cell lung cancer".CANCER MEDICINE (2020):12. |
入库方式： OAI收割
来源：上海药物研究所
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