抗体-药物偶联物
生长抑素
癌症研究
抗体
生长抑素受体2
医学
神经内分泌肿瘤
药理学
结合
生长抑素受体
体内
单克隆抗体
内科学
生物
免疫学
数学
数学分析
生物技术
作者
Yingnan Si,Seulhee Kim,Jianfa Ou,Yun Lü,Patrick Erñst,Kai Chen,Jason Whitt,Angela M. Carter,James M. Markert,James A. Bibb,Herbert Chen,Lufang Zhou,Renata Jaskula–Sztul,Margaret Liu
标识
DOI:10.1038/s41417-020-0196-5
摘要
Neuroendocrine (NE) tumors include a diverse spectrum of hormone-secreting neoplasms that arise from the endocrine and nervous systems. Current chemo- and radio-therapies have marginal curative benefits. The goal of this study was to develop an innovative antibody-drug conjugate (ADC) to effectively treat NE tumors (NETs). First, we confirmed that somatostatin receptor 2 (SSTR2) is an ideal cancer cell surface target by analyzing 38 patient-derived NET tissues, 33 normal organs, and three NET cell lines. Then, we developed a new monoclonal antibody (mAb, IgG1, and kappa) to target two extracellular domains of SSTR2, which showed strong and specific surface binding to NETs. The ADC was constructed by conjugating the anti-SSTR2 mAb and antimitotic monomethyl auristatin E. In vitro evaluations indicated that the ADC can effectively bind, internalize, release payload, and kill NET cells. Finally, the ADC was evaluated in vivo using a NET xenograft mouse model to assess cancer-specific targeting, tolerated dosage, pharmacokinetics, and antitumor efficacy. The anti-SSTR2 ADC exclusively targeted and killed NET cells with minimal toxicity and high stability in vivo. This study demonstrates that the anti-SSTR2 ADC has a high-therapeutic potential for NET therapy.
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