文章：

抗SSTR2抗体-药物偶联物治疗神经内分泌肿瘤

Anti-SSTR2 antibody-drug conjugate for neuroendocrine tumor therapy 

原文发布日期：2020-07-20 

英文摘要：

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. 

摘要翻译： 

神经内分泌（NE）肿瘤是一类起源于内分泌与神经系统的异质性激素分泌性肿瘤群。当前化疗与放疗方案的治愈效果有限。本研究旨在开发一种创新型抗体-药物偶联物（ADC），用于有效治疗神经内分泌肿瘤（NETs）。首先，我们通过分析38例NET患者来源的组织样本、33个正常器官及三种NET细胞系，证实生长抑素受体2（SSTR2）是理想的癌细胞表面靶点。随后研制出一种新型单克隆抗体（mAb，IgG1κ亚型），该抗体靶向SSTR2的两个胞外结构域，并显示出对NET细胞强效特异的表面结合能力。通过将抗SSTR2单抗与抗有丝分裂单甲基奥瑞他汀E进行偶联，成功构建ADC分子。体外实验表明，该ADC能有效结合并内化至NET细胞、释放有效载荷并杀伤肿瘤细胞。最后采用NET异种移植小鼠模型进行体内评估，检测其癌症特异性靶向能力、耐受剂量、药代动力学特征及抗肿瘤功效。该抗SSTR2-ADC在体内能特异性靶向并杀伤NET细胞，同时具有低毒性和高稳定性的特点。本研究证实抗SSTR2-ADC在NET治疗领域具有极高的临床应用潜力。

原文链接：

Anti-SSTR2 antibody-drug conjugate for neuroendocrine tumor therapy