Anti-glypican-1 antibody-drug conjugate is a potential therapy against pancreatic cancer.,British Journal of Cancer

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Anti-glypican-1 antibody-drug conjugate is a potential therapy against pancreatic cancer.
British Journal of Cancer ( IF 6.4 ) Pub Date : 2020-03-10 , DOI: 10.1038/s41416-020-0781-2
Takahiko Nishigaki _{1,

2} , Tsuyoshi Takahashi ₁ , Satoshi Serada _{2,

3} , Minoru Fujimoto _{2,

3} , Tomoharu Ohkawara _{2,

3} , Hisashi Hara _{1,

2} , Takahito Sugase _{1,

2,

3} , Toru Otsuru _{1,

2} , Yurina Saito _{1,

2} , Shigehiro Tsujii ₄ , Taisei Nomura ₅ , Koji Tanaka ₁ , Yasuhiro Miyazaki ₁ , Tomoki Makino ₁ , Yukinori Kurokawa ₁ , Kiyokazu Nakajima ₁ , Hidetoshi Eguchi ₁ , Makoto Yamasaki ₁ , Masaki Mori ₆ , Yuichiro Doki ₁ , Tetsuji Naka _{2,

3}

Affiliation

BACKGROUND Pancreatic cancer (PDAC) is the most lethal malignancy. New treatment options for it are urgently required. The aim was to develop an antibody-drug conjugate (ADC) targeting glypican-1 (GPC-1) as a new therapy for PDAC. METHODS We evaluated GPC-1 expression in resected PDAC specimens and PDAC cell lines. We then measured the antitumour effect of anti-GPC-1 monoclonal antibody conjugated with the cytotoxic agent monomethyl auristatin F (MMAF) in vitro and in vivo. RESULTS GPC-1 was overexpressed in most primary PDAC cells and tissues. The PDAC cell lines BxPC-3 and T3M-4 strongly expressed GPC-1 relative to SUIT-2 cells. Compared with control ADC, GPC-1-ADC showed a potent antitumour effect against BxPC-3 and T3M-4, but little activity against SUIT-2 cells. In the xenograft and patient-derived tumour models, GPC-1-ADC significantly and potently inhibited tumour growth in a dose-dependent manner. GPC-1-ADC-mediated G2/M-phase cell cycle arrest was detected in the tumour tissues of GPC-1-ADC-treated mice relative to those of control-ADC-treated mice. CONCLUSIONS GPC-1-ADC showed significant tumour growth inhibition against GPC-1-positive pancreatic cell lines and patient-derived, GPC-1-positive pancreatic cancer tissues. Our preclinical data demonstrated that targeting GPC-1 with ADC is a promising therapy for patients with GPC-1-positive pancreatic cancer.

中文翻译：

抗glypican-1抗体-药物偶联物是抗胰腺癌的潜在疗法。

背景技术胰腺癌（PDAC）是最致命的恶性肿瘤。迫切需要新的治疗方法。目的是开发针对Glypican-1（GPC-1）的抗体-药物偶联物（ADC），作为PDAC的新疗法。方法我们评估了切除的PDAC标本和PDAC细胞系中GPC-1的表达。然后，我们在体外和体内测量了与细胞毒剂单甲基澳瑞他汀F（MMAF）偶联的抗GPC-1单克隆抗体的抗肿瘤作用。结果GPC-1在大多数原代PDAC细胞和组织中过表达。相对于SUIT-2细胞，PDAC细胞系BxPC-3和T3M-4强烈表达GPC-1。与对照ADC相比，GPC-1-ADC对BxPC-3和T3M-4具有有效的抗肿瘤作用，但对SUIT-2细胞几乎没有活性。在异种移植和患者来源的肿瘤模型中，GPC-1-ADC以剂量依赖的方式显着有效地抑制了肿瘤的生长。相对于对照ADC处理的小鼠，在GPC-1-ADC处理的小鼠的肿瘤组织中检测到GPC-1-ADC介导的G2 / M期细胞周期停滞。结论GPC-1-ADC对GPC-1阳性胰腺细胞系和患者来源的GPC-1阳性胰腺癌组织具有显着的肿瘤生长抑制作用。我们的临床前数据表明，针对GPC-1阳性胰腺癌患者，ADC靶向GPC-1是一种有前途的疗法。结论GPC-1-ADC对GPC-1阳性胰腺细胞系和患者来源的GPC-1阳性胰腺癌组织具有显着的肿瘤生长抑制作用。我们的临床前数据表明，针对GPC-1阳性胰腺癌患者，ADC靶向GPC-1是一种有前途的疗法。结论GPC-1-ADC对GPC-1阳性胰腺细胞系和患者来源的GPC-1阳性胰腺癌组织具有显着的肿瘤生长抑制作用。我们的临床前数据表明，针对GPC-1阳性胰腺癌患者，ADC靶向GPC-1是一种有前途的疗法。

更新日期：2020-03-10

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