Antitumor effect of antitissue factor antibody-MMAE conjugate in human pancreatic tumor xenografts.
Antitumor effect of antitissue factor antibody-MMAE conjugate in human pancreatic tumor xenografts.
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DOI：
10.1002/ijc.29492
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发表时间：
2015-09-15
影响因子：
6.4
通讯作者：
Matsumura, Yasuhiro
中科院分区：
文献类型：
--
作者：
Koga, Yoshikatsu;Manabe, Shino;Aihara, Yoshiyuki;Sato, Ryuta;Tsumura, Ryo;Iwafuji, Hikaru;Furuya, Fumiaki;Fuchigami, Hirobumi;Fujiwara, Yuki;Hisada, Yohei;Yamamoto, Yoshiyuki;Yasunaga, Masahiro;Matsumura, Yasuhiro
组织因子（TF）触发外源性凝血级联反应，并在各种类型的癌症中高度表达。在这项研究中，我们研究了由抗TF单克隆抗体和单甲基澳瑞他汀E（MMAE）组成的抗体-药物偶联物（ADC）的抗肿瘤作用。使用缬氨酸-瓜氨酸接头将MMAE与抗人TF或抗小鼠TF抗体偶联，该接头可能在溶酶体的酸性环境中被组织蛋白酶B水解。分析ADC对四种胰腺癌细胞系的细胞毒性和抗肿瘤作用。具有抗人TF抗体的ADC和具有抗小鼠TF抗体的ADC在生理条件下均稳定。抗人ADC在表达TF的人肿瘤细胞系中内化，随后有效释放MMAE。对于所用的所有细胞系，MMAE的半数最大抑制浓度（IC 50）约为1 nM。同时，在显示高TF表达的细胞系中，抗人ADC的IC 50为1.15 nM，而在显示低TF表达水平的细胞中超过100 nM。与盐水组中观察到的相比，具有被动和主动靶向能力的抗人ADC对肿瘤生长产生显著抑制（p < 0.01）。由于EPR效应，与盐水组相比，在抗小鼠ADC和对照ADC组中还观察到显著的肿瘤生长抑制（p < 0.01）。由于各种临床人类癌症表达高量的TF，这种新的抗TF ADC可能值得临床评估。有什么新消息吗？组织因子（TF）触发正常的血液凝固，并且在各种类型的肿瘤中也高度表达，包括胰腺癌、恶性胶质瘤和胃癌。在这项研究中，作者开发了一种新的抗体药物偶联物（ADC），由抗TF单克隆抗体与单甲基澳瑞他汀E（MMAE）连接组成。ADC选择性地在肿瘤内积累，并在体内引起肿瘤生长的显著抑制。因为它通过渗漏的血管系统穿透肿瘤，但太大而不能穿过正常血管壁，所以这种ADC可能提供有希望的治疗策略。
Tissue factor (TF) triggers the extrinsic blood coagulation cascade and is highly expressed in various types of cancer. In this study, we investigated the antitumor effect of an antibody–drug conjugate (ADC) consisting of an anti‐TF monoclonal antibody and monomethyl auristatin E (MMAE). MMAE was conjugated to an anti‐human TF or anti‐mouse TF antibody using a valine‐citrulline linker that could be potentially hydrolyzed by cathepsin B in the acidic environment of the lysosome. The cytotoxic and antitumor effects of the ADCs against four pancreatic cancer cell lines were analyzed. Both the ADC with the anti‐human TF antibody and that with the anti‐mouse TF antibody were stable under physiological conditions. The anti‐human ADC was internalized in TF‐expressing human tumor cell lines, followed by effective MMAE release. The half maximal inhibitory concentration (IC50) of MMAE was approximately 1 nM for all of the cell lines used. Meanwhile, the IC50 of anti‐human ADC was 1.15 nM in the cell lines showing high TF expression, while exceeding 100 nM in the cells showing low TF expression levels. Anti‐human ADC with passive and active targeting ability exerted significant suppression of tumor growth as compared to that observed in the saline group (p < 0.01). Also significant tumor growth suppressions were seen at the anti‐mouse ADC and control ADC groups compared to the saline group (p < 0.01) due to EPR effect. Because various clinical human cancers express highly amount of TF, this new anti‐TF ADC may deserve a clinical evaluation. What's new? Tissue factor (TF) triggers normal blood coagulation, and is also highly expressed in various types of tumor, including pancreatic, malignant glioma, and gastric cancer. In this study, the authors developed a new antibody‐drug conjugate (ADC) consisting of an anti‐TF monoclonal antibody linked to monomethyl auristatin E (MMAE). The ADC accumulated selectively within tumors, and caused significant suppression of tumor growth in vivo. Because it penetrates tumors via their leaky vasculature, but is too large to pass through normal vessel walls, this ADC may provide a promising therapeutic strategy.
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影响因子：
11.5
作者：
Teicher, Beverly A.;Chari, Ravi V. J.
通讯作者：
Chari, Ravi V. J.
影响因子：
11.2
作者：
Breij, Esther C. W.;de Goeij, Bart E. C. G.;Parren, Paul W. H. I.
通讯作者：
Parren, Paul W. H. I.
影响因子：
8.4
作者：
Saito, Yohei;Hashimoto, Yuki;Matsumura, Yasuhiro
通讯作者：
Matsumura, Yasuhiro
影响因子：
45.3
作者：
Cunningham, David;Chau, Ian;Neoptolemos, John P.
通讯作者：
Neoptolemos, John P.
影响因子：
254.7
作者：
Siegel, Rebecca;Naishadham, Deepa;Jemal, Ahmedin
通讯作者：
Jemal, Ahmedin