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- Title
Antitumor effect of antitissue factor antibody-MMAE conjugate in human pancreatic tumor xenografts.
- Authors
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
- Abstract
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.
- Publication
International Journal of Cancer, 2015, Vol 137, Issue 6, p1457
- ISSN
0020-7136
- Publication type
Article
- DOI
10.1002/ijc.29492