Antitumor effect of antitissue factor antibody‐MMAE conjugate in human pancreatic tumor xenografts

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.

Utility of epirubicin‐incorporating micelles tagged with anti‐tissue factor antibody clone with no anticoagulant effect

“…In contrast with results in oncology patients, hematuria was observed in 44% patients who were treated with anti‐TF antibody for acute respiratory distress syndrome in a phase 1 clinical trial . With regard to solid tumors, anticancer drugs conjugated with human TF antibody were developed in preclinical studies . Safety and toxicity concerns are currently under evaluation in the first in‐human clinical trial …”

“…(16) With regard to solid tumors, anticancer drugs conjugated with human TF antibody were developed in preclinical studies. (17,18) Safety and toxicity concerns are currently under evaluation in the first in-human clinical trial. (17) In conclusion, anti-TF1859-NC-6300 has a low risk of bleeding because of its low anticoagulant activity, and it has a potent antitumor effect in a human pancreatic cancer model, especially TF-high expressing tumors.…”

Emerging cancer-specific therapeutic aptamers

“…The highly potent anti-mitotic drugs, monomethyl auristatin E (MMAE) and maytansinoid (DM1), have both been investigated in several pre-clinical studies (19, 20). However, because of their high toxicity, neither MMAE nor DM1 can be used as cytotoxic drugs in their own right in clinic.…”

Aptamer-Drug Conjugates of Active Metabolites of Nucleoside Analogs and Cytotoxic Agents Inhibit Pancreatic Tumor Cell Growth

“…The relatively new agents monomethyl auristatin E (MMAE), a synthetic analog of the natural product dolastatin, 11 and the maytansinoid DM1, a derivative of maytansine, have both been investigated in several preclinical studies 12, 13. Both MMAE and DM1 are highly potent antimitotic drugs that bind to microtubules 14 .…”