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

• Published in: Cancer science 2016-03, Vol.107 (3), p.335-340
• Main Authors: Sugaya, Akinori, Hyodo, Ichinosuke, Koga, Yoshikatsu, Yamamoto, Yoshiyuki, Takashima, Hiroki, Sato, Ryuta, Tsumura, Ryo, Furuya, Fumiaki, Yasunaga, Masahiro, Harada, Mitsunori, Tanaka, Ryosuke, Matsumura, Yasuhiro
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - chemistry; Anticoagulants; Anticoagulants - administration & dosage; Anticoagulants - chemistry; Antigens; Antitumor activity; Blood Coagulation; Cell Line, Tumor; Chemistry, Pharmaceutical; Clinical trials; Cloning; Drug delivery system (DDS); Epirubicin; Epirubicin - administration & dosage; Epirubicin - chemistry; Female; Flow cytometry; Humans; Immunoglobulin Fab Fragments - administration & dosage; Immunoglobulin Fab Fragments - chemistry; Immunoglobulin G; Immunoglobulins; Inhibitory Concentration 50; Ligands; Mice, Inbred BALB C; Mice, Nude; Micelles; Nanoparticles; NC‐6300; Original; Pancreatic cancer; Particle Size; polymeric micelles; R&D; Research & development; Studies; Thromboplastin - immunology; Thromboplastin - metabolism; Tissue factor; tissue factor (TF); Tumor Burden - drug effects; Tumor cell lines; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.12863

Tissue factor (TF), an initiator of the extrinsic blood coagulation cascade, is overexpressed in different types of cancer. Tissue factor overexpression is also known as a poor prognostic factor in pancreatic cancer. We recently developed anti‐TF antibody (clone1849)‐conjugated epirubicin‐incorporating micelles (NC‐6300), and reported that this anti‐TF1849‐NC‐6300 showed enhanced antitumor activity against TF‐high expressed human pancreatic cancer cells, when compared with NC‐6300 alone. However, clone 1849 antibody inhibited TF‐associated blood coagulation activity. We studied another anti‐TF antibody, clone 1859, which had no effect on blood coagulation and prepared anti‐TF1859‐NC‐6300. In addition, to determine the optimum size of the antibody fragment to conjugate with NC‐6300, three forms of the 1859 antibody (whole IgG, F[ab’]2, and Fab’) were conjugated to NC‐6300. The antitumor effect of each anti‐TF1859‐NC‐6300 was studied in vitro and in vivo, using two human pancreatic cancer cell lines, BxPC3 with high‐expressed TF, and SUIT2 with low levels of TF. In vitro, all forms of anti‐TF1859‐NC‐6300 showed higher cytocidal effects than NC‐6300 in BxPC3, whereas this enhanced effect was not observed in SUIT2. Likewise, all forms of anti‐TF1859‐NC‐6300 significantly suppressed tumor growth when compared to NC‐6300 in the BxPC3, but not in the SUIT2, xenograft model. Among the three forms of conjugates, anti‐TF1859‐IgG‐NC‐6300 had a higher antitumor tendency in TF‐high expressed cells. Thus, we have confirmed an enhanced antitumor effect of anti‐TF1859‐NC‐6300 in a TF‐high expressing tumor; anti‐TF1859‐IgG‐NC‐6300 could be used to simplify the manufacturing process of the antibody–micelle conjugation for future clinical studies. We studied anti‐TF antibody, clone 1859, which had no effect on blood coagulation and prepared anti‐TF antibody (clone1859)‐conjugated epirubicin‐incorporating micelles (NC‐6300). In addition, to determine the optimum size of the antibody fragment to conjugate with NC‐6300, three forms of the 1859 antibody (whole IgG, F[ab’]2, and Fab’) were conjugated to NC‐6300. All three different forms of anti‐TF1859‐NC‐6300 as follows: (i) anti‐TF1859‐IgG‐; (ii) anti‐TF1859‐F(ab’)2‐; and (iii) anti‐TF1859‐Fab’‐NC‐6300 significantly suppressed tumor growth when compared to NC‐6300 in the xenograft model of TF‐high‐expressing human pancreatic cancer cell lines, BxPC3.