title: Utility of epirubicin-incorporating micelles tagged with anti-tissue factor antibody clone with no anticoagulant effect.
abstract: 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.
authors.affiliation: Division of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.|Department of Gastroenterology and Hepatology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Sugaya
authors.affiliation: Department of Gastroenterology and Hepatology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Ichinosuke
authors.initials: I
authors.lastname: Hyodo
authors.affiliation: Division of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Koga
authors.affiliation: Department of Gastroenterology and Hepatology, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Division of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takashima
authors.affiliation: Division of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Sato
authors.affiliation: Division of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Tsumura
authors.affiliation: Division of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Furuya
authors.affiliation: Division of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yasunaga
authors.affiliation: Research Division, NanoCarrier Co., Ltd, Kashiwa, Japan.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Harada
authors.affiliation: Research Division, NanoCarrier Co., Ltd, Kashiwa, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Tanaka
authors.affiliation: Division of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D000925:Anticoagulants / Q000008:administration & dosage* / Q000737:chemistry; D001777:Blood Coagulation; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D015251:Epirubicin / Q000008:administration & dosage* / Q000737:chemistry; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage* / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D010316:Particle Size; D013925:Thromboplastin / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D000925:Anticoagulants; D007140:Immunoglobulin Fab Fragments; D008823:Micelles; D015251:Epirubicin; D013925:Thromboplastin
keywords: Drug delivery system (DDS); NC-6300; epirubicin; polymeric micelles; tissue factor (TF)