title: Enhanced antitumor effect of anti-tissue factor antibody-conjugated epirubicin-incorporating micelles in xenograft models.
abstract: For the creation of a successful antibody-drug conjugate (ADC), both scientific and clinical evidence has indicated that highly toxic anticancer agents (ACA) should be conjugated to a monoclonal antibody (mAb) to administer a reasonable amount of ADC to patients without compromising the affinity of the mAb. For ordinary ACA, the conjugation of a mAb to ACA-loaded micellar nanoparticles is clinically applicable. Tissue factor (TF) is often overexpressed in various cancer cells and tumor vascular endothelium. Accordingly, anti-TF-NC-6300, consisting of epirubicin-incorporating micelles (NC-6300) conjugated with the F(ab')2 of anti-TF mAb was developed. The in vitro and in vivo efficacy and pharmacokinetics of anti-TF-NC-6300 were compared to NC-6300 using two human pancreatic cancer cell lines, BxPC3 (high TF expression) and SUIT2 (low TF expression), and a gastric cancer cell line, 44As3 (high TF expression). The intracellular uptake of epirubicin was faster and greater in BxPC3 cells treated with anti-TF-NC-6300, compared with NC-6300. Anti-TF-NC-6300 showed a superior antitumor activity in BxPC3 and 44As3 xenografts, compared with NC-6300, while the activities of both micelles were similar in the SUIT2 xenograft. A higher tumor accumulation of anti-TF-NC-6300 compared to NC-6300 was seen, regardless of the TF expression levels. However, anti-TF-NC-6300 appeared to be localized to the tumor cells with high TF expression. These results indicated that the enhanced antitumor effect of anti-TF-NC6300 may be independent of the tumor accumulation but may depend on the selective intratumor localization and the preferential internalization of anti-TF-NC-6300 into high TF tumor cells.
authors.affiliation: Division of Developmental Therapeutics, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.|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: 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, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Koga
authors.affiliation: Division of Developmental Therapeutics, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Tsumura
authors.affiliation: Division of Developmental Therapeutics, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Sato
authors.affiliation: Division of Developmental Therapeutics, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Toshihumi
authors.initials: T
authors.lastname: Obonai
authors.affiliation: Division of Developmental Therapeutics, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Fuchigami
authors.affiliation: Division of Developmental Therapeutics, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Furuya
authors.affiliation: Division of Developmental Therapeutics, Research Center for Innovative Oncology, National Cancer Center Hospital East, 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: Yasuki
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
authors.affiliation: Division of Developmental Therapeutics, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D015251:Epirubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000378:metabolism / Q000494:pharmacology*; D008807:Mice, Inbred BALB C; D008823:Micelles; D013925:Thromboplastin / Q000276:immunology; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D008823:Micelles; D015251:Epirubicin; D013925:Thromboplastin
keywords: Antibody drug conjugate; drug delivery system; epirubicin; polymeric micelles; tissue factor