title: Antitumor activity of a monoclonal antibody against CD47 in xenograft models of human leukemia.
abstract: The ligation of CD47 induces the apoptosis of leukemic cells in a caspase-independent manner. We generated a monoclonal antibody against CD47 (mAb-MABL) that possibly induced apoptosis from the ligation of CD47 in CCRF-CEM and JOK-1 cells in vitro. To confirm whether the ligation of CD47 caused cell death in vivo, we examined the antitumor activity of F(ab')2 of mAb-MABL in two xenograft models: The acute lymphoblastic leukemia (CCRF-CEM) and the B-cell chronic lymphocytic leukemia (JOK-1) cell line. Furthermore, in order to clarify the apoptotic activity selective for the tumor cells, we examined F(ab')2 of mAb-MABL apoptotic effects on CD34+ hematopoietic progenitor/stem and human endothelial cells. Male SCID mice were intravenously injected with CCRF-CEM (5 x 10(6) cells/mouse) or JOK-1 cells (5 x 10(6) cells/mouse) and intraperitoneally with JOK-1 cells (2 x 10(7) cells/mice). After the implantation of the cells, the mice were intravenously administered the vehicle or the F(ab')2 fragment of mAb-MABL at several doses and the length of survival was measured. F(ab')2 of mAb-MABL markedly prolonged the survival of mice transplanted with CCRF-CEM and JOK-1. Significantly, 40% of the mice intraperitoneally injected with JOK-1 cells became tumor-free when administered F(ab')2 of mAb-MABL, whereas even a high dose of fludarabine only slightly prolonged the median survival time. On the contrary, F(ab')2 of mAb-MABL showed no apoptotic effect on CD34+ hematopoietic progenitor/stem or human endothelial cells. Thus, monoclonal antibodies that cause cell death from the ligation of CD47 could be novel therapeutic agents for incurable leukemia after further optimization such as humanization or making single chain diabodies.
authors: Fuji-Gotemba Research Labs, Chugai Pharmaceutical Co., Ltd., Shizuoka 412-8513, Japan.
authors: Shinsuke
authors: S
authors: Uno
authors: Yasuko
authors: Y
authors: Kinoshita
authors: Yumiko
authors: Y
authors: Azuma
authors: Toshiaki
authors: T
authors: Tsunenari
authors: Yasushi
authors: Y
authors: Yoshimura
authors: Shinichiro
authors: S
authors: Iida
authors: Yasufumi
authors: Y
authors: Kikuchi
authors: Hisafumi
authors: H
authors: Yamada-Okabe
authors: Naoshi
authors: N
authors: Fukushima
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051928:CD47 Antigen / Q000276:immunology*; D045744:Cell Line, Tumor; D006801:Humans; D007939:Leukemia L1210; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D051928:CD47 Antigen