A bivalent single-chain Fv fragment against CD47 induces apoptosis for leukemic cells |
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Authors: | Kikuchi Yasufumi Uno Shinsuke Yoshimura Yasushi Otabe Koji Iida Shin-ichiro Oheda Masayoshi Fukushima Naoshi Tsuchiya Masayuki |
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Institution: | Chugai Pharmaceutical Co., Ltd., Fuji-Gotemba Research Laboratories, 1-135 Komakado, Gotemba-shi, Shizuoka-ken 412-8513, Japan. kikuchiysf@chugai-pharm.co.jp |
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Abstract: | We constructed a single-chain antibody fragment (scFv) of murine monoclonal antibody, MABL, which specifically bound to human CD47 (hCD47) and induced apoptosis of the leukemic cells. The scFv of MABL antibody with a 15-residue linker (MABL scFv-15) formed both dimer (Mr 50 kDa) and monomer (Mr 25 kDa). Both MABL scFv-15 dimer and monomer had binding activity for hCD47. MABL scFv-15 dimer strongly induced apoptosis of hCD47-introduced mouse leukemic cells in vitro and exhibited anti-tumor effect in a myeloma transplanted mice model. However, MABL scFv-15 monomer scarcely exhibited these activities. These results strongly demonstrate that the ligation of CD47 antigen by two antigen-binding sites of MABL dimer is needed for inducing apoptosis. The parent MABL antibody caused hemagglutination due to the CD47 expressed on erythrocytes. Interestingly, MABL scFv-15 dimer did not cause hemagglutination. This apoptosis-inducing dimer appears to be a lead candidate for novel leukemic therapy. |
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Keywords: | Agonist antibody scFv CD47 Apoptosis Leukemia |
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