title: MT95-4, a fully humanized antibody raised against aminopeptidase N, reduces tumor progression in a mouse model.
abstract: Aminopeptidase N (APN/CD13) is involved in tumor cell invasion and tumor angiogenesis and is considered a promising therapeutic target in the treatment of cancer. To develop a novel monoclonal antibody-based cancer therapy targeting APN/CD13, we established a fully humanized anti-APN/CD13 monoclonal antibody, MT95-4. In vitro, MT95-4 inhibited APN/CD13 enzymatic activity on the tumor cell surface and blocked tumor cell invasion. B16 mouse melanoma cells stably expressing human APN/CD13 were also established and were inoculated s.c. or injected i.v. into nude mice. We found that expression of human APN/CD13 in murine melanoma cells increased the size of subcutaneous tumors, extent of lung metastasis and degree of angiogenesis in the subcutaneous tumors; these tumor-promoting and angiogenesis-promoting characteristics were reduced by the i.p. administration of MT95-4. To further verify the specificity of MT95-4 for neutralization of APN/CD13 activity, MT95-4 was administered into NOD/SCID mice inoculated s.c. with H1299 or PC14 cells, which exhibit high expression of APN/CD13, or with A549 cells, which exhibit weak expression of APN/CD13. MT95-4 reduced tumor growth and angiogenesis in mice bearing H1299-derived and PC14-derived tumors, but not in mice bearing A549-derived tumors. These results suggested that the antitumor and anti-angiogenic effects of MT95-4 were dependent on APN/CD13 expression in tumor cells. Given that MT95-4 is the first fully humanized monoclonal antibody against APN/CD13, MT95-4 should be recognized as a promising candidate for monoclonal antibody therapy against tumors expressing APN/CD13.
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Akita
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Hattori
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Masuda
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Horimasu
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Nakashima
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwamoto
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Fujitaka
authors.affiliation: Department of Thoracic Surgery, Koseikai Takeda Hospital, Kyoto, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyake
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Nobuoki
authors.initials: N
authors.lastname: Kohno
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D018826:CD13 Antigens / Q000276:immunology; D018450:Disease Progression; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D018826:CD13 Antigens
keywords: Aminopeptidase N; angiogenesis; fully humanized monoclonal antibody; invasion; tumor growth