title: The therapeutic potential of a novel PSMA antibody and its IL-2 conjugate in prostate cancer.
abstract: Prostate-specific membrane antigen (PSMA) is an attractive target for treatment of prostate cancer. Using the PSMA-recognizing mouse monoclonal antibody 2C9 obtained in our previous study, the biological activities of PSMA antibody were evaluated. Mouse-human chimeric IgG1 of 2C9 (KM2777) showed antibody-dependent cellular cytotoxicity activity against PSMA-expressing prostate cancer cells in the presence of human peripheral blood mononuclear cells (PBMCs). To increase lymphocyte-mediated cytotoxicity of KM2777, C-terminus interleukin-2 (IL-2)-fused KM2777 (KM2812) was constructed. KM2812 retained binding activity to PSMA and exhibited growth-stimulating activity equivalent to IL-2 on the IL-2-dependent T-cell line CTLL-2. Moreover, KM2812 exhibited enhanced cytotoxic activity against PSMA-expressing prostate cancer cells in the presence of PBMCs compared with KM2777. In a xenograft tumor model using PSMA-expressing prostate cancer cells, KM2812 exhibited marked antitumor activity, accompanied by complete regression of tumor in some of the KM2812-treated mice. These results suggest that KM2812 has a therapeutic potential for prostate cancer by stimulating lymphocyte-mediated antitumor cytotoxicity.
authors.affiliation: Biologics Research Laboratories, Tokyo Research Park, Kyowa Hakko Kirin Co., Ltd., 3-6-6 Asahi-machi, Machida-shi, Tokyo 194-8533, Japan. yoshiyuki.sugimoto@kyowa-kirin.co.jp.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Maiko
authors.initials: M
authors.lastname: Hirota
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshikawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Sumitomo
authors.forename: Kogenta
authors.initials: K
authors.lastname: Nakamura
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Ueda
authors.forename: Rinpei
authors.initials: R
authors.lastname: Niwa
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Suzawa
authors.forename: Motoo
authors.initials: M
authors.lastname: Yamasaki
authors.forename: Kenya
authors.initials: K
authors.lastname: Shitara
authors.forename: Takashi
authors.initials: T
authors.lastname: Kato
authors.forename: Kazuyasu
authors.initials: K
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D000954:Antigens, Surface / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005434:Flow Cytometry; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology* / Q000378:metabolism; D007963:Leukocytes, Mononuclear; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D007376:Interleukin-2; D008562:Membrane Glycoproteins; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; C579805:PSMA protein, mouse
keywords: IL-2; Prostate-specific membrane antigen; antibody-dependent cellular cytotoxicity; immunocytokine; prostate cancer