title: Combination with a defucosylated anti-HM1.24 monoclonal antibody plus lenalidomide induces marked ADCC against myeloma cells and their progenitors.
abstract: The immunomodulatory drug lenalidomide (Len) has drawn attention to potentiate antibody-dependent cellular cytotoxicity (ADCC)-mediated immunotherapies. We developed the defucosylated version (YB-AHM) of humanized monoclonal antibody against HM1.24 (CD317) overexpressed in multiple myeloma (MM) cells. In this study, we evaluated ADCC by YB-AHM and Len in combination against MM cells and their progenitors. YB-AHM was able to selectively kill via ADCC MM cells in bone marrow samples from patients with MM with low effector/target ratios, which was further enhanced by treatment with Len. Interestingly, Len also up-regulated HM1.24 expression on MM cells in an effector-dependent manner. HM1.24 was found to be highly expressed in a drug-resistant clonogenic "side population" in MM cells; and this combinatory treatment successfully reduced SP fractions in RPMI 8226 and KMS-11 cells in the presence of effector cells, and suppressed a clonogenic potential of MM cells in colony-forming assays. Collectively, the present study suggests that YB-AHM and Len in combination may become an effective therapeutic strategy in MM, warranting further study to target drug-resistant MM clonogenic cells.
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, Tokushima, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Harada
authors.affiliation: Department of Hematology, Tokushima Prefectural Central Hospital, Tokushima, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ozaki
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, Tokushima, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Oda
authors.affiliation: Department of Medicinal Biotechnology, Graduate School of Pharmaceutical Sciences, University of Tokushima, Tokushima, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsuji
authors.affiliation: Division of Medical Technology, Tokushima University Hospital, Tokushima, Japan.
authors.forename: Akishige
authors.initials: A
authors.lastname: Ikegame
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, Tokushima, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Iwasa
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, Tokushima, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Udaka
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, Tokushima, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Fujii
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, Tokushima, Japan.
authors.forename: Shingen
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, Tokushima, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Miki
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, Tokushima, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Kagawa
authors.affiliation: Department of Hematology and Oncology, RIRBM, Hiroshima University, Hiroshima, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kuroda
authors.affiliation: Research Division, Forerunner Pharma Research Co. Ltd., Tokyo, Japan.
authors.forename: Shigeto
authors.initials: S
authors.lastname: Kawai
authors.affiliation: Department of Medicinal Biotechnology, Graduate School of Pharmaceutical Sciences, University of Tokushima, Tokushima, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Research Division, Chugai Pharmaceutical Co. Ltd., Kanagawa, Japan.
authors.forename: Hisafumi
authors.initials: H
authors.lastname: Yamada-Okabe
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, Tokushima, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Department of Medicine and Bioregulatory Sciences, Graduate School of Medical Sciences, University of Tokushima, Tokushima, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Abe
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D058851:GPI-Linked Proteins / Q000276:immunology / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007167:Immunotherapy; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D058985:Side-Population Cells / Q000187:drug effects / Q000473:pathology; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D058851:GPI-Linked Proteins; D000077269:Lenalidomide; D013792:Thalidomide; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2