title: Humanized anti-HM1.24 antibody mediates myeloma cell cytotoxicity that is enhanced by cytokine stimulation of effector cells.
abstract: To develop a new immunotherapy for multiple myeloma, we have generated a monoclonal antibody (MoAb) that detects a human plasma cell-specific antigen, HM1.24. Our previous study has shown that mouse anti-HM1.24 MoAb inhibits the proliferation of human myeloma cells implanted into severe combined immunodeficiency mice. In this report, we evaluated the antitumor activity of the humanized anti-HM1.24 MoAb (IgG1kappa), which was constructed by grafting the complementarity-determining regions. In contrast to the parent mouse MoAb, humanized anti-HM1.24 MoAb mediated antibody-dependent cellular cytotoxicity (ADCC) against both myeloma cell lines and myeloma cells from patients in the presence of human peripheral blood mononuclear cells (PBMCs). The PBMCs from untreated myeloma patients exhibited ADCC activity as efficiently as those of healthy donors. Although decreased ADCC activity of PBMCs was observed in patients who responded poorly to conventional chemotherapy, it could be significantly augmented by the stimulation with interleukin-2 (IL-2), IL-12, or IL-15. There was a strong correlation between the percentage of CD16(+) cells and ADCC activity in the PBMCs of myeloma patients. Moreover, peripheral blood stem cell collections from myeloma patients contained higher numbers of CD16(+) cells than PBMCs and exhibited ADCC activity that was enhanced by IL-2. These results indicate that humanized anti-HM1.24 MoAb has potential as a new therapeutic strategy in multiple myeloma and that treatment of effector cells with immunomodulating cytokines can restore the effect of humanized anti-HM1.24 MoAb in patients with diminished ADCC activity.
authors.affiliation: First Department of Internal Medicine, School of Medicine, University of Tokushima, Tokushima, and Fuji-Gotemba Research Laboratory, Chugai Pharmaceutical Co, Ltd, Shizuoka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ozaki
authors.forename: M
authors.initials: M
authors.lastname: Kosaka
authors.forename: Y
authors.initials: Y
authors.lastname: Wakahara
authors.forename: Y
authors.initials: Y
authors.lastname: Ozaki
authors.forename: M
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: Y
authors.initials: Y
authors.lastname: Koishihara
authors.forename: T
authors.initials: T
authors.lastname: Goto
authors.forename: T
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005260:Female; D058851:GPI-Linked Proteins; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D007167:Immunotherapy; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000276:immunology; D019409:Interleukin-15 / Q000008:administration & dosage* / Q000276:immunology; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology* / Q000628:therapy*; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D058851:GPI-Linked Proteins; D018664:Interleukin-12; D019409:Interleukin-15; D007376:Interleukin-2; D008562:Membrane Glycoproteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2