Antitumor activity of humanized monoclonal antibody against HM1.24 antigen in human myeloma xenograft models.
A humanized monoclonal antibody against HM1.24 antigen (AHM), which is highly expressed on multiple myeloma (MM) cells, induced antibody-dependent cellular cytotoxicity (ADCC) in vitro. In this study, we further characterized AHM and evaluated its potency for clinical application. AHM bound to HM1.24 antigen with a dissociation constant of 0.35 nM, and its epitope resided between Leu116 and Leu127 of the HM1.24 antigen. Single intravenous injection of AHM significantly inhibited tumor growth in both orthotopic and ectopic human MM xenograft models. AHM reduced serum M protein levels and prolonged survival of mice intravenously inoculated with KPMM2 and ARH-77 cells. The number of KPMM2 cells in bone marrow or tumor volume of subcutaneously inoculated RPMI 8226 cells was also inhibited by AHM. The antitumor activity of AHM against tumor cells in bone marrow was diminished when the mice were pretreated with anti-Fcgamma receptor III/II antibody, demonstrating that antitumor activity by AHM requires effector cell functions in vivo. Experiments involving in vitro ADCC assays indicated that NK cells and monocytes/macrophages serve as effector cells for AHM-induced ADCC in mouse and human. Thus, AHM will provide an additional treatment option for MM.
Kawai
Shigeto
S
Pharmaceutical Research Department III, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
Yoshimura
Yasushi
Y
Iida
Shin-Ichiro
S
Kinoshita
Yasuko
Y
Koishihara
Yasuo
Y
Ozaki
Shuji
S
Matsumoto
Toshio
T
Kosaka
Masaaki
M
Yamada-Okabe
Hisafumi
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use*; D000915:Antibody Affinity / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D015703:Antigens, CD; D018604:Epitope Mapping; D005434:Flow Cytometry; D058851:GPI-Linked Proteins; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays; D000074010:Bone Marrow Stromal Antigen 2
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2