New xenograft model of multiple myeloma and efficacy of a humanized antibody against human interleukin-6 receptor.
A new xenograft model of multiple myeloma (MM), where growth is strongly regulated by interleukin-6 (IL-6), was established in severe combined immunodeficiency (SCID) mice. In this model, endogenous IL-6 from SCID mice was ineffective at eliciting growth of the established human MM cell line KPMM2; these cells achieved autonomous growth through their autocrine secretion of IL-6. The etiopathology in this disease model is consistent with that of human MM. When greater than 3 x 10(6) KPMM2 cells were injected intravenously (IV), tumors developed in all mice and were predominantly localized in their bone marrow. Tumors were also apparent in the lymph nodes, but absent from other organs. Immunostaining of cell surface antigen (CD38) showed that more than 40% of bone marrow cells in femur were of myeloma origin in the advanced stage of tumor progression (day 37). Histologic analysis of these mice show that bone marrow was largely occupied by plasmablastic cells and bones had developed osteolytic lesions at multiple sites. Concurrently, there was a decrease in bone density throughout the body and a significant increase in ionized plasma calcium. M-protein was detected in the serum within 10 days after transplantation, which correlated with the tumor progression. Between 30 and 40 days after the transplantation, mice presented with a rapid and severe loss of body weight, hind leg paralysis, and fatigue. Subsequently, the mice died within a week. A single IV injection of 0.2 mg humanized anti-IL-6 receptor antibody (hPM1) into mice on the day after tumor transplantation substantially suppressed the elevation of serum M-protein and development of the tumor-associated abnormalities and significantly increased in the life span of tumor-bearing mice. Our data show the usefulness of this model to analyze the pathologic role of IL-6 in MM and the efficacy of targeting the IL-6 receptor in IL-6-dependent KPMM2 cells.
Tsunenari
T
T
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka, Japan.
Koishihara
Y
Y
Nakamura
A
A
Moriya
M
M
Ohkawa
H
H
Goto
H
H
Shimazaki
C
C
Nakagawa
M
M
Ohsugi
Y
Y
Kishimoto
T
T
Akamatsu
K
K
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology*; D001862:Bone Resorption; D002118:Calcium / Q000097:blood; D004195:Disease Models, Animal; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007167:Immunotherapy; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000473:pathology* / Q000628:therapy; D009368:Neoplasm Transplantation; D018123:Receptors, Interleukin / Q000276:immunology*; D019947:Receptors, Interleukin-6; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000906:Antibodies; D015703:Antigens, CD; D007074:Immunoglobulin G; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D002118:Calcium