Therapeutic potential of humanized anti-interleukin-6 receptor antibody: antitumor activity in xenograft model of multiple myeloma.
A xenograft model of human multiple myeloma (MM) was established in athymic nude mice using S6B45 cells whose growth is dependent on IL-6 in an autocrine fashion. S6B45 cells were inoculated s.c. into mice pretreated with 500 cGy X-ray and anti-asialo GM1 antibody. In more than 90% of the mice, a palpable tumor emerged within 30 days at the inoculation site. Histological observation of the tumor section revealed that the tumor mass was composed of two different phenotypes of myeloma cells, corresponding to plasmablasts and mature plasma cells. I.v. injection of more than 0.125 mg of mouse monoclonal antibody (PM1) against human IL-6R (hIL-6R) on days 1, 3 and 5 markedly delayed the time of tumor incidence. One mg of anti-hIL-6 antibody (MH166) also strongly inhibited the growth of S6B45, whereas control antibody (MOPC31C) and anti-hIL-6R antibody without neutralizing activity (AUK181-6) produced no significant effects. To reduce the antigenicity of PM1 in human, mouse-human chimeric PM1 (chPM1) with human IgG1 constant region and humanized PM1 (hPM1), human IgG1 with mouse complimentarity determining regions, were constructed and evaluated for their in vivo antitumor activity in our model. The in vivo efficacy of these recombinant antibodies (chPM1 and hPM1) was shown to be equivalent to that of the original PM1. These results indicate that the antitumor activity of PM1 is completely recreated in hPM1, and that blocking of the IL-6 signal by this humanized antibody could be a potent therapy for MM.
Tsunenari
T
T
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
Akamatsu
K
K
Kaiho
S
S
Sato
K
K
Tsuchiya
M
M
Koishihara
Y
Y
Kishimoto
T
T
Ohsugi
Y
Y
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000628:therapy*; D018123:Receptors, Interleukin / Q000276:immunology*; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins / Q000276:immunology / Q000627:therapeutic use; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D007074:Immunoglobulin G; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins