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 at hymic nude mice using S6B45 cells whose growth is dependent on IL-6 in an autocrine fashion. S6B45 cells were inoculated s.c. into mice pret reated with 500 cGy X-ray and anti-asialo GM1 antibody. In more than 9 0% of the mice, a palpable tumor emerged within 30 days at the inocula tion site. Histological observation of the armor section revealed that the tumor mass was composed of two different phenotypes of myeloma ce lls, corresponding to plasmablasts and mature plasma cells. I.v. injec tion 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 t umor incidence. One mg of anti-hIL-6 antibody (MH166) also strongly in hibited the growth of S6B45, whereas control antibody (MOPC31C) and an ti-hIL-6R antibody without neutralizing activity (AUK181-6) produced n o significant effects. To reduce the antigenicity of PM1 in human, mou se-human chimeric PM1 (chPM1) with human IgG1 constant region and huma nized PM1 (hPM1), human IgG1 with mouse complimentarity determining re gions, were constructed and evaluated for their in vivo antitumor acti vity in our model. The in vivo efficacy of these recombinant antibodie s (chPM1 and hPM1) was shown to be equivalent to that of the original PM1. These results indicate that the antitumor activity of PM1 is comp letely recreated in hPM1, and that blocking of the IL-6 signal by this humanized antibody could be a potent therapy for MM.