Tsunenari T, Akamatsu K, Kaiho S, Sato K, Tsuchiya M, Koishihara Y, Kishimoto T, Ohsugi Y
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
Anticancer Res. 1996 Sep-Oct;16(5A):2537-44.
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.
使用以自分泌方式依赖白细胞介素-6（IL-6）生长的S6B45细胞，在无胸腺裸鼠中建立了人多发性骨髓瘤（MM）的异种移植模型。将S6B45细胞皮下接种到经500 cGy X射线和抗去唾液酸GM1抗体预处理的小鼠体内。在超过90%的小鼠中，接种部位在30天内出现可触及的肿瘤。对肿瘤切片进行组织学观察发现，肿瘤块由两种不同表型的骨髓瘤细胞组成，分别对应于原始浆细胞和成熟浆细胞。在第1、3和5天静脉注射超过0.125 mg抗人IL-6受体（hIL-6R）的小鼠单克隆抗体（PM1）显著延迟了肿瘤发生的时间。1 mg抗hIL-6抗体（MH166）也强烈抑制S6B45的生长，而对照抗体（MOPC31C）和无中和活性的抗hIL-6R抗体（AUK181-6）没有产生显著影响。为了降低PM1在人体内的抗原性，构建了具有人IgG1恒定区的小鼠-人嵌合PM1（chPM1）和具有小鼠互补决定区的人IgG1人源化PM1（hPM1），并在我们的模型中评估了它们的体内抗肿瘤活性。这些重组抗体（chPM1和hPM1）的体内疗效显示与原始PM1相当。这些结果表明，hPM1完全重现了PM1的抗肿瘤活性，并且这种人源化抗体阻断IL-6信号可能是治疗MM的有效方法。
