Yang Jing, Cao Yabing, Hong Sungyongl, Li Haiyan, Qian Jianfei, Kwak Larry W, Yi Qing
Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Clin Cancer Res. 2009 Feb 1;15(3):951-9. doi: 10.1158/1078-0432.CCR-08-1823.
We showed recently that anti-beta2-microglobulin (beta2M) monoclonal antibodies (mAb) have remarkably strong apoptotic effects on myeloma cells in vitro and in SCID-hu mice. However, whether the mAbs will be therapeutic and safe in the treatment of myeloma patients, in whom every tissue expresses low densities of MHC class I molecules and elevated levels of soluble beta2M are present, remains to be determined.
In this study, human-like myeloma mouse models (HLA-A2-transgenic NOD/SCID mice) were developed, which express mature and functional human MHC class I (HLA-A2 and human beta2M) on murine organs and present high levels of circulating human beta2M derived from human myeloma cells. Myeloma-bearing mice were treated intraperitoneally with anti-beta2M mAbs, and the distribution and effects of the mAbs on normal organs and established tumors were examined.
Our results show that anti-beta2M mAbs were effective in suppressing myeloma growth in treated mice. The therapeutic efficacy of the mAbs in these mice are comparable with those observed in myeloma-bearing nontransgenic NOD/SCID mice in which no human MHC class I is expressed on murine organs. Furthermore, although the mAbs can be detected on different organs, no tissue damage or cell apoptosis was observed in the mice.
Based on the antimyeloma efficacy and low toxicity in the mice, our study suggests that anti-beta2M mAbs may be safe and the tissue-expressing and soluble beta2M may not compromise their therapeutic effects in myeloma patients. This study provides further support for the future application of the mAbs as therapeutic agents for multiple myeloma.
我们最近发现，抗β2微球蛋白（β2M）单克隆抗体（mAb）在体外和SCID-hu小鼠体内对骨髓瘤细胞具有显著的强凋亡作用。然而，这些单克隆抗体在治疗骨髓瘤患者时是否具有治疗效果且安全，仍有待确定。在骨髓瘤患者中，每个组织均表达低密度的MHC I类分子，且可溶性β2M水平升高。
在本研究中，构建了类人骨髓瘤小鼠模型（HLA-A2转基因NOD/SCID小鼠），其在鼠器官上表达成熟且有功能的人MHC I类分子（HLA-A2和人β2M），并呈现源自人骨髓瘤细胞的高水平循环人β2M。给荷瘤小鼠腹腔注射抗β2M单克隆抗体，并检测这些单克隆抗体在正常器官和已形成肿瘤中的分布及作用。
我们的结果表明，抗β2M单克隆抗体在治疗小鼠中能有效抑制骨髓瘤生长。这些小鼠中该单克隆抗体的治疗效果与在荷瘤非转基因NOD/SCID小鼠中观察到的效果相当，在后者的鼠器官上不表达人MHC I类分子。此外，尽管在不同器官上能检测到单克隆抗体，但未观察到小鼠出现组织损伤或细胞凋亡。
基于在小鼠中的抗骨髓瘤疗效和低毒性，我们的研究表明抗β2M单克隆抗体可能是安全的，且组织表达的和可溶性β2M可能不会损害其在骨髓瘤患者中的治疗效果。本研究为该单克隆抗体作为多发性骨髓瘤治疗药物的未来应用提供了进一步支持。
