Human-like mouse models for testing the efficacy and safety of anti-beta2-microglobulin monoclonal antibodies to treat myeloma.

Abstract

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.