Anti-β2-microglobulin monoclonal antibodies overcome bortezomib resistance in multiple myeloma by inhibiting autophagy

Our previous studies showed that anti-beta M-2 monoclonal antibodies (mAbs) have strong and direct apoptotic effects on multiple myeloma (MM) cells, suggesting that anti-beta M-2 mAbs might be developed as a novel therapeutic agent. In this study, we investigated the anti-MM effects of combination treatment with anti-beta M-2 mAbs and bortezomib (BTZ). Our results showed that anti-beta M-2 mAbs enhanced BTZ-induced apoptosis of MM cell lines and primary MM cells. Combination treatment could also induce apoptosis of BTZ-resistant MM cells, and the enhanced effect depended on the surface expression of beta M-2 on MM cells. BTZ up-regulated the expression of autophagy proteins, whereas combination with anti-beta M-2 mAbs inhibited autophagy. Sequence analysis of the promoter region of beclin 1 identified 3 putative NF-kappa B-binding sites from -615 to -789 bp. BTZ treatment increased, whereas combination with anti-beta M-2 mAbs reduced, NF-kappa B transcription activities in MM cells, and combination treatment inhibited NF-kappa B p65 binding to the beclin 1 promoter. Furthermore, anti-beta M-2 mAbs and BTZ combination treatment had anti-MM activities in an established MM mouse model. Thus, our studies provide new insight and support for the clinical development of an anti-beta M-2 mAb and BTZ combination treatment to overcome BTZ drug resistance and improve MM patient survival.