The monoclonal antibody nBT 062 conjugated to maytansinoids has potent and selective cytotoxicity against CD 138 positive multiple myeloma cells in vitro and in vivo

CD138 (Syndecan1) is highly expressed on multiple myeloma (MM) cells. In this study, we examined the anti-MM effect of murine/human chimeric CD138-specific monoclonal antibody (mAb) nBT062 conjugated with highly cytotoxic maytansinoid derivatives in vitro and in vivo. These agents significantly inhibited growth of CD138-positive MM cell lines and primary tumor cells from MM patients, without cytotoxicity against peripheral blood mononuclear cells from healthy volunteers. In MM cells, they induced G2/M cell cycle arrest followed by apoptosis associated with cleavage of PARP and caspase-3, -8 and -9. Non-conjugated nBT062 completely blocked cytotoxicity induced by nBT062-maytansinoid conjugate, confirming that binding is required for inducing cytotoxicity. Moreover, nBT062-maytansinoid conjugates blocked adhesion of MM cells to bone marrow stromal cells (BMSCs). Co-culture of MM cells with BMSCs, which protects against dexamethasone-induced death, had no impact on the cytotoxicity of the immunoconjugates. Importantly, nBT062-SPDB-DM4 and nBT062-SPP-DM1 significantly inhibited MM tumor growth in vivo in both human multiple myeloma xenograft mouse models and in SCID-human bone grafts (SCID-hu mouse model). These studies provide the preclinical framework supporting evaluation of nBT062-maytansinoid derivatives in clinical trials to improve patient outcome in MM. Introduction The cell surface proteoglycan CD138 (Syndecan1) is an integral membrane protein acting as a receptor for the extracellular matrix. Within the normal human hematopoetic compartment, CD138 is expressed exclusively on differentiated plasma cells and is a primary diagnostic marker of multiple myeloma (MM). Several monoclonal antibodies (mAbs) (i.e., B-B4, BC/B-B4, B-B2, DL-101, 1 D4, MI15, 1.BB.210, 2Q1484, 5F7, 104-9, 281-2) specific for CD138 have been reported. B-B4, 1D4 and MI15 Abs, which bind to similar or closely-related epitopes, recognize both the intact CD138 molecule and the core protein (with the heparin sulphate chains removed), and target the same or closely related epitopes. B-B4 preferentially binds to membrane bound versus soluble CD138. It is a murine IgG1 monoclonal antibody that binds to a linear epitope between residues 90-95 of the core protein

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