The Monoclonal Antibody nBT062 Conjugated to Cytotoxic Maytansinoids Has Selective Cytotoxicity Against CD138-Positive Multiple Myeloma CellsIn vitroandIn vivo

Abstract

Purpose: We investigated the antitumor effect of murine/human chimeric CD138-specific monoclonal antibody nBT062 conjugated with highly cytotoxic maytansinoid derivatives against multiple myeloma (MM) cells in vitro and in vivo. Experimental Design: We examined the growth inhibitory effect of BT062-SPDB-DM4, BT062-SMCC-DM1, and BT062-SPP-DM1 against MM cell lines and primary tumor cells from MM patients. We also examined in vivo activity of these agents in murine MM cell xenograft model of human and severe combined immunodeficient (SCID) mice bearing implant bone chips injected with human MM cells (SCID-hu model). Results: Anti-CD138 immunoconjugates significantly inhibited growth of 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 G 2 -M cell cycle arrest, followed by apoptosis associated with cleavage of caspase-3, caspase-8, caspase-9, and poly(ADP-ribose) polymerase. Nonconjugated nBT062 completely blocked cytotoxicity induced by nBT062-maytansinoid conjugate, confirming that specific binding is required for inducing cytotoxicity. Moreover, nBT062-maytansinoid conjugates blocked adhesion of MM cells to bone marrow stromal cells. The coculture of MM cells with bone marrow stromal cells protects against dexamethasone-induced death but had no effect on the cytotoxicity of immunoconjugates. Importantly, nBT062-SPDB-DM4 and nBT062-SPP-DM1 significantly inhibited MM tumor growth in vivo and prolonged host survival in both the xenograft mouse models of human MM and SCID-hu mouse model. Conclusion: These results provide the preclinical framework supporting evaluation of nBT062-maytansinoid derivatives in clinical trials to improve patient outcome in MM.The cell surface proteoglycan CD138 (syndecan-1) is an integral membrane protein acting as a receptor for the extracellular matrix. Within the normal human hematopoetic compartment, CD138 is expressed on differentiated plasma cells and is a primary diagnostic marker of multiple myeloma (MM; ref. 1). The large extracellular domain of CD138 binds via its heparin sulfate chains to soluble extracellular molecules, including the growth factors epidermal growth factor, fibroblast growth factor, and hepatocyte growth factor, and to insoluble extracellular molecules, such as collagen and fibronectin (2, 3). CD138 also mediates cell-cell adhesion through interactions with heparinbinding molecules. Studies of plasma cell differentiation show that CD138 is a differentiation antigen (4) and a coreceptor for MM growth factors (5).Several monoclonal antibodies (mAb; i.e.,

FcRL5 as a Target of Antibody–Drug Conjugates for the Treatment of Multiple Myeloma

“…18 and references therein). nBT062 has shown promising preclinical activity in xenograft models of multiple myeloma (19,20) and, on the basis of these data, a phase 1 clinical trial was started where patients were treated every 3 weeks at 7 dose levels ranging from 10 to 200 mg/m 2 . The skin, eye, and gastrointestinal tract are the target organs for toxicity at high doses (21).…”

Targeting B-Cell Maturation Antigen in Multiple Myeloma

“…Since the immune system in the majority of relapsed MM patients is impaired by the disease and/or cancer treatment, it is critical to develop ADCs targeting more specific antigens to direct and indirectly kill MM cells. To date, three ADC molecules with classical or novel drug payloads can directly kill MM cells, but do not induce effectormediated activity in preclinical studies: CD56-maytansinoid (DM1) (Lorvotuzumab/IMGN901) [37,38], CD138-DM1/DM4 (BT062) [39,40] and CD74-doxo-future science group Targeting B-cell maturation antigen in multiple myeloma Review rubicin (IMMU-110) [41]. A Phase II study combining BT062 (CD138-DM4) with len and dex is ongoing, demonstrating good tolerability and encouraging efficacy in Phase I clinical trial [40].…”

Monoclonal antibody-based therapy as a new treatment strategy in multiple myeloma

“…Three immunoconjugates of nBT062 with DM1 or DM4 were developed, which also showed potent antimyeloma activities in vitro as well as in vivo in myeloma mouse models. 17 The most potent immunoconjugate tested was nBT062-SPBD-DM4. 17 In a dose-escalation study, this immunoconjugate (BT062) was administered once every 3 weeks in relapsed/refractory myeloma patients.…”

“…17 The most potent immunoconjugate tested was nBT062-SPBD-DM4. 17 In a dose-escalation study, this immunoconjugate (BT062) was administered once every 3 weeks in relapsed/refractory myeloma patients. DLT consisted of mucositis and the maximum-tolerated dose (MTD) was defined as 160 mg/m 2 .…”