The monoclonal antibody nBT062 conjugated to cytotoxic maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo

Hiroshi Ikeda, Teru Hideshima, Mariateresa Fulciniti, Robert J. Lutz, Hiroshi Yasui, Yutaka Okawa, Tanyel Kiziltepe, Sonia Vallet, Samantha Pozzi, Loredana Santo, Giulia Perrone, Yu Tzu Tai, Diana Cirstea, Noopur S. Raje, Christoph Uherek, Benjamin Dälken, Silke Aigner, Frank Osterroth, Nikhil Munshi, Paul RichardsonKenneth C. Anderson

Publikation: Beitrag in Fachzeitschrift (peer-reviewed)Artikel in Fachzeitschrift

191 Zitate (Scopus)

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 G2-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.

OriginalspracheEnglisch
Seiten (von - bis)4028-4037
Seitenumfang10
FachzeitschriftClinical Cancer Research
Jahrgang15
Ausgabenummer12
DOIs
PublikationsstatusVeröffentlicht - 15 Juni 2009
Extern publiziertJa

ASJC Scopus Sachgebiete

  • Allgemeine Medizin

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