title: The monoclonal antibody nBT062 conjugated to cytotoxic Maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  These results provide the preclinical framework supporting evaluation of nBT062-maytansinoid derivatives in clinical trials to improve patient outcome in MM.
authors.affiliation: Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ikeda
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Fulciniti
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lutz
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yasui
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Okawa
authors.forename: Tanyel
authors.initials: T
authors.lastname: Kiziltepe
authors.forename: Sonia
authors.initials: S
authors.lastname: Vallet
authors.forename: Samantha
authors.initials: S
authors.lastname: Pozzi
authors.forename: Loredana
authors.initials: L
authors.lastname: Santo
authors.forename: Giulia
authors.initials: G
authors.lastname: Perrone
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.forename: Diana
authors.initials: D
authors.lastname: Cirstea
authors.forename: Noopur S
authors.initials: NS
authors.lastname: Raje
authors.forename: Christoph
authors.initials: C
authors.lastname: Uherek
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dälken
authors.forename: Silke
authors.initials: S
authors.lastname: Aigner
authors.forename: Frank
authors.initials: F
authors.lastname: Osterroth
authors.forename: Nikhil
authors.initials: N
authors.lastname: Munshi
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008453:Maytansine / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism; D053668:Syndecan-1 / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; C508600:IL6 protein, human; D018796:Immunoconjugates; D015850:Interleukin-6; D053668:Syndecan-1; D008453:Maytansine; D007334:Insulin-Like Growth Factor I