The monoclonal antibody nBT062 conjugated to cytotoxic Maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo.
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.
Ikeda
Hiroshi
H
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.
Hideshima
Teru
T
Fulciniti
Mariateresa
M
Lutz
Robert J
RJ
Yasui
Hiroshi
H
Okawa
Yutaka
Y
Kiziltepe
Tanyel
T
Vallet
Sonia
S
Pozzi
Samantha
S
Santo
Loredana
L
Perrone
Giulia
G
Tai
Yu-Tzu
YT
Cirstea
Diana
D
Raje
Noopur S
NS
Uherek
Christoph
C
Dälken
Benjamin
B
Aigner
Silke
S
Osterroth
Frank
F
Munshi
Nikhil
N
Richardson
Paul
P
Anderson
Kenneth C
KC
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
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