The Monoclonal Antibody nBT062 Conjugated to Cytotoxic Maytansinoids Has Selective Cytotoxicity Against CD138-Positive Multiple Myeloma Cells In vitro and In vivo

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.

[1]  R. Wahl,et al.  Comparison of 90Y-Ibritumomab Tiuxetan and 131I-Tositumomab in Clinical Practice , 2007, Journal of Nuclear Medicine.

[2]  B. Barlogie,et al.  The syndecan-1 heparan sulfate proteoglycan is a viable target for myeloma therapy. , 2007, Blood.

[3]  D. Chauhan,et al.  5-Azacytidine, a DNA methyltransferase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells , 2007, Molecular Cancer Therapeutics.

[4]  F. Zhan,et al.  Heparanase Enhances Syndecan-1 Shedding , 2007, Journal of Biological Chemistry.

[5]  J. D. Vos,et al.  Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma , 2006, Oncogene.

[6]  Hiroshi Yasui,et al.  MLN120B, a Novel IκB Kinase β Inhibitor, Blocks Multiple Myeloma Cell Growth In vitro and In vivo , 2006, Clinical Cancer Research.

[7]  A. Takaoka,et al.  Comparing antibody and small-molecule therapies for cancer , 2006, Nature Reviews Cancer.

[8]  R. Lutz,et al.  Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing. , 2006, Cancer research.

[9]  T. Chittenden,et al.  Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. , 2006, Cancer research.

[10]  J. Tchinda,et al.  Targeting receptor kinases by a novel indolinone derivative in multiple myeloma: abrogation of stroma-derived interleukin-6 secretion and induction of apoptosis in cytogenetically defined subgroups. , 2006, Blood.

[11]  H. Kantarjian,et al.  The role of gemtuzumab ozogamicin in acute leukaemia therapy , 2005, British journal of haematology.

[12]  M. Toyota,et al.  The role of T-fimbrin in the response to DNA damage: silencing of T-fimbrin by small interfering RNA sensitizes human liver cancer cells to DNA-damaging agents. , 2005, International journal of oncology.

[13]  N. Munshi,et al.  SDX-101, the R-enantiomer of etodolac, induces cytotoxicity, overcomes drug resistance, and enhances the activity of dexamethasone in multiple myeloma. , 2005, Blood.

[14]  N. Munshi,et al.  Human anti-CD40 antagonist antibody triggers significant antitumor activity against human multiple myeloma. , 2005, Cancer research.

[15]  D. Carrasco,et al.  Cytotoxic activity of the maytansinoid immunoconjugate B-B4-DM1 against CD138+ multiple myeloma cells. , 2004, Blood.

[16]  D. Carrasco,et al.  In Vitro and in Vivo Activity of the Maytansinoid Immunoconjugate huN901-N2′-Deacetyl-N2′-(3-Mercapto-1-Oxopropyl)-Maytansine against CD56+ Multiple Myeloma Cells , 2004, Cancer Research.

[17]  F. E. Bertrand,et al.  JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis , 2004, Leukemia.

[18]  K. Anderson,et al.  Antitumor activity of lysophosphatidic acid acyltransferase-beta inhibitors, a novel class of agents, in multiple myeloma. , 2003, Cancer research.

[19]  L. Cantley,et al.  Targeting the PI3K-Akt pathway in human cancer: rationale and promise. , 2003, Cancer cell.

[20]  N. Munshi,et al.  Arsenic trioxide inhibits growth of human multiple myeloma cells in the bone marrow microenvironment. , 2002, Molecular cancer therapeutics.

[21]  J. Epstein,et al.  Soluble syndecan-1 promotes growth of myeloma tumors in vivo. , 2002, Blood.

[22]  Lewis C Cantley,et al.  The phosphoinositide 3-kinase pathway. , 2002, Science.

[23]  M. V. van Oers,et al.  Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma. , 2002, Blood.

[24]  P. Richardson,et al.  Novel therapies targeting the myeloma cell and its bone marrow microenvironment. , 2001, Seminars in oncology.

[25]  X. H. Chen,et al.  Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[26]  J. Epstein,et al.  Syndecan-1 is targeted to the uropods of polarized myeloma cells where it promotes adhesion and sequesters heparin-binding proteins. , 2000, Blood.

[27]  J. Byrd,et al.  Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: association with increased infusion-related side effects and rapid blood tumor clearance. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  D. Trono,et al.  Self-Inactivating Lentivirus Vector for Safe and Efficient In Vivo Gene Delivery , 1998, Journal of Virology.

[29]  B. Barlogie,et al.  Syndecan-1 is a multifunctional regulator of myeloma pathobiology: control of tumor cell survival, growth, and bone cell differentiation. , 1998, Blood.

[30]  G. Pinkus,et al.  The development of a model for the homing of multiple myeloma cells to human bone marrow. , 1997, Blood.

[31]  A. Lander,et al.  Fine structure of heparan sulfate regulates syndecan-1 function and cell behavior. , 1994, The Journal of biological chemistry.

[32]  R. Sanderson,et al.  B lymphocytes express and lose syndecan at specific stages of differentiation. , 1989, Cell regulation.

[33]  C. Huff,et al.  Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. , 2008, Cancer research.

[34]  R. Bataille,et al.  The phenotype of normal, reactive and malignant plasma cells. Identification of "many and multiple myelomas" and of new targets for myeloma therapy. , 2006, Haematologica.

[35]  W. Dalton,et al.  Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. , 1999, Blood.