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

Hiroshi Ikeda¹, Teru Hideshima¹, Robert J. Lutz², Hiroshi Yasui¹, Yutaka Okawa¹, Tanyel Kiziltepe¹, Sonia Vallet¹, Samantha Pozzi³, Loredana Santo¹, Giulia Perrone¹, Mariateresa Fulciniti⁴, Yu-Tzu Tai¹, Diana Cristea¹, Noopur S. Raje¹, Christoph Uherek⁵, Benjamin Dälken⁵, Silkie Aigner⁵, Frank Osterroth⁵, Nikhil C. Munshi ¹, Paul Richardson¹ & Kenneth C. Anderson ¹

Correspondence: (Login to view email address)

1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School
2. ImmunoGen Inc., Waltham, Massachusetts
3. Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School
4. VA Boston Healthcare System, Dana-Farber Cancer Institute, Harvard Medical School
5. Biotest AG, Dreieich, Germany

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Document Type:

Manuscript

Date:

Received 07 October 2008 22:33 UTC; Posted 08 October 2008

Subjects:

Cancer, Molecular Cell Biology

Tags:

• multiple myeloma
• targeted therapy
• monoclonal antibodies
• mAbs
• cancer
• microenvironment

Abstract:

CD138 (Syndecan1) is highly expressed on multiple myeloma (MM) cells. In this study, we examined the anti-MM effect of murine/human chimeric CD138-specific monoclonal antibody (mAb) nBT062 conjugated with highly cytotoxic maytansinoid derivatives in vitro and in vivo. These agents significantly inhibited growth of CD138-positive 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 PARP and caspase-3, -8 and -9. Non-conjugated nBT062 completely blocked cytotoxicity induced by nBT062-maytansinoid conjugate, confirming that binding is required for inducing cytotoxicity. Moreover, nBT062-maytansinoid conjugates blocked adhesion of MM cells to bone marrow stromal cells (BMSCs). Co-culture of MM cells with BMSCs, which protects against dexamethasone-induced death, had no impact on the cytotoxicity of the immunoconjugates. Importantly, nBT062-SPDB-DM4 and nBT062-SPP-DM1 significantly inhibited MM tumor growth in vivo in both human multiple myeloma xenograft mouse models and in SCID-human bone grafts (SCID-hu mouse model). These studies provide the preclinical framework supporting evaluation of nBT062-maytansinoid derivatives in clinical trials to improve patient outcome in MM.

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This document is licensed to the public under the Creative Commons Attribution 3.0 License

How to cite this document:

Ikeda, Hiroshi, Hideshima, Teru, Lutz, Robert, Yasui, Hiroshi, Okawa, Yutaka, Kiziltepe, Tanyel, Vallet, Sonia, Pozzi, Samantha, Santo, Loredana, Perrone, Giulia, Fulciniti, Mariateresa, Tai, Yu-Tzu, Cristea, Diana, Raje, Noopur, Uherek, Christoph, Dälken, Benjamin, Aigner, Silkie, Osterroth, Frank, Munshi , Nikhil, Richardson, Paul, and Anderson , Kenneth. The monoclonal antibody nBT062 conjugated to maytansinoids has potent and selective cytotoxicity against CD138 positive multiple myeloma cells in vitro and in vivo. Available from Nature Precedings <http://hdl.handle.net/10101/npre.2008.2374.1> (2008)

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