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 Blood, 9 July 2009, Vol. 114, No. 2, pp. 371-379.
Prepublished online as a Blood First Edition Paper on May 5, 2009; DOI 10.1182/blood-2008-11-191577.

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LYMPHOID NEOPLASIA

Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma

Mariateresa Fulciniti13, Pierfrancesco Tassone3, Teru Hideshima1, Sonia Vallet1, Puru Nanjappa1, Seth A. Ettenberg4, Zhenxin Shen5, Nipun Patel5, Yu-tzu Tai1, Dharminder Chauhan1, Constantine Mitsiades1, Rao Prabhala2, Noopur Raje1, Kenneth C. Anderson1, David R. Stover4, and Nikhil C. Munshi1,2

1 Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA; 2 VA Boston Healthcare System, Harvard Medical School, MA; 3 University of "Magna Græcia," Catanzaro, Italy; 4 Novartis Institutes for Biomedical Research, Oncology Biotherapeutics, Cambridge, MA; and 5 Beth Israel Deaconess Medical Center, Boston, MA

Decreased activity of osteoblasts (OBs) contributes to osteolytic lesions in multiple myeloma (MM). The production of the soluble Wnt inhibitor Dickkopf-1 (DKK1) by MM cells inhibits OB activity, and its serum level correlates with focal bone lesions in MM. Therefore, we have evaluated bone anabolic effects of a DKK1 neutralizing antibody (BHQ880) in MM. In vitro BHQ880 increased OB differentiation, neutralized the negative effect of MM cells on osteoblastogenesis, and reduced IL-6 secretion. In a severe combined immunodeficiency (SCID)–hu murine model of human MM, BHQ880 treatment led to a significant increase in OB number, serum human osteocalcin level, and trabecular bone. Although BHQ880 had no direct effect on MM cell growth, it significantly inhibited growth of MM cells in the presence of bone marrow stromal cells (BMSCs) in vitro. This effect was associated with inhibition of BMSC/MM cell adhesion and production of IL-6. In addition, BHQ880 up-regulated β-catenin level while down-regulating nuclear factor-{kappa}B (NF-{kappa}B) activity in BMSC. Interestingly, we also observed in vivo inhibition of MM cell growth by BHQ880 treatment in the SCID-hu murine model. These results confirm DKK1 as an important therapeutic target in myeloma and provide the rationale for clinical evaluation of BHQ880 to improve bone disease and to inhibit MM growth.


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