Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma.
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 beta-catenin level while down-regulating nuclear factor-kappaB (NF-kappaB) 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.
Fulciniti
Mariateresa
M
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Tassone
Pierfrancesco
P
Hideshima
Teru
T
Vallet
Sonia
S
Nanjappa
Puru
P
Ettenberg
Seth A
SA
Shen
Zhenxin
Z
Patel
Nipun
N
Tai
Yu-Tzu
YT
Chauhan
Dharminder
D
Mitsiades
Constantine
C
Prabhala
Rao
R
Raje
Noopur
N
Anderson
Kenneth C
KC
Stover
David R
DR
Munshi
Nikhil C
NC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002454:Cell Differentiation; D002478:Cells, Cultured; D018450:Disease Progression; D006801:Humans; D007167:Immunotherapy; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D010012:Osteogenesis / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins