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

被引：315

作者：

Fulciniti, Mariateresa ^{[1
,2
,3
]}

Tassone, Pierfrancesco ^{[3
]}

Hideshima, Teru ^{[1
]}

Vallet, Sonia ^{[1
]}

Nanjappa, Puru ^{[1
]}

Ettenberg, Seth A. ^{[4
]}

Shen, Zhenxin ^{[5
]}

Patel, Nipun ^{[5
]}

Tai, Yu-tzu ^{[1
]}

Chauhan, Dharminder ^{[1
]}

Mitsiades, Constantine ^{[1
]}

Prabhala, Rao ^{[2
]}

Raje, Noopur ^{[1
]}

Anderson, Kenneth C. ^{[1
]}

Stover, David R. ^{[4
]}

Munshi, Nikhil C. ^{[1
,2
]}

机构：

[1] Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, VA Boston Healthcare Syst, Cambridge, MA 02138 USA

[3] Magna Graecia Univ Catanzaro, Catanzaro, Italy

[4] Novartis Inst Biomed Res, Cambridge, MA USA

[5] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA

来源：

BLOOD | 2009年 / 114卷 / 02期

基金：

美国国家卫生研究院;

关键词：

MARROW STROMAL CELLS; BONE-DISEASE; OSTEOBLAST DIFFERENTIATION; SERUM CONCENTRATIONS; BETA-CATENIN; WNT PATHWAY; IN-VIVO; EXPRESSION; CANCER; GROWTH;

D O I：

10.1182/blood-2008-11-191577

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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-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. (Blood. 2009; 114: 371-379)

引用

页码：371 / 379

页数：9

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