Hematopoietic Stem and Progenitor Cell Mobilization in Mice and Humans by a First-in-Class Mirror-Image Oligonucleotide Inhibitor of CXCL12

被引：77

作者：

Vater, A. ^{[1
]}

Sahlmann, J. ^{[2
]}

Kroeger, N. ^{[3
]}

Zoellner, S. ^{[1
]}

Lioznov, M. ^{[3
]}

Maasch, C. ^{[1
]}

Buchner, K. ^{[1
]}

Vossmeyer, D. ^{[1
]}

Schwoebel, F. ^{[1
]}

Purschke, W. G. ^{[1
]}

Vonhoff, S. ^{[1
]}

Kruschinski, A. ^{[1
]}

Huebel, K. ^{[4
]}

Humphrey, M. ^{[1
]}

Klussmann, S. ^{[1
]}

Fliegert, F. ^{[1
]}

机构：

[1] NOXXON Pharma AG, Berlin, Germany

[2] Scope Life Sci GmbH, Hamburg, Germany

[3] Univ Klinikum Hamburg, Interdisziplinare Klin Stammzelltransplantat, Hamburg, Germany

[4] Univ Klinikum Koln, Innere Med Klin 1, Cologne, Germany

来源：

CLINICAL PHARMACOLOGY & THERAPEUTICS | 2013年 / 94卷 / 01期

关键词：

RAPID MOBILIZATION; CHEMOKINE RECEPTOR; PERIPHERAL-BLOOD; MULTIPLE-MYELOMA; CXCR4; ANTAGONIST; IN-VIVO; AMD3100; SDF-1; MICROENVIRONMENT; MECHANISMS;

D O I：

10.1038/clpt.2013.58

中图分类号：

R9 [药学];

学科分类号：

100702 [药剂学];

摘要：

NOX-A12 is a PEGylated mirror-image oligonucleotide (a so-called Spiegelmer) that binds to CXCL12 (stromal cell-derived factor-1, SDF-1) with high affinity thereby inhibiting CXCL12 signaling on both its receptors, CXCR4 and CXCR7. In animals, NOX-A12 mobilized white blood cells (WBCs) and hematopoietic stem and progenitor cells (HSCs) into peripheral blood (PB). In healthy volunteers, single doses of NOX-A12 had a benign safety profile and also dose-dependently mobilized WBCs and HSCs into PB. HSC peak mobilization reached a plateau at five times the baseline level at an i.v. dose of 5.4 mg/kg. In accordance with the plasma half-life of 38 h, the duration of the WBC and HSC mobilization was long lasting and increased dose-dependently to more than 4 days at the highest dose (10.8 mg/kg). In conclusion, NOX-A12 may be appropriate for therapeutic use in and beyond mobilization of HSCs, e.g., in long-lasting mobilization and chemosensitization of hematological cancer cells.

引用

页码：150 / 157

页数：8

共 30 条

[1]

The chemokine SDF-1 is a chemoattractant for human CD34(+) hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34(+) progenitors to peripheral blood [J].

Aiuti, A ;

Webb, IJ ;

Bleul, C ;

Springer, T ;

GutierrezRamos, JC .

JOURNAL OF EXPERIMENTAL MEDICINE, 1997, 185 (01) :111-120

[2]

Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma [J].

Alsayed, Yazan ;

Ngo, Hai ;

Runnels, Judith ;

Leleu, Xavier ;

Singha, Ujjal K. ;

Pitsillides, Costas M. ;

Spencer, Joel A. ;

Kimlinger, Teresa ;

Ghobrial, Joanna M. ;

Jia, Xiaoying ;

Lu, Ganwei ;

Timm, Michael ;

Kumar, Ashok ;

Cote, Daniel ;

Veilleux, Israel ;

Hedin, Karen E. ;

Roodman, G. David ;

WitZig, Thomas E. ;

Kung, Andrew L. ;

Hideshima, Teru ;

Anderson, Kenneth C. ;

Lin, Charles P. ;

Ghobrial, Irene M. .

BLOOD, 2007, 109 (07) :2708-2717

[3]

CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy [J].

Azab, Abdel Kareem ;

Runnels, Judith M. ;

Pitsillides, Costas ;

Moreau, Anne-Sophie ;

Azab, Feda ;

Leleu, Xavier ;

Jia, Xiaoying ;

Wright, Renee ;

Ospina, Beatriz ;

Carlson, Alicia L. ;

Alt, Clemens ;

Burwick, Nicholas ;

Roccaro, Aldo M. ;

Ngo, Hai T. ;

Farag, Mena ;

Melhem, Molly R. ;

Sacco, Antonio ;

Munshi, Nikhil C. ;

Hideshima, Teru ;

Rollins, Barrett J. ;

Anderson, Kenneth C. ;

Kung, Andrew L. ;

Lin, Charles P. ;

Ghobrial, Irene M. .

BLOOD, 2009, 113 (18) :4341-4351

[4]

In vivo biodistribution and pharmacokinetics of 18F-labelled Spiegelmers:: a new class of oligonucleotidic radiopharmaceuticals [J].

Boisgard, R ;

Kuhnast, B ;

Vonhoff, S ;

Younes, C ;

Hinnen, F ;

Verbavatz, JM ;

Rousseau, B ;

Fürste, J ;

Wlotzka, B ;

Dollé, F ;

Klussmann, S ;

Tavitian, B .

EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, 2005, 32 (04) :470-477

[5]

Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist [J].

Broxmeyer, HE ;

Orschell, CM ;

Clapp, DW ;

Hangoc, G ;

Cooper, S ;

Plett, PA ;

Liles, WC ;

Li, XX ;

Graham-Evans, B ;

Campbell, TB ;

Calandra, G ;

Bridger, G ;

Dale, DC ;

Srour, EF .

JOURNAL OF EXPERIMENTAL MEDICINE, 2005, 201 (08) :1307-1318

[6]

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers [J].

Burger, J. A. ;

Peled, A. .

LEUKEMIA, 2009, 23 (01) :43-52

[7]

A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development [J].

Burns, Jennifer M. ;

Summers, Bretton C. ;

Wang, Yu ;

Melikian, Anita ;

Berahovich, Rob ;

Miao, Zhenhua ;

Penfold, Mark E. T. ;

Sunshine, Mary Jean ;

Littman, Dan R. ;

Kuo, Calvin J. ;

Wei, Kevin ;

McMaster, Brian E. ;

Wright, Kim ;

Howard, Maureen C. ;

Schall, Thomas J. .

JOURNAL OF EXPERIMENTAL MEDICINE, 2006, 203 (09) :2201-2213

[8]

Rapid mobilization of hematopoietic progenitors by AMD3100 and catecholamines is mediated by CXCR4-dependent SDF-1 release from bone marrow stromal cells [J].

Dar, A. ;

Schajnovitz, A. ;

Lapid, K. ;

Kalinkovich, A. ;

Itkin, T. ;

Ludin, A. ;

Kao, W-M ;

Battista, M. ;

Tesio, M. ;

Kollet, O. ;

Cohen, N. N. ;

Margalit, R. ;

Buss, E. C. ;

Baleux, F. ;

Oishi, S. ;

Fujii, N. ;

Larochelle, A. ;

Dunbar, C. E. ;

Broxmeyer, H. E. ;

Frenette, P. S. ;

Lapidot, T. .

LEUKEMIA, 2011, 25 (08) :1286-1296

[9]

Rapid mobilization of functional donor hematopoietic cells without G-CSF using AMD3100, an antagonist of the CXCR4/SDF-1 interaction [J].

Devine, Steven M. ;

Vij, Ravi ;

Rettig, Michael ;

Todt, Laura ;

McGlauchlen, Kiley ;

Fisher, Nicholas ;

Devine, Hollie ;

Link, Daniel C. ;

Calandra, Gary ;

Bridger, Gary ;

Westervelt, Peter ;

DiPersio, John F. .

BLOOD, 2008, 112 (04) :990-998

[10]

A review on CXCR4/CXCL12 axis in oncology: No place to hide [J].

Domanska, Urszula M. ;

Kruizinga, Roeliene C. ;

Nagengast, Wouter B. ;

Timmer-Bosscha, Hetty ;

Huls, Gerwin ;

de Vries, Elisabeth G. E. ;

Walenkamp, Annemiek M. E. .

EUROPEAN JOURNAL OF CANCER, 2013, 49 (01) :219-230

← 1 2 3 →