Hematopoietic stem and progenitor cell mobilization in mice and humans by a first-in-class mirror-image oligonucleotide inhibitor of CXCL12
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Hematopoietic stem and progenitor cell mobilization in mice and humans by a first-in-class mirror-image oligonucleotide inhibitor of CXCL12. / Vater, A; Sahlmann, J; Kröger, N; Zöllner, S; Lioznov, M; Maasch, C; Buchner, K; Vossmeyer, D; Schwoebel, F; Purschke, W G; Vonhoff, S; Kruschinski, A; Hübel, K; Humphrey, M; Klussmann, S; Fliegert, F.
in: CLIN PHARMACOL THER, Jahrgang 94, Nr. 1, 01.07.2013, S. 150-7.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Hematopoietic stem and progenitor cell mobilization in mice and humans by a first-in-class mirror-image oligonucleotide inhibitor of CXCL12
AU - Vater, A
AU - Sahlmann, J
AU - Kröger, N
AU - Zöllner, S
AU - Lioznov, M
AU - Maasch, C
AU - Buchner, K
AU - Vossmeyer, D
AU - Schwoebel, F
AU - Purschke, W G
AU - Vonhoff, S
AU - Kruschinski, A
AU - Hübel, K
AU - Humphrey, M
AU - Klussmann, S
AU - Fliegert, F
PY - 2013/7/1
Y1 - 2013/7/1
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Animals
KW - Chemokine CXCL12
KW - Dose-Response Relationship, Drug
KW - Female
KW - Hematopoietic Stem Cell Mobilization
KW - Hematopoietic Stem Cells
KW - Humans
KW - Leukocyte Count
KW - Leukocytes
KW - Macaca
KW - Male
KW - Mice
KW - Middle Aged
KW - Models, Animal
KW - Oligonucleotides
KW - Young Adult
U2 - 10.1038/clpt.2013.58
DO - 10.1038/clpt.2013.58
M3 - SCORING: Journal article
C2 - 23588307
VL - 94
SP - 150
EP - 157
JO - CLIN PHARMACOL THER
JF - CLIN PHARMACOL THER
SN - 0009-9236
IS - 1
ER -