Rapid mobilization of murine hematopoietic stem cells with enhanced engraftment properties and evaluation of hematopoietic progenitor cell mobilization in rhesus monkeys by a single injection of SB-251353, a specific truncated form of the human CXC chemokine GRObeta.
SB-251353 is an N-terminal truncated form of the human CXC chemokine GRObeta. Recombinant SB-251353 was profiled in murine and rhesus monkey peripheral blood stem cell mobilization and transplantation models. SB-251353 rapidly and transiently mobilized hematopoietic stem cells and neutrophils into the peripheral blood after a single subcutaneous injection. Transplantation of equivalent numbers of hematopoietic stem cells mobilized by SB-251353 into lethally irradiated mice resulted in faster neutrophil and platelet recovery than stem cells mobilized by granulocyte colony-stimulating factor (G-CSF). A single injection of SB-251353 in combination with 4 days of G-CSF administration resulted in augmented stem and progenitor cell mobilization 5-fold greater than G-CSF alone. Augmented stem cell mobilization could also be demonstrated in mice when a single injection of SB-251353 was administered with only one-day treatment with G-CSF. In addition, SB-251353, when used as a single agent or in combination with G-CSF, mobilized long-term repopulating stem cells capable of hematopoietic reconstitution of lethally irradiated mice. In rhesus monkeys, a single injection of SB-251353 induced rapid increases in peripheral blood hematopoietic progenitor cells at a 50-fold lower dose than in mice, which indicates a shift in potency. These studies provide evidence that the use of SB-251353 alone or in combination with G-CSF mobilizes hematopoietic stem cells with long-term repopulating ability. In addition, this treatment may (1) reduce the number of apheresis sessions and/or amount of G-CSF required to collect adequate numbers of hematopoietic stem cells for successful peripheral blood cell transplantation and (2) improve hematopoietic recovery after transplantation.
Department of Molecular Virology and Host Defense, SmithKline Beecham Pharmaceuticals, Collegeville, PA 19426-0989, USA. andrew_g_king@sbphrd.com
A G
AG
King
D
D
Horowitz
S B
SB
Dillon
R
R
Levin
A M
AM
Farese
T J
TJ
MacVittie
L M
LM
Pelus
D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use; D002630:Chemotactic Factors / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006133:Growth Substances / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use; D006410:Hematopoiesis / Q000187:drug effects; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods* / Q000592:standards; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods / Q000592:standards; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008253:Macaca mulatta; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009363:Neoplasm Proteins / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D013045:Species Specificity
C475829:CXCL1 protein, human; C499706:CXCL2 protein, human; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D016179:Granulocyte Colony-Stimulating Factor; D020780:Matrix Metalloproteinase 9; C424342:SB251353