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.
King
A G
AG
Department of Molecular Virology and Host Defense, SmithKline Beecham Pharmaceuticals, Collegeville, PA 19426-0989, USA. andrew_g_king@sbphrd.com
Horowitz
D
D
Dillon
S B
SB
Levin
R
R
Farese
A M
AM
MacVittie
T J
TJ
Pelus
L M
LM
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