The enhanced in vitro hematopoietic activity of leridistim, a chimeric dual G-CSF and IL-3 receptor agonist.
The in vitro activity of leridistim was characterized for cell proliferation, generation of colony-forming units (CFU) and differentiation of CD34+ cells. In AML-193.1.3 cells, leridistim exhibited a significant increase in potency compared to rhG-CSF, SC-65303 (an IL-3 receptor agonist) or an equimolar combination of rhG-CSF and SC-65303. CFU-GM assays demonstrated that at 50% of the maximum response, the relative potency of leridistim was 12-fold greater than the combination of rhG-CSF and rhIL-3 and 44-fold more potent than rhG-CSF alone. In multi-lineage CFU assays, a combination of erythropoietin (rhEPO) and leridistim resulted in greater numbers of BFU-E, CFU-GEMM and CFU-Mk than rhEPO alone. Ex vivo culture of peripheral blood or bone marrow CD34+ cells with leridistim substantially increased total viable cells over cultures stimulated with rhG-CSF, SC-65303, or a combination of rhG-CSF and SC-65303. Culture with leridistim, resulted in a greater increase in myeloid (CD15+/CD11b+), monocytic (CD41-/CD14+) and megakaryocytic (CD41+/CD14-) precursor cells without depleting the progenitor pool (CD34+/CD15-/CD11b-). These results demonstrate that leridistim is a more potent stimulator of hematopoietic proliferation and differentiation than the single receptor agonists (rhG-CSF and SC-65303) either alone or combined. These unique attributes suggest that leridistim may enhance hematopoietic reconstitution following myelosuppressive chemotherapy.
Abegg
A L
AL
Pharmacia Discovery Research, 700 Chesterfield Village Parkway North, St Louis, MO 63198, USA.
Vickery
L E
LE
Bremer
M E
ME
Donnelly
A M
AM
Doshi
P D
PD
Evans
M L
ML
Thurman
T L
TL
Braford
S R
SR
Caparon
M H
MH
Bauer
S C
SC
Giri
J G
JG
Welply
J K
JK
McKearn
J P
JP
Smith
W G
WG
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001853:Bone Marrow / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000819:agonists* / Q000494:pharmacology; D006397:Hematinics / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D016130:Immunophenotyping; D066298:In Vitro Techniques; D007377:Interleukin-3 / Q000494:pharmacology*; D008533:Megakaryocytes / Q000378:metabolism; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism; D016185:Receptors, Interleukin-3 / Q000819:agonists* / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins
D015703:Antigens, CD; D000970:Antineoplastic Agents; D006397:Hematinics; D007377:Interleukin-3; D016185:Receptors, Interleukin-3; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; C400711:leridistim