scholarly journals Formation of 1:1 Complex of the Cytokine Receptor Homologous Region of Granulocyte Colony-stimulating Factor Receptor with Ligand

1995 ◽  
Vol 59 (12) ◽  
pp. 2351-2354 ◽  
Author(s):  
Osamu Hiraoka ◽  
Hiroyuki Anaguchi ◽  
Yoshimi Ota
Keyword(s):  
Cytokine Receptor ◽  
Homologous Region ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Stimulating Factor

scholarly journals Pre-Clinical Studies of a Novel Recombinant Human Granulocyte Colony-Stimulating Factor

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2920-2920
Author(s):  
Zhihua Ren ◽  
Wenhong Jiang ◽  
Zhenwang Jie ◽  
Xiaoxiao Liu ◽  
Fei Xia ◽  
...  
Keyword(s):  
Half Life ◽  
Safety Evaluation ◽  
Amino Terminus ◽  
Homologous Region ◽  
Preclinical Studies ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Stimulating Factor

Abstract The human granulocyte colony-stimulating factor (G-CSF), a glycoprotein consisting of 174 amino acids, enhances the survival, proliferation, and differentiation of neutrophil precursors. G-CSF also induces the mobilization of hematopoietic stem cells and progenitors, which further stimulates recovery from neutropenia. Further studies indicates that Glu19 in the A helix of G-CSF molecule electrostatically inter-reacts with Arg288 of G-CSF-R. A recent study on the crystal structure of G-CSF, complexed with the cytokine homologous region of G-CSF-R, reveals that residues in the amino-terminus of G-CSF may act as additional contact sites with G-CSF-R. In this investigation, we designed and purified a novel recombinant human granulocyte colony-stimulating factor analog (rhG-CSFa), which has three extra amino acid residues (arginine, glycine, and serine) added at the amino-terminus. The structural modification resulted in more positive charge in the amino-terminus of G-CSFa, and was expected to further enhance the binding between the cytokine and its receptor. We optimized the purification procedure, achieving further improvements in refolding rate and overall yield. In preclinical studies, we evaluated the pharmacodynamics, pharmacokinetics, acute, subacute, and chronic toxicity of rhG-CSFa. Pharmacodynamics study in non-human primates demonstrated that intravenous rhG-CSFa induces typical peripheral neutrophil responses (with two peaks from treatment day 8 to day 20) and dramatic increases in the recovery rate in the animal model. More importantly, rhG-CSFa induced a higher peak of neutrophil recovery on day 7 than wild G-CSF did in monkeys, a result indicating that rhG-CSFa would provide greater benefit for patients receiving myeloid-suppressive therapies. In addition, rhG-CSFa maintained higher neutrophil counts than wild-type G-CSF did after cessation of G-CSF administration in monkeys; its effects persisted over 20 days post-treatment, which should be more helpful to patients for combating deleterious infections and preparing for the next round of treatment in clinic. In pharmacokinetics studies, the novel rhG-CSFa displayed a lower plasma clearance rate, 0.28 ml/min/kg (vs 0.5-0.7 ml/min/kg for wild-type G-CSF). This result suggests that rhG-CSFa may dissociate from its receptor at a slower rate than does wild-type G-CSF, which is possibly due to a tighter binding to its cognate receptor, and would result in a much extended plasma functional half-life. In further preclinical safety evaluation, no obvious toxicity or immunogenicity was observed, neither was any adverse drug reaction. In conclusion, we have generated a novel rhG-CSFa protein, with much higher yield, enhanced circulation half-life, improved thermal stability and greater bioactivity (without changing the overall conformation), compared with wild type G-CSF. Our preclinical studies strongly suggest that rhG-CSFa can be further explored for clinical trials for eventual applications in the clinic. Disclosures Ren: Biopharmagen corp: Employment. Jiang:Biopharmagen.corp: Employment. Shi:Biopharmagen corp: Employment. Jiang:Biopharmagen.corp: Employment.

scholarly journals Effects of granulocyte colony-stimulating factor on plasma cytokine and cytokine receptor levels and on the in vivo host response to endotoxin in healthy men

Blood ◽  
1996 ◽  
Vol 87 (3) ◽  
pp. 900-905 ◽  
Author(s):  
T Pollmacher ◽  
C Korth ◽  
J Mullington ◽  
W Schreiber ◽  
J Sauer ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Host Response ◽  
Cytokine Receptor ◽  
Tnf Alpha ◽  
Control Group ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Healthy Humans ◽  
Stimulating Factor

We investigated the effects of granulocyte colony-stimulating factor (G- CSF) on cytokine and cytokine receptor plasma levels and on the in vivo host response to Salmonella abortus equi endotoxin in healthy males. Twenty volunteers received 0.8 ng/kg endotoxin and saline intravenously 1 week apart in randomized order. Twelve hours before both experiments, 10 of these subjects were pretreated with 300 micrograms G-CSF subcutaneously. G-CSF itself increased granulocyte and monocyte counts and the plasma levels of tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors (sTNF-R) p55, and p75 and interleukin-1 receptor antagonist (IL-1ra). G-CSF did not influence plasma IL-1 beta and IL-6 levels. In the G-CSF-pretreated subjects endotoxin-induced surges in rectal temperature and in the plasma levels of TNF-alpha plasma levels were about 50% increased, and surges in the plasma levels of both sTNF- Rs and IL-1ra were about twice as high as in the control group. Endotoxin-induced increases in IL-6, cortisol, and heart rate were not modified by G-CSF pretreatment. Endotoxin administration induced a transient 50% reduction in leukocyte counts in the G-CSF-pretreated subjects that was not seen in the control group. We conclude that a single stand dose of G-CSF increases the plasma levels of cytokines and cytokine receptors and considerably modifies the host response of healthy humans to a low dose of endotoxin.

Granulocyte-colony stimulating factor for the treatment of neurodegenerative diseases

2008 ◽  
Vol 35 (S 01) ◽  
Author(s):  
T Frank ◽  
K Meuer ◽  
C Pitzer ◽  
J Schulz ◽  
M Bähr ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Stimulating Factor
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