The Characterization and Potential use of G-CSF Dimers and their Pegylated Conjugates.
G-CSF successfully prevents chemotherapy-induced neutropenia. Two second-generation drugs with improved therapeutic properties are already available and the development of new forms is still ongoing. For an efficient receptor dimerization two G-CSF molecules have to bind. Development of G-CSF dimers acting as receptor dimerizers was explored and their potential use evaluated. The in vitro biological activities of the prepared dimers were lower than G-CSF monomer activity, presumably due to non-optimal spatial orientation of the molecules. Most likely two dimers had to bind to trigger receptor dimerization instead of one dimer acting as a dimerizer. Although significantly lower in the residual in vitro biological activity, the diPEG-Fdim conjugate exhibited pharmacokinetical (PK) and pharmacodynamical (PD) properties comparable to pegfilgrastim or even better. An interesting PD profile with the second maximum in absolute neutrophil count (ANC) and a balanced elevated ANC profile over the longer time interval was namely observed.
Katarina
K
Fidler
Simona
S
Jevševar
Tatjana
T
Milunović
Spela
S
Skrajnar
Aleš
A
Premzl
Menči
M
Kunstelj
Irena
I
Zore
Barbara
B
Podobnik
Mateja
M
Kusterle
Simon
S
Caserman
Maja
M
Kenig
Vanja
V
Smilović
Ladka
L
Gaberc-Porekar