In vivo effect of human granulocyte colony-stimulating factor derivatives on hematopoiesis in primates

Using cynomolgus monkeys, we studied the hematopoietic effect and antigenicity of the human granulocyte colony-stimulating factor (hG-CSF) derivatives mutated at N-terminal amino acids (NC-59 and KW-2228) and that lacking N-terminal amino acids (M-7) in comparison with intact hG-CSF. These compounds were subcutaneously administered daily into the back of cynomolgus monkeys at the doses of 1 and 100 micrograms/kg for 2 weeks, and withdrawn for 2 weeks (1st course). After that, the same schedule was repeated (2nd course), and intact hG-CSF and KW-2228 were further administered for 2 weeks (3rd course). In the first course, all of the G-CSF derivatives showed excellent dose-dependent granulopoietic activities. In the 2nd course, however, the activities of NC-59 and M-7 were decreased and the elevations of binding and neutralizing antibody titers were observed. On the other hand, KW-2228 showed granulopoietic activities equal to or better than that of intact hG-CSF and had low antibody titer throughout all the courses.