Abstract
e19574 Background: Chemical modification of recombinant human interleukin-11 (rhIL-11) by polyethylene glycol improved the pharmacokinetics (PK), but not remaining biological activity. Human interleukin-11 mutein (mIL-11) has been shown the improved safety and equivalent efficacy at one-third of the clinical dose of rhIL-11 in chemotherapy-induced thrombocytopenia (CIT) patients. Methods: To evaluate whether PEGylated mIL-11 (PEG-mIL-11) could reduce the toxicity and the frequency of administration without compromising biological activities, comparative preclinical studies on PEG-mIL-11 and mIL-11 in normal and myelosuppressed animals were performed. Results: In vitro biological assay showed that the ED50 value of purified mono-PEG-mIL11 was comparable to that of mIL-11. The PK parameters such as AUC of PEG-mIL-11 were at least 4-fold larger than those of mIL-11 at the same dosage. The thrombopoietic activity resulting from a single PEG-mIL-11 administration was almost similar to that achieved from multiple administrations of mIL-11 in normal rodents and monkeys. In myelosuppressed model, PEG-mIL-11 was s.c. administered twice at doses of 200, 420 or 900 μg/kg and the platelet number of each group was compared with that of control group injected with 200 μg/kg of mIL-11 once daily for 9 days. The high dose group of PEG-mIL-11 showed 2-fold increase in the nadir platelet count and the mean time to platelet recovery of PEG-mIL-11 groups was shortened up to a maximum of 7 days as compared with mIL-11 or untreated group. PEG-mIL-11 also significantly prevented the reduction of WBC and RBC counts which was considered a major hematological AE of chemotherapy and radiotherapy for cancer as compared with mIL-11 or naïve group. Conclusions: These results suggest that the PEG-mIL-11 show improved PK profile without compromising biological activities and prevent CIT more effectively with better safety profile than mIL-11.
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