Improvement of biological and pharmacokinetic features of human interleukin-11 by site-directed mutagenesis.
Recombinant human interleukin-11 (rhIL-11) has been shown to increase platelet counts in animals and humans and is the only drug approved for its use in chemotherapy-induced thrombocytopenia (CIT). However, due to its serious side effects, its clinical use has been limited. The current work presents significantly improved efficacy of rhIL-11 via knowledge based re-designing process. The interleukin-11 mutein (mIL-11) was found to endure chemical and proteolytic stresses, while retaining the biological activity of rhIL-11. The improved efficacy of mIL-11 was evident after subcutaneous administration of mIL-11 and rhIL-11 in the rodent and primate models. More than three-fold increase in maximum plasma concentration (Cmax) and area-under-the curve (AUC) was observed. Furthermore, three-fold higher increase in the platelet counts was obtained after seven consecutive daily subcutaneous mIL-11 injections than that with rhIL-11. The mIL-11 demonstrated not only improved stability but also enhanced efficacy over the currently used rhIL-11 regimen, thereby suggesting less toxicity.
ViroMed Co., Ltd., Seoul, Republic of Korea. yunijung@viromed.co.kr
Yuni
Y
Jung
Haesook
H
Ahn
Dong-Sik
DS
Kim
Yu Ri
YR
Hwang
Seong-Hyun
SH
Ho
Jong-Mook
JM
Kim
Sujeong
S
Kim
Suyong
S
Ma
Sunyoung
S
Kim
D000595:Amino Acid Sequence; D000818:Animals; D000882:Haplorhini; D006801:Humans; D017370:Interleukin-11 / Q000737:chemistry* / Q000235:genetics / Q000493:pharmacokinetics*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D055550:Protein Stability; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics
D017370:Interleukin-11; D011994:Recombinant Proteins; C105308:oprelvekin