Long-Acting Interleukin-11 Shows Improved Activity to Increase Platelet Numbers.

Abstract 3512

Poster Board III-449

Often the clinical efficacy of a therapeutic protein relies on the structural stability, bioavailability, and clearance rate of the protein. The current work presents greatly improved efficacy of human interleukin-11 mutein conjugated with single polyethylene glycol polymer (PEG-mIL-11). The interleukin-11 mutein (mIL-11) is newly redesigned human interleukin-11 to endure chemical and proteolytic stresses while retaining all the biological activities, which reduces chance of causing side effects in clinics. The interleukin-11 mutein is currently under phase II clinical trial in China to evaluate ability to increase platelet counts after chemotherapy. Further, single methoxy-polyethylene glycol succinimidyl carbonate was attached onto mIL-11 via surface exposed amines to prolong the circulation time in vivo. Unlike often observed cases with other PEGylated proteins, the attached bulky PEG provided no hindrance to the receptor binding of IL-11, when in vitro cell proliferation activity was monitored on Ba/F3 cells expressing IL-11 receptors. Interestingly, single subcutaneous administration of PEG-mIL-11 showed higher efficacy to increase platelet counts than daily subcutaneous administration of unmodified mIL-11 of same dosage for 7 days in rats. The pharmacokinetic profile of PEG-mIL-11 was monitored after single subcutaneous injection in rats. The half-time (t_1/2), time to reach the maximum level (T_max), and bioavailability (area-under-curve) of PEG-mIL-11 increased 5-, 6- and 5-fold as compared to the values of unmodified mIL-11 of same dosage, respectively. Mono-PEGylated IL-11 mutein demonstrated not only the prolonged circulation time but also the retained biological activity, thereby the possibility for clinical applications such as the treatment or prevention of the chemotherapy-induced thrombocytopenia.