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. Disclosures: No relevant conflicts of interest to declare.