title: Enhanced pharmacological activity of recombinant human interleukin-11 (rhIL11) by chemical modification with polyethylene glycol.
abstract: In order to improve the pharmacological efficacy of recombinant human interleukin-11 (rhIL11) and to reduce the frequency of administration, we examined the feasibility of chemical modification of rhIL11 by polyethylene glycol. The rhIL11 was chemically modified by using branched type (PEG2), or linear type (PEG) polyethylene glycol-N-hydroxysuccinimide with various molecular weights. Plasma profiles of immunoreactive rhIL11 after i.v. injection of the 20 kDa PEG2 conjugated rhIL11 (PEG2 (20 K)-rhIL11) were determined by ELISA. Peripheral platelet counts after the administration of the various conjugates were measured. Pharmacokinetic analysis revealed that the mean residence time of PEG2 (20 K)-rhIL11 after i.v. injection extensively increased by a factor of ca 60 compared with the native rhIL11. Maximum peripheral platelet increase of 67% for PEG2 (20 K)-rhIL11 and that of 50% for PEG (20 K)-rhIL11 over the control was observed whereas no significant change was associated with the bolus i.v. injection of native rhIL11. On the other hand, the remaining biological activity of these PEGylated-rhIL11s was 14-16% of native rhIL11, suggesting that retention of rhIL11 in plasma is much effective in order to potentiate the pharmacological efficacy of the cytokine. Chemical modification of rhIL11 by PEG is a promising approach for improving the clinical efficacy of rhIL11 by prolonged retention in plasma.
authors.affiliation: Pharmaceutical Research and Technology Laboratories, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka, Japan. akira-takagi@jp.astellas.com <akira-takagi@jp.astellas.com>
authors.forename: Akira
authors.initials: A
authors.lastname: Takagi
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamashita
authors.forename: Tatsunobu
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Takaishi
authors.forename: Kyoko
authors.initials: K
authors.lastname: Sano
authors.forename: Hideto
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Maeda
authors.forename: Katsumi
authors.initials: K
authors.lastname: Saito
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Takakura
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Hashida
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007275:Injections, Intravenous; D017370:Interleukin-11 / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008815:Mice, Inbred Strains; D008970:Molecular Weight; D010976:Platelet Count; D011092:Polyethylene Glycols / Q000737:chemistry*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; C508611:IL11 protein, human; D017370:Interleukin-11; D011994:Recombinant Proteins; D011092:Polyethylene Glycols