title: Potent interleukin 3 receptor agonist with selectively enhanced hematopoietic activity relative to recombinant human interleukin 3.
abstract: A systematic evaluation of structure-activity information led to the construction of genetically engineered interleukin 3 (IL-3) receptor agonists (synthokines) with enhanced hematopoietic potency. SC-55494, the most extensively characterized member of this series, exhibits 10- to 20-fold greater biological activity than recombinant human IL-3 (rhIL-3) in human hematopoietic cell proliferation and marrow colony-forming-unit assays. In contrast, SC-55494 is only twice as active as rhIL-3 in priming the synthesis of inflammatory mediators such as leukotriene C4 and triggering the release of histamine from peripheral blood leukocytes. The enhanced hematopoietic activity of SC-55494 correlates with a 60-fold increase in IL-3 alpha-subunit binding affinity and a 20-fold greater affinity for binding to alpha/beta receptor complexes on intact cells relative to rhIL-3. SC-55494 demonstrates a 5- to 10-fold enhanced hematopoietic response relative to its ability to activate the priming and release of inflammatory mediators. Therefore, SC-55494 may ameliorate the myeloablation of cancer therapeutic regimens while minimizing dose-limiting inflammatory side effects.
authors.affiliation: Searle R & D, Monsanto Co, St. Louis, MO 63198, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Thomas
authors.forename: C M
authors.initials: CM
authors.lastname: Baum
authors.forename: W F
authors.initials: WF
authors.lastname: Hood
authors.forename: B
authors.initials: B
authors.lastname: Klein
authors.forename: J B
authors.initials: JB
authors.lastname: Monahan
authors.forename: K
authors.initials: K
authors.lastname: Paik
authors.forename: N
authors.initials: N
authors.lastname: Staten
authors.forename: M
authors.initials: M
authors.lastname: Abrams
authors.forename: J P
authors.initials: JP
authors.lastname: McKearn
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D007377:Interleukin-3 / Q000096:biosynthesis / Q000494:pharmacology* / Q000031:analogs & derivatives; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute; D017997:Leukotriene C4 / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments; D010455:Peptides / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D016185:Receptors, Interleukin-3 / Q000819:agonists* / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000819:agonists / Q000096:biosynthesis / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D017931:DNA Primers; D007377:Interleukin-3; D010446:Peptide Fragments; D010455:Peptides; D016185:Receptors, Interleukin-3; D011994:Recombinant Proteins; D017997:Leukotriene C4; C093340:daniplestim