title: Engineering a pharmacologically superior form of leptin for the treatment of obesity.
abstract: Leptin plays a central role in the homeostasis of body weight through its regulatory effects on appetite and energy expenditure, yet in trials as a therapeutic agent for the treatment of obesity in humans it has been disappointing. The poor clinical efficacy of leptin results from its short circulating half-life, low potency and poor solubility, necessitating large and frequent doses to obtain even modest clinical benefit. Engineered Fc-leptin immunofusins, consisting of the Fc fragment of an immunoglobulin gamma chain followed by leptin, exhibit improved pharmacological properties with very consistent and potent biological activities. Furthermore, in extending the circulating half-life of the protein in vivo from a few minutes for leptin to many hours for Fc-leptin, these proteins have the potential to reduce drastically the dosage and frequency of administration required to obtain clinical benefit. The results of this study show that the engineered leptin immunofusins described here have significantly enhanced pharmacological properties in comparison with the recombinant leptin that was used in clinical trials. As such, they could represent an important step towards a therapeutically superior form of leptin if the disappointing performance of leptin in early clinical trials was due to its poor pharmacological properties rather than any conceptual weakness in the strategy of using leptin for the treatment of obesity and its related disorders.
authors.affiliation: EMD-Lexigen Research Center, Bedford Campus, 45A Middlesex Turnpike, Billerica, MA 01821, USA. klo@emdlexigen.com
authors.forename: Kin-Ming
authors.initials: KM
authors.lastname: Lo
authors.forename: Jinyang
authors.initials: J
authors.lastname: Zhang
authors.forename: Yaping
authors.initials: Y
authors.lastname: Sun
authors.forename: Bo
authors.initials: B
authors.lastname: Morelli
authors.forename: Yan
authors.initials: Y
authors.lastname: Lan
authors.forename: Scott
authors.initials: S
authors.lastname: Lauder
authors.forename: Beatrice
authors.initials: B
authors.lastname: Brunkhorst
authors.forename: Gordon
authors.initials: G
authors.lastname: Webster
authors.forename: Sophie
authors.initials: S
authors.lastname: Hallakou-Bozec
authors.forename: Lilliane
authors.initials: L
authors.lastname: Doaré
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Gillies
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D003001:Cloning, Molecular; D017931:DNA Primers; D004334:Drug Administration Schedule; D006801:Humans; D020738:Leptin / Q000008:administration & dosage / Q000235:genetics* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D009765:Obesity / Q000188:drug therapy*; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D017931:DNA Primers; D020738:Leptin; D011993:Recombinant Fusion Proteins