Engineering a pharmacologically superior form of leptin for the treatment of obesity.
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.
Lo
Kin-Ming
KM
EMD-Lexigen Research Center, Bedford Campus, 45A Middlesex Turnpike, Billerica, MA 01821, USA. klo@emdlexigen.com
Zhang
Jinyang
J
Sun
Yaping
Y
Morelli
Bo
B
Lan
Yan
Y
Lauder
Scott
S
Brunkhorst
Beatrice
B
Webster
Gordon
G
Hallakou-Bozec
Sophie
S
Doaré
Lilliane
L
Gillies
Stephen D
SD
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
D017931:DNA Primers; D020738:Leptin; D011993:Recombinant Fusion Proteins