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PEDS Advance Access published online on March 14, 2005
Protein Engineering Design and Selection, doi:10.1093/protein/gzh102
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org
Received April 7, 2004
Revised November 12, 2004
Accepted December 13, 2004

Article

Engineering a pharmacologically superior form of leptin for the treatment of obesity

Kin-Ming Lo 1*, Jinyang Zhang 1, Yaping Sun 1, Bo Morelli 1, Yan Lan 1, Scott Lauder 1, Beatrice Brunkhorst 1, Gordon Webster 1, Sophie Hallakou-Bozec 2, Lilliane Doaré 2, and Stephen D. Gillies 1

1 EMD-Lexigen Research Center, Bedford Campus, 45A Middlesex Turnpike, Billerica, MA 01821, USA
2 Merck-Santé S.A., 4 Avenue du President François Mitterand, 91380 Chilly-Mazarin, France

* To whom correspondence should be addressed.
Kin-Ming Lo, E-mail: klo{at}emdlexigen.com


  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.

Keywords: diabetes; Fc; immunoglobulin; leptin; obesity.
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