| Autor: |
Bhaskar, Vinay, Goldfine, Ira D., Gerstner, Resi, Michelson, Kristen, Tran, Catarina, Nonet, Genevieve, Bohmann, David, Pongo, Elizabeth, Zhao, Jingsong, Horwitz, Arnold H., Takeuchi, Toshihiko, White, Mark, Corbin, John A. |
| Předmět: |
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| Zdroj: |
Obesity (19307381); Aug2016, Vol. 24 Issue 8, p1687-1694, 8p |
| Abstrakt: |
Objective: Leptin (LEP) deficiency results in major metabolic perturbations, including obesity, dyslipidemia, and diabetes. Although LEP deficiency can be treated with daily injections of a recombinant LEP, generation of an antibody activating the LEP receptor (LEPR) that has both an intrinsically long half-life and low immunogenicity could be useful in the treatment of this condition.Methods: Phage display technology coupled with flow cytometry and cell-based in vitro assays were employed to identify an allosteric agonist of the mouse LEPR. LEP-deficient Lep(ob) /Lep(ob) mice were used to compare in vivo effects of LEP to antibody administration. To evaluate hypothalamic effects of treatment, changes in mRNA levels of neuropeptide Y and proopiomelanocortin were measured.Results: XPA.80.037 is a monoclonal antibody that demonstrates allosteric agonism of the mouse LEPR. Treatment of Lep(ob) /Lep(ob) mice with XPA.80.037 markedly reduced hyperphagia and body weight, normalized blood glucose and plasma insulin levels, and corrected dyslipidemia. These metabolic alterations correlated with changes in mRNA levels of neuropeptide Y and proopiomelanocortin, suggesting that XPA.80.037 had hypothalamic effects.Conclusions: Agonist allosteric monoclonal antibodies to the LEPR can correct metabolic effects associated with LEP deficiency in vivo and thereby have the potential to treat conditions of LEP deficiency. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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