An allosteric antibody to the leptin receptor reduces body weight and reverses the diabetic phenotype in the Lep(ob) /Lep(ob) mouse

Obesity (Silver Spring). 2016 Aug;24(8):1687-94. doi: 10.1002/oby.21539. Epub 2016 Jun 21.


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.

MeSH terms

  • Allosteric Regulation
  • Animals
  • Blood Glucose / metabolism*
  • Body Weight
  • Diabetes Mellitus / metabolism
  • Half-Life
  • Hypothalamus / metabolism
  • Insulin Resistance / physiology
  • Leptin / metabolism*
  • Leptin / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Obesity / metabolism*
  • Phenotype
  • Pro-Opiomelanocortin / metabolism*
  • Receptors, Leptin / metabolism*


  • Blood Glucose
  • Leptin
  • Receptors, Leptin
  • Pro-Opiomelanocortin