title: An allosteric antibody to the leptin receptor reduces body weight and reverses the diabetic phenotype in the Lep(ob) /Lep(ob) mouse.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Preclinical Development, XOMA Corporation, Berkeley, California, USA.
authors.forename: Vinay
authors.initials: V
authors.lastname: Bhaskar
authors.affiliation: Preclinical Development, XOMA Corporation, Berkeley, California, USA.
authors.forename: Ira D
authors.initials: ID
authors.lastname: Goldfine
authors.affiliation: Discovery Research, XOMA Corporation, Berkeley, California, USA.
authors.forename: Resi
authors.initials: R
authors.lastname: Gerstner
authors.affiliation: Discovery Research, XOMA Corporation, Berkeley, California, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Michelson
authors.affiliation: Discovery Research, XOMA Corporation, Berkeley, California, USA.
authors.forename: Catarina
authors.initials: C
authors.lastname: Tran
authors.affiliation: Discovery Research, XOMA Corporation, Berkeley, California, USA.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Nonet
authors.affiliation: Discovery Research, XOMA Corporation, Berkeley, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Bohmann
authors.affiliation: Discovery Research, XOMA Corporation, Berkeley, California, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pongo
authors.affiliation: Preclinical Development, XOMA Corporation, Berkeley, California, USA.
authors.forename: Jingsong
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Discovery Research, XOMA Corporation, Berkeley, California, USA.
authors.forename: Arnold H
authors.initials: AH
authors.lastname: Horwitz
authors.affiliation: Discovery Research, XOMA Corporation, Berkeley, California, USA.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Takeuchi
authors.affiliation: Discovery Research, XOMA Corporation, Berkeley, California, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: White
authors.affiliation: Discovery Research, XOMA Corporation, Berkeley, California, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Corbin
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight; D003920:Diabetes Mellitus / Q000378:metabolism; D006207:Half-Life; D007031:Hypothalamus / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D020738:Leptin / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism*; D010641:Phenotype; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D054411:Receptors, Leptin / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D020738:Leptin; D054411:Receptors, Leptin; D011333:Pro-Opiomelanocortin