title: Immunogenicity associated with metreleptin treatment in patients with obesity or lipodystrophy.
abstract: Recombinant human leptin (metreleptin) improves glycaemia and hypertriglyceridaemia in patients with generalized lipodystrophy; antibody development with in vitro neutralizing activity has been reported. We aimed to characterize antimetreleptin antibody development, including in vitro neutralizing activity.
  
  
  
  Two randomized controlled studies in patients with obesity (twice-daily metreleptin ± pramlintide for 20-52 weeks; 2006-2009); two long-term, open-label studies in patients with lipodystrophy (once-daily or twice-daily metreleptin for 2 months to 12·3 years; 2000-2014).
  
  
  
  A total of 579 metreleptin-treated patients with obesity and 134 metreleptin-treated patients with lipodystrophy (antibody/neutralizing activity data: n = 105).
  
  
  
  Antimetreleptin antibodies, in vitro neutralizing activity.
  
  
  
  Antimetreleptin antibodies developed in most patients (obese: 96-100%; lipodystrophy: 86-92%). Peak antibody titers (approximately 1:125 to 1:3125) generally occurred within 4-6 months and decreased with continued therapy (lipodystrophy). Antibody development did not adversely impact efficacy or safety (patients with obesity), except for inflammatory injection site reactions, but was associated with elevated leptin concentrations. Three patients with obesity developed in vitro neutralizing activity coincident with weight gain. Weight later returned to baseline in one patient despite persistent neutralizing activity. Four patients with generalized lipodystrophy developed in vitro neutralizing activity concurrent with worsened metabolic control; two with confounding comorbidities had sepsis. One patient with lipodystrophy had resolution of neutralizing activity on metreleptin.
  
  
  
  Development of in vitro neutralizing activity could be associated with loss of efficacy but has not been consistently associated with adverse clinical consequences. Whether neutralization of endogenous leptin with clinical consequences occurs remains unclear.
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Jean L
authors.initials: JL
authors.lastname: Chan
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Koda
authors.affiliation: AstraZeneca, San Diego, CA, USA.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Heilig
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Elaine K
authors.initials: EK
authors.lastname: Cochran
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Gorden
authors.affiliation: Division of Metabolism, Endocrinology & Diabetes (MEND), University of Michigan, Ann Arbor, MI, USA.
authors.forename: Elif A
authors.initials: EA
authors.lastname: Oral
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Brown
mesh_terms: D000293:Adolescent; D000328:Adult; D000906:Antibodies / Q000097:blood; D000917:Antibody Formation; D002648:Child; D005260:Female; D006801:Humans; D055261:Immunogenetic Phenomena; D058228:Islet Amyloid Polypeptide / Q000627:therapeutic use; D020738:Leptin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000276:immunology / Q000627:therapeutic use; D008060:Lipodystrophy / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000906:Antibodies; D058228:Islet Amyloid Polypeptide; D020738:Leptin; C105254:pramlintide; C415771:metreleptin