title: The LIF receptor antagonist PEGLA is effectively delivered to the uterine endometrium and blocks LIF activity in cynomolgus monkeys.
abstract: BACKGROUND
  Leukemia inhibitory factor (LIF) is a cytokine with an essential role in the preparation of the endometrium for implantation. Previous studies demonstrated that PEGLA, a LIF receptor antagonist (LA) conjugated with polyethylene glycol (PEG), effectively prevents implantation in mice, identifying PEGLA as a potential contraceptive for women.
  
  
  METHODS
  Adult female cynomolgus macaques were used to determine the optimal route of administration to deliver PEGLA to the uterine endometrium. Endometrial explants were used to examine the ability of PEGLA to block LIF action at endometrial cells.
  
  
  RESULTS
  Both intramuscular and subcutaneous PEGLA administration resulted in peak serum PEGLA 24 h after administration; serum PEGLA was detectable throughout the 144-h sampling period. In contrast, serum PEGLA was near or below the limit of detection after vaginal administration. After intramuscular administration, PEGLA was localized to both luminal and glandular epithelial cells of the uterine endometrium, and PEGLA was measurable in endometrial lysates. PEGLA administration reduced endometrial signal transducer and activator of transcription protein 3 (STAT3) phosphorylation in vivo and in vitro. PEGLA also blocked LIF's ability to elevate expression of cochlin, insulin-like growth factor-binding protein 3, vascular endothelial growth factor A, and cyclooxygenase-2 (also known as PTGS2) in endometrial explants in vitro.
  
  
  CONCLUSIONS
  PEGLA was delivered to the non-human primate uterine endometrium with systemic administration, and PEGLA blocked LIF actions associated with implantation. Blocking LIF receptor activity with the antagonist PEGLA may prevent pregnancy in women and provide a novel alternative to currently-available hormonal and barrier contraceptives.
authors.affiliation: Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA 23507, USA.
authors.forename: Lindsey C
authors.initials: LC
authors.lastname: Aschenbach
authors.forename: Kim E
authors.initials: KE
authors.lastname: Hester
authors.forename: Nicole C
authors.initials: NC
authors.lastname: McCann
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Zhang
authors.forename: Evdokia
authors.initials: E
authors.lastname: Dimitriadis
authors.forename: Diane M
authors.initials: DM
authors.lastname: Duffy
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D003271:Contraceptive Agents, Female / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D004717:Endometrium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D007150:Immunohistochemistry; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D053605:Leukemia Inhibitory Factor / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D008657:Metabolic Clearance Rate; D009994:Osmolar Concentration; D010766:Phosphorylation / Q000187:drug effects; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D046509:Tissue Culture Techniques; D014018:Tissue Distribution
chemical_list: D003271:Contraceptive Agents, Female; D053605:Leukemia Inhibitory Factor; D050796:STAT3 Transcription Factor; C525879:pegylated MH35-BD-Q29A+G124R protein; D011092:Polyethylene Glycols