title: AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, inhibits angiogenesis in models of ocular neovascular diseases.
abstract: OBJECTIVE
  To determine whether systemic treatment with AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, inhibits neovascular processes in animal models of ocular disease.
  
  
  METHODS
  AMG 386 was tested in a laser-induced choroidal neovascularization (CNV) model in monkeys using fluorescein angiography. The biodistribution of (125)I-AMG 386 was determined in cynomolgus monkeys by whole-body autoradiography and radioanalysis of ocular tissues. A murine retinopathy of prematurity (ROP) model was used to examine the effect of AMG 386 on established and newly formed retinal vessels, either as a single agent or when combined with VEGF inhibition.AMG 386 pharmacokinetics were evaluated in each model.
  
  
  RESULTS
  In the CNV model, AMG 386 significantly decreased fluorescent angiographic leakage and reduced fibroplasia, indicating an impaired healing response consistent with angiogenesis blockade. Radiolabeled AMG 386 was widely distributed across ocular tissues, with highest concentrations in the choroid, cornea, retinal pigmented epithelium, iris/ciliary body, and sclera. In the ROP model, AMG 386 prevented pathologic retinal angiogenesis when administered from P8 to P16 but transiently impeded regression of these abnormal vessels when administered from P17 to P23. Combining AMG 386 with VEGF inhibition led to cooperative prevention of retinal angiogenesis in this model. No AMG 386-related ocular toxicities occurred, and no treatment-related clinical observations were made in any of the studies.
  
  
  CONCLUSIONS
  In this study, AMG 386 inhibited angiogenesis in animal models of CNV and ROP, supporting investigation of AMG 386 for the treatment of ocular neovascular diseases in the clinical setting.
authors.affiliation: Department of Oncology Research, Amgen Inc, Thousand Oaks, California 91320, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Oliner
authors.forename: James
authors.initials: J
authors.lastname: Bready
authors.forename: Linh
authors.initials: L
authors.lastname: Nguyen
authors.forename: Juan
authors.initials: J
authors.lastname: Estrada
authors.forename: Eunju
authors.initials: E
authors.lastname: Hurh
authors.forename: Hongjin
authors.initials: H
authors.lastname: Ma
authors.forename: James
authors.initials: J
authors.lastname: Pretorius
authors.forename: William
authors.initials: W
authors.lastname: Fanslow
authors.forename: T Michael
authors.initials: TM
authors.lastname: Nork
authors.forename: Robert A
authors.initials: RA
authors.lastname: Leedle
authors.forename: Stephen
authors.initials: S
authors.lastname: Kaufman
authors.forename: Angela
authors.initials: A
authors.lastname: Coxon
mesh_terms: D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D042683:Angiopoietin-1 / Q000037:antagonists & inhibitors; D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors; D000818:Animals; D000831:Animals, Newborn; D001345:Autoradiography; D002199:Capillary Permeability / Q000187:drug effects; D020256:Choroidal Neovascularization / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005123:Eye / Q000378:metabolism; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D017403:In Situ Hybridization; D007231:Infant, Newborn; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000494:pharmacology*; D015861:Retinal Neovascularization / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012171:Retinal Vessels / Q000187:drug effects; D012178:Retinopathy of Prematurity / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014018:Tissue Distribution
chemical_list: D020533:Angiogenesis Inhibitors; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D011993:Recombinant Fusion Proteins; C551398:trebananib