title: Toxicity and Pharmacokinetic Profile for Single-Dose Injection of ABY-029: a Fluorescent Anti-EGFR Synthetic Affibody Molecule for Human Use.
abstract: ABY-029, a synthetic Affibody peptide, Z03115-Cys, labeled with a near-infrared fluorophore, IRDye® 800CW, targeting epidermal growth factor receptor (EGFR) has been produced under good manufacturing practices for a US Food and Drug Administration-approved first-in-use human study during surgical resection of glioma, as well as other tumors. Here, the pharmacology, phototoxicity, receptor activity, and biodistribution studies of ABY-029 were completed in rats, prior to the intended human use.
  
  
  
  Male and female Sprague Dawley rats were administered a single intravenous dose of varying concentrations (0, 245, 2449, and 24,490 μg/kg corresponding to 10×, 100×, and 1000× an equivalent human microdose level) of ABY-029 and observed for up to 14 days. Histopathological assessment of organs and tissues, clinical chemistry, and hematology were performed. In addition, pharmacokinetic clearance and biodistribution of ABY-029 were studied in subgroups of the animals. Phototoxicity and ABY-029 binding to human and rat EGFR were assessed in cell culture and on immobilized receptors, respectively.
  
  
  
  Histopathological assessment and hematological and clinical chemistry analysis demonstrated that single-dose ABY-029 produced no pathological evidence of toxicity at any dose level. No phototoxicity was observed in EGFR-positive and EGFR-negative glioma cell lines. Binding strength and pharmacokinetics of the anti-EGFR Affibody molecules were retained after labeling with the dye.
  
  
  
  Based on the successful safety profile of ABY-029, the 1000× human microdose 24.5 mg/kg was identified as the no observed adverse effect level following intravenous administration. Conserved binding strength and no observed light toxicity also demonstrated ABY-029 safety for human use.
authors.affiliation: Department of Surgery, Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, NH, 03755, USA. kimberley.s.samkoe@dartmouth.edu.|Thayer School of Engineering, Dartmouth College, Hanover, NH, 03755, USA. kimberley.s.samkoe@dartmouth.edu.
authors.forename: Kimberley S
authors.initials: KS
authors.lastname: Samkoe
authors.affiliation: Thayer School of Engineering, Dartmouth College, Hanover, NH, 03755, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Gunn
authors.affiliation: Thayer School of Engineering, Dartmouth College, Hanover, NH, 03755, USA.
authors.forename: Kayla
authors.initials: K
authors.lastname: Marra
authors.affiliation: Thayer School of Engineering, Dartmouth College, Hanover, NH, 03755, USA.
authors.forename: Sally M
authors.initials: SM
authors.lastname: Hull
authors.affiliation: Center for Comparative Medicine and Research, Dartmouth College, Hanover, NH, 03755, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Moodie
authors.affiliation: Affibody AB, 171 69, Solna, Sweden.
authors.forename: Joachim
authors.initials: J
authors.lastname: Feldwisch
authors.affiliation: Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35294, USA.
authors.forename: Theresa V
authors.initials: TV
authors.lastname: Strong
authors.affiliation: LI-COR Biosciences, Lincoln, NB, 68504, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Draney
authors.affiliation: Department of Surgery, Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, NH, 03755, USA.|Thayer School of Engineering, Dartmouth College, Hanover, NH, 03755, USA.|Center for Comparative Medicine and Research, Dartmouth College, Hanover, NH, 03755, USA.
authors.forename: P Jack
authors.initials: PJ
authors.lastname: Hoopes
authors.affiliation: Department of Surgery, Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, NH, 03755, USA.|Thayer School of Engineering, Dartmouth College, Hanover, NH, 03755, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Roberts
authors.affiliation: Department of Surgery, Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, NH, 03755, USA.|Thayer School of Engineering, Dartmouth College, Hanover, NH, 03755, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Paulsen
authors.affiliation: Department of Surgery, Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, NH, 03755, USA. brian.w.pogue@dartmouth.edu.|Thayer School of Engineering, Dartmouth College, Hanover, NH, 03755, USA. brian.w.pogue@dartmouth.edu.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Pogue
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D005453:Fluorescence; D006801:Humans; D007267:Injections; D008027:Light; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity*; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D013205:Staphylococcal Protein A / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity*; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: C549680:ABY-025; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D013205:Staphylococcal Protein A; D066246:ErbB Receptors
keywords: ABY-029; Affibody; EGFR; Epidermal growth factor receptor; Fluorescence guided surgery; Glioma; IRDye 800CW