Journal Article

Toxicity and Pharmacokinetic Profile for Single-Dose Injection of ABY-029: a Fluorescent Anti-EGFR Synthetic Affibody Molecule for Human Use

Samkoe, Kimberley S., Marra, Kayla, Feldwisch, Joachim, Paulsen, Keith, Hoopes, P. Jack, Gunn, Jason R., Hull, Sally M., Pogue, Brian W., Draney, Daniel R., Moodie, Karen L., Strong, Theresa V., Roberts, David W.

2017

Overview

Purpose 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. Procedures 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. Results 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. Conclusion 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.

• Publisher: Springer US,Springer Nature B.V
• Subject: Animals / Binding / Body Weight - drug effects / Brain tumors / Cell culture / Chemistry / Epidermal growth factor / Epidermal growth factor receptors / ErbB Receptors - antagonists & inhibitors / ErbB Receptors - metabolism / Female / Fluorescence / Glioma / Glioma cells / Growth factors / Hematology / Humans / I.R. radiation / Imaging / Injection / Injections / Intravenous administration / Light / Male / Medicine / Medicine & Public Health / Organ Size - drug effects / Organs / Peptide Fragments - administration & dosage / Peptide Fragments - pharmacology / Peptide Fragments - toxicity / Pharmacokinetics / Pharmacology / Phototoxicity / Radiology / Rats / Rats, Sprague-Dawley / Receptors / Recombinant Fusion Proteins - administration & dosage / Recombinant Fusion Proteins - pharmacokinetics / Recombinant Fusion Proteins - toxicity / Research Article / Rodents / Safety / Staphylococcal Protein A - administration & dosage / Staphylococcal Protein A - pharmacology / Staphylococcal Protein A - toxicity / Subgroups / Surgery / Tissue Distribution - drug effects / Tissues / Toxicity / Tumors