IND-directed safety and biodistribution study of intravenously injected cetuximab-IRDye800 in cynomolgus macaques.

Academic Article

Abstract

  • PURPOSE: The use of receptor-targeted antibodies conjugated to fluorophores is actively being explored for real-time imaging of disease states; however, the toxicity of the bioconjugate has not been assessed in non-human primates. PROCEDURES: To this end, the in vivo toxicity and pharmacokinetics of IRDye800 conjugated to cetuximab (cetuximab-IRDye800; 21 mg/kg; equivalent to 250 mg/m(2) human dose) were assessed in male cynomolgus monkeys over 15 days following intravenous injection and compared with an unlabeled cetuximab-dosed control group. RESULTS: Cetuximab-IRDye800 was well tolerated. There were no infusion reactions, adverse clinical signs, mortality, weight loss, or clinical histopathology findings. The plasma half-life for the cetuximab-IRDye800 and cetuximab groups was equivalent (2.5 days). The total recovered cetuximab-IRDye800 in all tissues at study termination was estimated to be 12 % of the total dose. Both cetuximab-IRDye800 and cetuximab groups showed increased QTc after dosing. The QTc for the cetuximab-dosed group returned to baseline by day 15, while the QTc of the cetuximab-IRDye800 remained elevated compared to baseline. CONCLUSION: IRDye800 in low molar ratios does not significantly impact cetuximab half-life or result in organ toxicity. These studies support careful cardiac monitoring (ECG) for human studies using fluorescent dyes.
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    Keywords

  • Animals, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Cetuximab, Dose-Response Relationship, Drug, Electrocardiography, Fluorescent Dyes, Indoles, Injections, Intravenous, Macaca fascicularis, Male, Neoplasms, Signal-To-Noise Ratio, Tissue Distribution
  • Digital Object Identifier (doi)

    Author List

  • Zinn KR; Korb M; Samuel S; Warram JM; Dion D; Killingsworth C; Fan J; Schoeb T; Strong TV; Rosenthal EL
  • Start Page

  • 49
  • End Page

  • 57
  • Volume

  • 17
  • Issue

  • 1