Development, preclinical safety, formulation, and stability of clinical grade bevacizumab-800CW, a new near infrared fluorescent imaging agent for first in human use

作者：ter Weele Eva J; van Scheltinga Anton G T Terwisscha; Linssen Matthijs D; Nagengast Wouter B; Lindner Ingo; Jorritsma Smit Annelies; de Vries Elisabeth G E; Kosterink Jos G W; Lub de Hooge Marjolijn N

来源：European Journal of Pharmaceutics and Biopharmaceutics, 2016, 104: 226-234.

DOI：10.1016/j.ejpb.2016.05.008

• Bevacizumab-800CW
• IRDye 800CW
• Bevacizumab
• Optical imaging
• Clinical application
• For human use

There is a dire need for better visualization of cancer and analysis of specific targets in vivo. Molecular imaging with fluorescence is gaining more and more attention, as it allows detection of these targets and has advantages over radioactivity, such as no radiation dose, and lower costs. A key challenge in optical imaging however, is translation of the newly developed tracers from pre-clinical phase to clinical application. We describe the development and safety testing of clinical grade bevacizumab-800CW, an antibody-based targeted agent for non-invasive imaging of vascular endothelial growth factor A (VEGF-A).
Development included implementing the manufacturing process and analytical methods according to current Good Manufacturing Practice (cGMP), formulation studies, extended characterization and stability testing. For safety pharmacology an extended single dose toxicity study in mice was performed.
Bevacizumab-800CW was formulated in isotonic phosphate buffered sodium chloride solution at pH 7. The production was robust and showed a reproducible labeling efficiency, and no impurities. The binding affinity to VEGF-A remained intact. The optimized product meets all release specifications, is stable up to at least 3 months and its characteristics did not significantly differ from the unlabeled bevacizumab. Toxicity testing in mice showed no remarkable findings.
In conclusion, sterile bevacizumab-800CW (6 mg = 6 ml) can be produced in stock according to current Good Manufacturing Practice. It is ready for first-in-human use.

• 出版日期2016-7