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A Kit Formulated Under Good Manufacturing Practices for Labeling Human Epidermal Growth Factor with ¹¹¹In for Radiotherapeutic Applications

¹ Division of Nuclear Medicine, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
² Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada
³ Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada
⁴ Viral Therapeutics Inc., Ithaca, New York
⁵ Department of Radiation Oncology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada
⁶ Department of Medical Biophysics, University of Toronto, Toronto, Canada

Our goal was to design and manufacture a kit under good manufacturing practices (GMP) for the preparation of ¹¹¹In-DTPA-hEGF Injection, a novel targeted radiotherapeutic agent for advanced epidermal growth factor receptor (EGFR)-positive breast cancer. Methods: Human EGF (hEGF) was derivatized with diethylenetriaminepentaacetic acid (DTPA) and then purified by size-exclusion chromatography and ultrafiltration. Kits were prepared by dispensing 0.25 mg (1 mL) of DTPA-hEGF in 1 mol/L sodium acetate buffer [pH 6.0] into single-dose glass vials. Raw materials were pharmacopoieal or reagent grade according to the American Chemical Society and were tested for identity and purity. Kits were tested for protein concentration, purity and homogeneity (sodium dodecyl sulfate polyacrylamide gel electrophoresis and size-exclusion high-performance liquid chromatography), pH, clarity and color, volume, DTPA substitution, labeling efficiency, receptor binding to MDA-MB-468 human breast cancer cells, and sterility and apyrogenicity. ¹¹¹In-DTPA-hEGF Injection was tested for pH, radionuclidic and radiochemical purity, clarity and color, and sterility and apyrogenicity. Results: Four lots of kits and 8 lots of ¹¹¹In-DTPA-hEGF Injection passed all quality specifications. The labeling efficiency was 94%–99% with 115–773 MBq ¹¹¹In chloride added to a single kit. ¹¹¹In-DTPA-hEGF exhibited preserved receptor binding against MDA-MB-468 cells (affinity constant [K_a], 0.9–1.1 x 10⁷ L/mol; maximum number of binding sites per cell [B_max], 1.1–2.2 x 10⁶ sites per cell). In addition, labeling of aliquots of the kit suggested that a single vial could be labeled with up to 3,083 MBq ¹¹¹In while maintaining a radiochemical purity of >90%. Kits were stable for >90 d and ¹¹¹In-DTPA-hEGF Injection was stable for >24 h stored at 4°C. Conclusion: The kit formulation is suitable for preparing ¹¹¹In-DTPA-hEGF Injection for a phase I clinical trial in patients with advanced EGFR-positive breast cancer. Establishment of the GMP processes for ¹¹¹In-DTPA-hEGF Injection provides a useful example of manufacturing biotechnology-based investigational radiopharmaceuticals in an academic environment for early phase I clinical trials.

Key Words: Auger electrons • ¹¹¹In • epidermal growth factor • kit • good manufacturing practices

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				Z. Cai, Z. Chen, K. E. Bailey, D. A. Scollard, R. M. Reilly, and K. A. Vallis Relationship Between Induction of Phosphorylated H2AX and Survival in Breast Cancer Cells Exposed to 111In-DTPA-hEGF J. Nucl. Med., August 1, 2008; 49(8): 1353 - 1361. [Abstract] [Full Text] [PDF]

				R. M. Reilly, P. Chen, J. Wang, D. Scollard, R. Cameron, and K. A. Vallis Preclinical Pharmacokinetic, Biodistribution, Toxicology, and Dosimetry Studies of 111In-DTPA-Human Epidermal Growth Factor: An Auger Electron-Emitting Radiotherapeutic Agent for Epidermal Growth Factor Receptor-Positive Breast Cancer J. Nucl. Med., June 1, 2006; 47(6): 1023 - 1031. [Abstract] [Full Text] [PDF]