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A Comparison of EGF and MAb 528 Labeled with ¹¹¹In for Imaging Human Breast Cancer

Division of Nuclear Medicine and Departments of Pathology and Radiation Oncology, Toronto General Hospital/Princess Margaret Hospital, University Health Network, Toronto
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto
Departments of Medical Imaging, Pharmaceutical Sciences, Radiation Oncology, and Medical Biophysics, University of Toronto, Toronto, Canada

Correspondence: For correspondence or reprints contact: Raymond M. Reilly, PhD, Division of Nuclear Medicine, Toronto General Hospital, 585 University Ave., Toronto, Ontario, M5G 2C4 Canada.

ABSTRACT

Our objective was to compare ¹¹¹In-labeled human epidermal growth factor (hEGF), a 53-amino acid peptide with anti-epidermal growth factor receptor (EGFR) monoclonal antibody (MAb) 528 (lgG_2a) for imaging EGFR-positive breast cancer. Methods: hEGF and MAb 528 were derivatized with diethylenetriamine pentaacetic acid (DTPA) and labeled with ¹¹¹In acetate. Receptor binding assays were conducted in vitro against MDA-MB-468 human breast cancer cells. Biodistribution and tumor imaging studies were conducted after intravenous injection of the radiopharmaceuticals in athymic mice bearing subcutaneous MCF-7, MDA-MB-231, or MDA-MB-468 human breast cancer xenografts or in severe combined immunodeficiency mice implanted with a breast cancer metastasis (JW-97 cells). MCF-7, MDA-MB-231, JW-97, and MDA-MB-468 cells expressed 1.5 x 10⁴, 1.3 x 10⁵, 2.7 x 10⁵, and 1.3 x 10⁶ EGFR/cell, respectively in vitro. Results: ¹¹¹In-DTPA-hEGF and ¹¹¹In-DTPA-MAb 528 bound with high affinity to MDA-MB-468 cells (K_a of 7.5 x 10⁸ and 1.2 x 10⁸ L/mol, respectively). ¹¹¹In-DTPA-hEGF was eliminated rapidly from the blood with < 0.2% injected dose/g (%ID/g) circulating at 72 h after injection, whereas ¹¹¹In-DTPA-MAb 528 was cleared more slowly (3 %ID/g in the blood at 72 h). Maximum localization of ¹¹¹In-DTPA-hEGF in MDA-MB-468 tumors (2.2 %ID/g) was 10-fold lower than with ¹¹¹In-DTPA-MAb 528 (21.6 %ID/g). There was high uptake in the liver and kidneys for both radiopharmaceuticals. Tumor-to-blood ratios were greater for ¹¹¹In-labeled hEGF than for MAb 528 (12:1 versus 6:1), but all other tumor-to-normal tissue ratios were higher for MAb 528. MDA-MB-468 and JW-97 tumors were imaged successfully with both radiopharmaceuticals, but tumors were more easily visualized using ¹¹¹In-labeled MAb 528. There was no direct quantitative relationship between EGFR expression on breast cancer cell lines in vitro, and tumor uptake of the radiopharmaceuticals in vivo, but control studies showed that tumor uptake was receptor mediated. Conclusion: Our results suggest that the tumor uptake in vivo of receptor-binding radiopharmaceuticals is controlled to a greater extent by their elimination rate from the blood than by the level of receptor expression on the cancer cells. Radiolabeled anti-EGFR MAbs would be more effective for tumor imaging in cancer patients than peptide-based radiopharmaceuticals such as hEGF, because they exhibit higher tumor uptake at only moderately lower tumor-to-blood ratios.

Key Words: breast cancer • epidermal growth factor • monoclonal antibody 528 • ¹¹¹In • imaging • epidermal growth factor receptor

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