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In vivo Diagnosis of Epidermal Growth Factor Receptor Expression using Molecular Imaging with a Cocktail of Optically Labeled Monoclonal Antibodies

Authors' Affiliations: ¹ Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, and ² Nuclear Medicine Department, Warren Magnuson Clinical Center, NIH, Bethesda, Maryland; and ³ Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

Requests for reprints: Hisataka Kobayashi, Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, NIH, Building 10, Room 1B40, Bethesda, MD 20892-1088. Phone: 301-435-4086; Fax: 301-402-3191; E-mail: kobayash{at}mail.nih.gov.

Purpose: Epidermal growth factor receptors (EGFR) play an important role in tumorigenesis and, therefore, have become targets for new molecular therapies. Here, we use a "cocktail" of optically labeled monoclonal antibodies directed against EGFR-1 (HER1) and EGFR-2 (HER2) to distinguish tumors by their cell surface expression profiles.

Experimental Design: In vivo imaging experiments were done in tumor-bearing mice following s.c. injection of A431 (overexpressing HER1), NIH3T3/HER2+ (overexpressing HER2), and Balb3T3/DsRed (non-expression control) cell lines. After tumor establishment, a cocktail of optically labeled antibodies: Cy5.5-labeled cetuximab (anti-HER1) and Cy7-labeled trastuzumab (anti-HER2) was i.v. injected. In vivo and ex vivo fluorescence imaging was done. For comparison with radionuclide imaging, experiments were undertaken using ¹¹¹Indium-labeled antibodies. Additionally, a "blinded" diagnostic study was done for mice bearing one tumor type.

Results: In vivo spectral fluorescent molecular imaging of 14 mice with three tumor types clearly differentiated tumors using the cocktail of optically labeled antibodies both in vivo and ex vivo. Twenty-four hours after injection, A431 and NIH3T3/HER2+ tumors were detected distinctly by their peak on Cy5.5 and Cy7 spectral images, respectively; radionuclide imaging was unable to clearly distinguish tumors at this time point. In blinded single tumor experiments, investigators were able to correctly diagnose a total of 40 tumors.

Conclusion: An in vivo imaging technique using an antibody cocktail simultaneously differentiated two tumors expressing distinct EGFRs and enabled an accurate characterization of each subtype.

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