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In this project we proposed to establish feasibility of the development of targeted tracers for radionuclide imaging of epidermal growth factor receptors (EGFR) in cancer patients. The significance and impact of the proposed radiotracers are determined by the crucial role that EGFR plays in many cancers and by the rapid entrance of EGFR-inhibiting drugs into clinic. Clinical experience, however, revealed that only 10-25% of patients that are defined as EGFR-positive by immunohistochemical analysis respond to EGFR-directed therapeutics and there is poor correlation between EGFR immunohistochemistry and treatment. Therefore, for more efficacious use of EGFR-targeting therapeutics, there is a need for information about EGFR activity in patients. We hypothesized that radionuclide imaging of functionally active EGFR will provide such information and would allow for 1) rational patient stratification, 2) rapid monitoring of responses to therapy, and 3) development of personalized treatment regimens. We hypothesized that tracers based epidermal growth factor (EGF), a natural EGFR ligand, as a targeting vector would be particularly advantageous. First, only functionally active and therefore critical for disease progression EGFRs will bind and internalize an EGF-based tracer. Second, continuous internalization of EGF-based tracers by recyclable EGFR would lead to intracellular accumulation of radionuclide and improved signal-to-background ratio. Third, small size of EGF relative to antibodies would facilitate tumor penetration with vastly better non-specific soft tissue and blood clearance rates. Fourth, as a human protein, EGF is not expected to be immunogenic. Finally, at the beginning of this project, we have already engineered and expressed functionally active EGF with an N-terminal Cys-tag for site-specific conjugation of various payloads, including radionuclide chelators. In the Phase I of this project, in collaboration with Dr. Blankenberg’s group at Stanford University, 1. To synthesize and validate in vitro EGF-PEG-DOTA conjugate. The key accomplishment in this part of the project is synthesis of functionally active EGF-PEG-DOTA, construction, expression, and purification of functionally active Cys-tagged dimeric EGF (dEGF) and synthesis of corresponding dEGF-PEG-DOTA, development of protocols for radiolabeling EGF-PEG-DOTA and dEGF-PEG-DOTA with 64Cu. 2. To establish clearance, biodistribution, and stability of EGF-based PET 64Cu radiotracer. These characteristics are established for both EGF-PEG-DOTA/64Cu and dEGF-PEG-DOTA/64Cu and found to be comparable with reported data on 64Cu-radiolabeled antibodies. 3. To evaluate PET tumor imaging with EGF-based 64Cu radiotracer in mouse tumor models. Tumor imaging was evaluated in orthotopic human MDA231luc breast carcinoma model in SCID mice. Tracers accumulated in tumor area, allowing for detection of as small as few millimeter tumors. The Technical Objectives of the projects are accomplished and the results are published in Bioconjugate Chem. 20, 742, 2009

Development of Cu-64 labeled EGF for In Vivo PET Imaging of EGFR Expression