Imaging of Growth Factor Receptors Background The recognition of the role of epithelial growth factor receptors (EGFRs) in the growth and progression of tumors has had widespread implications for cancer treatment. Not only have blocking antibodies been developed against members of the EGFR family, but downstream small molecule inhibitors have also been developed. Both drug types have already had impact on the management of several major cancers. EGFR imaging represents a potentially important avenue of research. Potential uses of imaging agents targeting EGFRs include more accurate sampling of tissue, patient selection for drug trials, monitoring of therapies directed at EGFR or its downstream clients which impact EGFR expression, developing immuno-conjugates for delivering specific drug therapy and radioimmunotherapy in which therapeutic isotopes are attached to the antibody. We are conducting a variety of pre-clinical and clinical studies to investigate the potential roles of this class of imaging agents. Pre-Clinical Research The potential use of optically labeled monoclonal antibodies for diagnosis is being explored by mixing combinations of antibodies and injecting the cocktail. Cocktails of optically labeled antibodies (Trastuzumab-anti HER2, Cetuximab, anti-HER2, and Declizimab anti-IL2) are injected into mice growing tumors expressing different antigens. The optically labeled antibodies attach to their respective tumors indicating that it is possible to perform in vivo immunohistochemistry(1). This may have direct application in improving the sampling of tumors during surgery or during endoscopy. However, another potential use is to use various pro-drug strategies to deliver each part of the pro-drug via different monoclonal antibody vectors. Proof of this concept is provided by optical imaging that can demonstrate the co-localization and internalization of two or more monoclonal antibodies in vivo. An advantage of optical imaging over radionuclide imaging is that optical imaging is potentially polychromatic allowing each agent to be tagged individually. This allows real time pharmacodynamic analysis of drug effects of tumors (visible superficially at least) and is of potential importance to drug discovery and drug testing(2). In collaboration with Dr. Brechbiels lab we are testing PET labeled monoclonal antibodies and have performed this with both trastuzumab and cetuximab(3). It is still unclear whether SPECT or PET imaging is preferred and a comparison trial using the Small Animal Imaging Programs PET-SPECT-CT device will be conducted when that unit becomes available in late 2007. Over the past two years we have also sponsored a NIH-Oxford Graduate student, Ambika Bumb who has designed an implemented a nanoparticle with antibody targeting. The nanoparticle consists of a core of iron oxide (for MRI) with a shell of silica embedded with C5.5 (for optical imaging) (presented by A. Bumb NanoTech 07 San Diego,CA, 2007). To this platform agent, trastuzumab, chelated with Indium (for SPECT imaging) will be attached. We intend to test this nanoparticle in several in vivo murine models of HER2+ tumors. A variety of investigators have approach the MIP regarding radiolabeling studies of novel antibodies and antibody fragments developed in their laboratories and elsewhere. These include anti-c-MET antibody (Don Bottaro, Urologic Oncology Branch), anti-Mesothelin antibody (Raffit Hassan, Ira Pastan, Laboratory of Molecular Biology) and anti EpCAM antibody (Mike Buck, Laboratory of Pathology). While there are current limitations in the capacity of MIP to perform multiple antibody studies simultaneously we are developing an infrastructure to allow high throughput in this area with the collaboration of Chang Paik in the Nuclear Medicine Department and strategic new recruitments Clinical Studies In May 2007 a clinical study of 111Indium trastuzumab was approved for use in breast cancer patients. This protocols tests the uptake of trastuzumab (Herceptin) in patients with breast cancer who either overexpress or do not overexpress HER2/neu. Following JDC approval in late 2005, the MIP wrote SOPs, GMP contracts, protocols and worked with CTEP over the ensuing months in order to permit this protocol to move forward. Finally the agent was delivered in late 2006 and an exploratory IND was issued in February 2007. Recruiting for this trial has been slow owing to the lack of a dedicated breast oncologist in CCR but the protocol will be shortly expanded to include all patients (exclusive of lymphoma and melanoma) with imageable disease. We are currently working with the NCI-Navy, Shady Grove American Oncologic Group and Georgetown to recruit patients to this trial. Preliminary JDC approval was also received for 111Indium-cetuximab to be used in patients with colon and lung cancer. The preliminary pre-clinical work (still unpublished) has been submitted to the Cancer Imaging Program for incorporation into an xIND submission and SOPs are being written for a GMP product. The recent installation of a clinical SPECT-CT device in the Nuclear Medicine Departement should aid this research. Although only indirectly related to this topic we are also conducting studies with a novel PET agent for human use, 18 F-L-thymidine, a proliferation marker for cancer. Manipulation of EGFR with a variety of therapeutic strategies could result in downregulation of proliferation which could be reflected in uptake values of FLT. This work is ongoing in a trial of lymphoma and pediatric medulloblastoma. 1. Koyama, Y., Hama, Y., Urano, Y., Nguyen, D. M., Choyke, P. L., and Kobayashi, H. Spectral fluorescence molecular imaging of lung metastases targeting HER2/neu. Clin Cancer Res, 13: 2936-2945, 2007. 2. Hama, Y., Koyama, Y., Choyke, P. L., and Kobayashi, H. Two-color in vivo dynamic contrast-enhanced pharmacokinetic imaging. J Biomed Opt, 12: 034016, 2007. 3. Xu, H., Baidoo, K., Gunn, A. J., Boswell, C. A., Milenic, D. E., Choyke, P. L., and Brechbiel, M. W. Design, Synthesis, and Characterization of a Dual Modality Positron Emission Tomography and Fluorescence Imaging Agent for Monoclonal Antibody Tumor-Targeted Imaging. J Med Chem, 2007.
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