Imaging of Growth Factor Receptors Background The recognition of the role of growth factor receptors in the growth and progression of tumors has had widespread implications for cancer treatment. Not only have blocking antibodies been developed , but downstream small molecule inhibitors have also been developed. Both drug types have already had impact on the management of several major cancers. Regardless of the receptor imaged, imaging represents a potentially important avenue of research. Potential uses of imaging agents targeting receptors include more accurate sampling of tissue, patient selection for drug trials, monitoring of therapies directed at the receptor or its downstream clients which impact receptor expression, developing immuno-conjugates for delivering specific drug therapy and radioimmunotherapy/photoimmunotherapy in which therapeutic isotopes or photosensitizers 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 Individual antibodies have limitations because a tumor may express polyclonal distribution of receptors. For instance, part of the tumor may express HER2 but another part may express MET, HER1 or Mesothelin. We have explored the idea of a labeled cocktail of antibodies for tumor diagnosis and characterization. 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, each labeled with a fluorophore of a unique wavelenth, attach to their respective cancer cells opening the possibility of performing in vivo immunohistochemistry. This may find particular 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 inherently 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). Recently, we have discovered that when the antibody is attached to a unique photofluor, near infrared light at one intensity could be used for diagnosis but by increasing the intensity the tumor can actually be treated. This process is known as photoimmunotherapy and holds great promise for the treatment of some forms of cancer that can be approached with near infrared light. In collaboration with Dr. Brechbiels lab we are testing PET and SPECT labeled monoclonal antibodies and have performed this with both trastuzumab and cetuximab and panitumimab(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. Recently, this work has been enabled in Bethesda using microSPECT and microPET cameras in the Molecular Imaging Program. We have also explored theuse of radiolabeled affibodies which are considerably smaller than antibodies. HER2 binding affibodies have proven to be more sensitive than FDG PET for detecting metastases in mouse models of lung metastases. Extensive work has been done on MET receptor where we have labeled both the external and internal domains of this receptor. We are developing an F18 labeled version of this agent for human use. Over the past two years we have also sponsored an 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 originally by A. Bumb NanoTech 07 San Diego,CA, 2007). To this platform agent, trastuzumab, chelated with Indium (for SPECT imaging) is attached. We intend to test this nanoparticle in several in vivo murine models of HER2+ tumors. Anti-Mesothelin antibody (Raffit Hassan, Ira Pastan, Laboratory of Molecular Biology) has also been developed. This receptor is associated with an aggressive phenotype. We have performed preclinical studies in mice with this labeled antibody and will shortly initiate a clinical trial. Clinical Studies We are conducting several studies involving growth factor receptors. The original clinical study used 111Indium trastuzumab 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. Preliminary JDC approval was also received for 111Indium-panitumimab to be used in patients with colon and lung cancer. The preliminary pre-clinical work has been submitted to the Cancer Imaging Program for incorporation into an xIND submission and SOPs are being written for a GMP product. Indium labeled mesothelin (MORAb009) will begin clinical trials shortly. Cell proliferation is a direct result of activation of the growth factor receptors. We have investigated the ability to measure proliferation with a novel PET agent for human use, 18 F-L-thymidine, a proliferation marker for cancer. We have been using this agent in a variety of tumors and have demonstrated its utility. This work is ongoing in a trial of lymphoma and pediatric medulloblastoma, neurofibromatosis and leukemia post transplant. 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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