Zirconium-89 labeled panitumumab: a potential immuno-PET probe for HER1-expressing carcinomas
Introduction
Positron emission tomography (PET) is a well-established clinical imaging modality used to non-invasively identify disease presence and extent, and to monitor the effect of treatment effects [1], [2], [3], [4]. PET imaging using a radio-labeled monoclonal antibody (immuno-PET) is a very powerful technique to improve tumor detection because it combines the high sensitivity, image spatial resolution and quantitative potential of PET with the specificity of a monoclonal antibody (mAb) [4], [5], [6], [7]. For immuno-PET, the physical half-life of a positron emitter has to be compatible with the biological half-life of a mAb to achieve optimal tumor imaging. Developing a target specific PET imaging probe is one of the challenging areas of current biomedical research.
The epidermal growth factor receptor (EGFR, erb1, HER1) is a glycoprotein belonging to subclass I of the tyrosine kinase receptor super family [8]. This receptor is dysregulated in a variety of cancers, including lung, colorectal, head and neck, prostate, breast, glioma, pancreatic and ovarian cancers [9]. Overexpression of this receptor is associated with disease progression and treatment resistance. The anti-HER1 mAb, panitumumab (Vectibix) is a fully human mAb approved by the FDA for the treatment of HER1-expressing colorectal cancers [10], [11]. Currently, it is being evaluated in patients with other types of HER1-expressing cancers, such as breast, lung, head and neck, renal, and ovarian tumors [12]. Panitumumab binds to domain III of HER1 and is rapidly internalized, leading to downregulation of cell surface HER1. It also arrests the cell cycle and inhibits tumor growth by suppressing the production of proangiogenic factors (VEGF, IL-8) by tumor cells [13]. Moreover, because it is a fully human antibody, panitumumab has minimal immunogenicity when administered intravenously.
In recent years, 89Zr has emerged as a promising positron-emitting radionuclide [14], [15], [16], [17], [18], [19] for diagnostic immuno-PET imaging because of its longer half-life (78.4 h), which provides a close match to the biological half-life of an intact mAb. While its positron yield (22.7%) is less than 18F, the mostly widely used PET radiotracer, it is comparable to other longer lived radiometal based tracers used in human PET imaging (i.e. 64Cu and 86Y) and is inert in the biological system [4]. Moreover, based on recent clinical trials in Europe, 89Zr-labeled mAbs appear to be safe for human injection [4], [18]. 89Zr-immuno-PET with panitumumab as a targeting ligand may be useful as a non-invasive, in vivo, quantitative biomarker of HER1-expression that may be useful in patient selection and monitoring of HER1-targeted therapies.
Herein, we report the production of 89Zr-labeled panitumumab, compare its biodistribution and human dosimetry estimates with that of 111In-CHX-A”-DTPA-panitumumab, and evaluate tumor uptake in three human breast cancer xenografts expressing different levels of HER1.
Section snippets
General
Isothiocyanatobenzyl derivative of desferrioxamine (DFO-Bz-NCS) was obtained from Macrocyclics, Inc. Clinical grade panitumumab was obtained from Amgen, Inc. Water (> 18.2 MΩ.cm at 25°C, Milli Q, Millipore, MA) was purified by passing it through a 10-cm-long column of chelex resin (Bio-Rad Laboratories). All other chemicals, unless otherwise stated, were purchased from Sigma Aldrich (St. Louis, MO). Zirconium-89 was produced at the National Institute of Health (Bethesda, MD) cyclotron facility
Results and discussions
During the course of our investigations, Nayak et al. reported initial studies on 89Zr-labeled panitumumab as an immunoPET probe for colorectal cancer [19]. In our current studies, we validate the use of 89Zr-DFO-panitumumab as a immuno-PET probe in human breast cancer xenografts with variations in HER1 expression: BT-474 (negative control); MDA-MB-231 (moderate expression); and MDA-MB-468 (very high expression). We have additionally compared the biodistribution of 89Zr-DFO-panitumumab with
Conclusions
89Zr-DFO-panitumumab has been prepared with high radiochemical purity and specific activity. The immunoconjugate was found to be stable with respect to loss of the radioisotope in human serum. While the biodistribution showed slow clearance and physiologic uptake in the lymph nodes, when administered to humans at tracer levels, this is not expected to be a problem. Despite these limitations, immuno-PET studies revealed that 89Zr-DFO-panitumumab uptake correlated strongly with HER1 expression.
Acknowledgments
This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. Authors are grateful to Dr. Lawrence Szajek of cyclotron facility at NIH Bethesda
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