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111In-Labeled anti-epidermal growth factor receptor Affibody PEP09239.


Chopra A.


Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2013 Mar 28 [updated 2013 May 02].


The human epidermal growth factor receptor-2 (HER2, ErbB2) modulates its activity through a tyrosine kinase (TK) signaling pathway and is involved in the development of a variety of cancers (1, 2). Overexpression or amplification of the HER2 gene is known to occur in many cancer types (e.g., ~20% of breast cancer) and predicts a poor prognosis for the patient. Invasive methods, such as biopsies, in conjunction with immunohistochemistry and an in situ fluorescence hybridization kit (PathVysion) approved by the United States Food and Drug Administration are used to assess the HER2 status of the primary and metastasized neoplastic tumors; however, because of sampling bias and tumor heterogeneity, results obtained with these procedures are not reliable (2). In the clinic, 18F-labeled fluorodeoxyglucose ([18F]-FDG) is commonly used with positron emission tomography (PET) to detect and determine the tumor burden of a patient, but this imaging agent does not distinguish between benign and malignant lesions, cannot differentiate tumors that overexpress HER2 from those that have a low or no expression of the receptor, and often identifies inflammation as a false-positive neoplasm (1). An Affibody molecule is a chain of 58 amino acids (~6.5 kDa) that contains a modified B domain of the staphylococcal protein A and can be obtained via chemical synthesis or produced in bacteria with the use of recombinant DNA technology (3). The Affibody scaffold consists of 3-helix peptide chains: helix chains 1 and 2 are composed of 13 randomized amino acids and contain the receptor-binding moieties of the Affibody (4), and the third helix chain functions as a stabilizer of the Affibody molecule (5). Affibody molecules have high affinity and specificity of binding to the targeted molecule and are considered to be extremely suitable for the noninvasive imaging of solid tumors (6). The radionuclide-labeled Affibody ZHER2:342 (and its derivatives), directed against the HER2 (ZHER2:342Kd = 22 pM for HER2), has been used successfully with molecular imaging techniques to screen for breast cancer patients who are likely to benefit most from treatment with trastuzumab (a monoclonal antibody that targets HER2) or lapatinib (a small-molecule drug that inhibits the TK activity of the HER2 signaling pathway) (6, 7). To further improve the imaging properties of radiolabeled Affibodies, it was hypothesized that reducing the size of the molecule is likely to facilitate rapid clearance of the tracer from circulation, high penetration into solid tumors, ameliorate the uptake of label in nontargeted organs (such as the liver), and generate increased tumor/background ratios compared with the 3-helix molecule (8). To test the hypothesis, the stabilizing helix chain was removed from the 3-helix ZHER2:342 molecule, and the 2-helix Affibody (MUT-DS; ~4.6 kDa) was determined to have a binding affinity of 5 nM for HER2 (8). In another study, MUT-DS was conjugated with DOTA, a metal chelator, labeled with 68Ga ([68Ga]-DOTA-MUT-DS), and evaluated for the detection of human ovarian carcinoma SKOV3 cell xenograft tumors (these cells overexpress HER2) in nude mice (9). Although [68Ga]-DOTA-MUT-DS was rapidly cleared from circulation and had a high binding specificity for the tumors, it was observed that the uptake of radioactivity in the lesions was considerably lower (4.12 ± 0.83% injected dose per gram tissue (ID/g) at 2 h postinjection (p.i.)) (9) than the accumulation of label observed in the SKOV3 cell tumors with a similarly labeled HER2-binding 3-helix Affibody ([68Ga]-ABY-002; 12.4 ± 3.8% at 2 h p.i.) (10). This indicated that there was no particular advantage in using a smaller Affibody compared with the larger parent 3-helix molecule. In addition, the comparison between the two Affibody types may be inaccurate for two reasons. First, the data that were compared were obtained from two separate studies in which the two SKOV3 cell subclones used to generate the tumors in the mice may not have produced lesions of the same size. Second, the same amounts of HER2 may not have been expressed in the neoplasms (4). Therefore, to ascertain the similarities or dissimilarities between MUT-DS and ABY-002 Affibodies, it was necessary to investigate the biological characteristics of the two entities simultaneously with the use of identical handling techniques and to perform similar in vitro and in vivo studies simultaneously with the two Affibodies (4). Rosik et al. compared the receptor targeting and biodistribution characteristics of 111In-labeled MUT-DS ( [111In]PEP09239) and 111In-labeled ABY-002 ([111In]ABY-002) in a side-by-side study of mice bearing xenograft tumors generated with SKOV3 cells (these cells express ~1.2 × 106 HER2 receptor/cell) and human colorectal LS174T cells (these cells express low levels of HER2; ~3.9 × 104 receptors/cell), respectively (4).

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