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177Lu-1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic acid-human serum albumin-Ac-Cys-ZEGFR:1907.


Leung K1.


Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2012 Jun 25 [updated 2012 Nov 15].

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National Center for Biotechnology Information, NLM, NIH


Epidermal growth factor (EGF) is a growth factor composed of 53 amino acids (6.2 kDa) that is secreted by ectodermic cells, monocytes, kidneys, and duodenal glands (1). EGF stimulates growth of epidermal and epithelial cells. EGF and at least seven other growth factors and their transmembrane receptor kinases play important roles in cell proliferation, survival, adhesion, migration, and differentiation. The EGF receptor (EGFR) family consists of four transmembrane receptors: EGFR (HER1/erbB-1), HER2 (erbB-2/neu), HER3 (erbB-3), and HER4 (erbB-4) (2). HER1, HER3, and HER4 comprise three major functional domains: an extracellular ligand-binding domain, a hydrophobic transmembrane domain, and a cytoplasmic tyrosine kinase domain. No ligand has been clearly identified for HER2; however, HER2 can be activated as a result of ligand binding to other HER receptors with the formation of receptor homodimers and/or heterodimers (3). HER1 and HER2 are overexpressed on many solid tumor cells such as breast, non-small cell lung, head and neck, and colon cancers (4-6). The high levels of HER1 and HER2 expression on cancer cells are associated with a poor prognosis because high levels are related to increased proliferation (7-10). Trastuzumab is a humanized IgG1 monoclonal antibody (mAb) against the extracellular domain of recombinant HER2 with an affinity constant (Kd) of 0.1 nM (11). Trastuzumab is approved for clinical use for anti-cancer therapies in both Europe and North America. 111In-Trastuzumab, Cy5.5-trastuzumab, and 68Ga-trastuzumab -F(ab')2 have been developed for imaging human breast cancer (12-16). However, the pharmacokinetics of the intact radiolabeled mAb, with high liver uptake and slow blood elimination, are generally not ideal for imaging. Smaller antibody fragments, such as Fab or F(abĀ“)2, have better imaging pharmacokinetics because they are rapidly excreted by the kidneys. A novel class of recombinant affinity ligands (Affibody molecules) for HER2 based on the Z-domain residues (58 amino acids) from one of the IgG-binding domains of staphylococcal protein A was constructed (17). Affibody molecules exhibit high binding affinity to HER2 with Kd values <100 pM. Various radiolabeled Affibody molecules have been studied in terms of their ability to image HER2 in tumors [PubMed]. The EGFR-specific Affibody ZEGFR:1907 (6.7 kDa) was identified to have good affinity (Kd = 5.4 nM) for EGFR (HER1) and labeled with 111In via isothiocyanate-benzoyl-diethylenetriaminepentaacetic acid (DTPA) to form 111In-Bz-DTPA-ZEGFR:1907 for single-photon emission computed tomography (SPECT) imaging in nude mice bearing human tumors (18). To facilitate site-specific conjugation, Ac-Cys-ZEGFR:1907 (Cys at the N terminal) was synthesized and conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7-tris-aceticacid-10-maleimidethylacetamide (maleimido-mono-amide-DOTA) to form Ac-Cys(DOTA)-ZEGFR:1907 (DOTA-ZEGFR:1907) and labeled with 64Cu (t1/2, 12.7 h) to form 64Cu-DOTA-ZEGFR:1907 for positron emission tomography imaging studies in tumor-bearing mice (19). Although high specific tumor accumulation was observed with 111In- and 64Cu-labeled ZEGFR:1907, very high kidney accumulation (>100% injected dose per gram (ID/g)) was also observed. Addition of human serum albumin (HSA) to Affibody ZHER2:342 dramatically reduced kidney accumulation and improved tumor accumulation (20). Therefore, Hoppmann et al. (21) prepared 177Lu-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid-human serum albumin-ZEGFR:1907 (177Lu-DO3A-HSA-ZEGFR:1907) for use in SPECT imaging of EGFR in nude mice bearing human solid tumors showing good tumor contrast but low kidney accumulation.

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