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177 Lu-Labeled Humanized Monoclonal Antibody Against Human Epidermal Growth Factor Receptor 2

In: Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004–2013.
[updated ].

177 Lu-Labeled Humanized Monoclonal Antibody Against Human Epidermal Growth Factor Receptor 2

Arvind Chopra.


The human epidermal growth factor (EGF) receptor 2 (HER2 or Erb2/neu) is known to be overexpressed in cells of certain cancers and to play a key role in promoting the growth and proliferation of primary and metastasized cancer cells, particularly in breast, ovarian, and urinary bladder cancers (1-4). HER2 is a glycoprotein that belongs to the EGF receptor (EGFR or ErbB1) family (for details regarding other HER or ErbB receptors and their ligands, see Friedlander et al. and Adams et al. (5, 6)). The ErbB receptors have four domains (designated I to IV): an extracellular region, a membrane-spanning region, an intracellular tyrosine kinase (TK), and a noncatalytic domain (7). Under normal conditions the EGFR and ErbB exist as monomers, but the binding of a ligand to the extracellular domain of the receptor results in conformational changes that promote the interaction of receptor domains I and III (7, 8). This interaction between two receptor domains leads to the formation of homodimers or heterodimers of the receptor and activation of the intracellular tyrosine kinase (TK). Subsequently, a complex intracellular signaling pathway may be activated, which results in malignant transformation of cells, cancer progression and survival, possible resistance to anticancer drugs, and the formation of tumors (6). In addition, overexpression or mutations of the ErbB1 or ErbB2 receptors have also been shown to promote oncogenic transformations of cells (5). Among the ErbB receptors, ErbB2 has been shown to be the preferred receptor for the formation of heterodimers with other ErbBs (ErbB1, ErbB3, and ErbB4) because it has an open extracellular domain confirmation that facilitates the formation of potent, mitogenic heterodimers (5). Formation of the ErbB2/ErbB3 heterodimers has been reported in breast, prostate, lung, and colorectal cancers (5, 9-12). Because ErbB receptors have been shown to have a prominent role in the development of cancers, these receptors have been targeted with different antibodies (Abs) for the molecular therapy of this disease (5). Among the various Abs directed against the EGF/ErbB receptor, trastuzumab and pertuzumab specifically bind to and inhibit ErbB2 receptor activity (5). Trastuzumab is a humanized monoclonal antibody (MAb) that inhibits cell proliferation by binding to the extracellular domain of the ErbB2 receptor and by blocking activation of the intracellular TK; however, the exact mode by which it inhibits the TK is unknown, and several mechanisms have been proposed for its activity (5, 13). This MAb is commercially available in the United States and has been approved by the United States Food and Drug Administration for the treatment of breast cancer; some patients undergoing treatment with this MAb develop resistance against it or may experience cardiac toxicity (5). Pertuzumab is a new class of humanized MAbs against ErbB2 and is known as a receptor dimerization inhibitor. On binding to the dimerization domain of the ErbB2 receptor, pertuzumab sterically hinders receptor dimerization and inhibits the signal transduction pathway (7). It has been tested in vitro and in preclinical animal studies, and it is being evaluated in several clinical trials to treat a variety of cancers as a monotherapy or in combination with other drugs and MAbs (14-19). Pertuzumab has been labeled with radioactive lutetium (177Lu) to obtain [177Lu]pertuzumab and used for biodistribution and imaging studies in mice (20, 21).

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