111In-Diethylenetriamine pentaacetic acid-pertuzumab

Excerpt

Epidermal growth factor (EGF) is a cytokine 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 each: 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 (7-10).

Trastuzumab is a humanized IgG₁ monoclonal antibody (mAb) against the extracellular domain of recombinant HER2 with an affinity constant (K_d) of 0.1 nM (11). Trastuzumab is approved for clinical use for anti-cancer therapies in both Europe and North America. Labeled trastuzumab (¹¹¹In-trastuzumab, Cy5.5-trastuzumab, and ⁶⁸Ga-trastuzumab-F(ab')₂) has been developed for HER2 imaging in human breast cancer (12-16). Resistance to trastuzumab therapy may be a result of its induction of HER2 receptor downmodulation (17). Pertuzumab is a new class of humanized mAb against HER2 that binds to a different epitope than trastuzumab does. On binding to the HER2 receptor, pertuzumab inhibits the receptor dimerization and the downstream signal transduction pathway. It is being evaluated in several clinical trials to treat a variety of cancers. McLarty et al. (18) has performed single-photon emission computed tomography (SPECT) studies using ¹¹¹In-diethylenetriamine pentaacetic acid-pertuzumab (¹¹¹In-DTPA-pertuzumab) to investigate trastuzumab-mediated HER2 downregulation in human breast cancer xenografts in nude mice.