Panitumumab, a Monoclonal Anti–Epidermal Growth Factor Receptor Antibody in Colorectal Cancer: Another One or the One?

Abstract

Panitumumab (Vectibix, Amgen, Inc.) is a fully human IgG2 monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Panitumumab, formerly called ABX-EGF, was initially developed by Abgenix using the XenoMouse transgenic technology. This methodology is based on inactivating the mouse immunoglobulin genes that are replaced by a megabase gene containing the human heavy and n chains. The result is the generation of fully human antibodies that do not contain murine portions of the IgG molecule as chimeric antibodies do. This property avoids the formation of human antimouse antibodies, which may result in more frequent hypersensitivity reactions and shorter half-life (1).Panitumumab binds specifically and selectively to the EGFR, preventing binding of activating ligands, such as the EGF and transforming growth factor-a. In preclinical studies, this action reduces EGFR signaling and causes cell cycle arrest. The panitumumab-coated receptor is rapidly internalized resulting in receptor down-regulation although is not clear if the receptor is next degraded or recycled to the plasma membrane. In selected studies, panitumumab reduces angiogenesis as well. The preclinical activity of the agent is more pronounced in cells expressing the EGFR at levels of z15,000 per cell and inactive in EGFR-negative tumors. As with most of the EGFR-targeting agents, preclinical studies do show synergistic effects when combined with chemotherapy and radiation therapy (2, 3).The initial clinical development of panitumumab aimed to define the most effective and safe dose and schedule for patient treatment. Based on previous experiences with cetuximab, a chimeric anti-EGFR antibody, it was unlikely that an approach based solely on toxicity was appropriate to that end. Two important factors were considered in the design of these studies. First, it was expected that clearance of the antibody would be dose dependent, reflecting full saturation of EGFR binding sites because the principal mechanism of elimination of the agent is by degradation of antibody-occupied receptors (4). Second, it was already apparent that patients who developed skin rash after treatment with EGFR inhibitors had better treatment outcome. Thus, the phase I studies with the agent recommended a dose of 2.5 mg/kg based on saturation of elimination, frequency and severity of rash, and achievement of plasma levels above the levels needed for activity in preclinical models (5). Subsequent studies showed that a dose of 6 and 9 mg/kg resulted in equivalent exposure and that a loading dose was not needed to achieve the desired plasma levels (6). As discussed below, the dose of 6 mg/kg was selected for phase III studies.It should be noted, however, that there are some limitations in the criteria used for dose selection. Although the hypothesis of the EGFR sink is appealing and pharmacokinetically intuitive, the notion that receptor saturation is the only and principal factor accounting for the observed saturation in clearance has not been shown experimentally. Second,...

EGFR Signaling and its inhibition by EGFR inhibitors in NSCLC

“…Among, all patients with EGFR activating mutations, 70% patients respond to TKI treatment, while remaining 30% show intrinsic resistance to these inhibitors (Siegelin and Borczuk 2013). Among 90% of the EGFR mutations are clustered in exon 19-24 (Gridelli, Bareschino et al 2007, Messersmith and Hidalgo 2007, Wheeler, Dunn et al 2010. These mutations include L747S and D761Y both on exon 19 (Wu, Yang et al 2010) around codons 746-750 (45% -50% of all EGFR mutations) (Gridelli, Bareschino et al 2007, Seshacharyulu, Ponnusamy et al 2012 in exon 21 around codon 858 (T854) (Wu, Yang et al 2010) accounts for another 40% of mutations (Gridelli, Bareschino et al 2007) .…”

“…In xeno graft models of lung cancer, the combination of cetuximab with erlotinib or gefitinib achieved a greater tumor regression and regrowth delay compare to either of the drug used alone. Next strategy to overcome TKIs resistance is the use of mTOR/PI3K Inhibitors as the activation of PI3K/Akt signaling pathways by either MET amplification (Messersmith and Hidalgo 2007) or by PI3KC mutation is also a major cause of EGFR TKIs resistance. So, mTOR, PI3K and both mTOR/PI3K are either use alone or use with combination of erlotinib or gefitinib.…”

“…Panitumumab is the first FDA (2006) approved fully human IgG2 kappa monoclonal antibody used for the treatment of EGFR-expressing metastatic colorectal cancer (Messersmith and Hidalgo 2007, Dubois and Cohen 2009, Seshacharyulu, Ponnusamy et al 2012. It is developed by immunizing transgenic mice or Xeno-Mouse transgenic Technology (Messersmith andHidalgo 2007, Martinelli, De Palma et al 2009).…”

“…It is developed by immunizing transgenic mice or Xeno-Mouse transgenic Technology (Messersmith andHidalgo 2007, Martinelli, De Palma et al 2009). This methodology is based on inactivation of mouse immunoglobulin genes which are replaced by mega base gene containing light and heavy chains.…”

“…It targets the EGFR by binding to it and prevents the binding of EGF to it and induces internalization of EGFR. Thus, panitumumab prevent the intracellular processes like dimerization, autophosphorylation and signal transduction and ultimately leads to the increased apoptosis, reduced growth and development of tumor cells and reduced angiogenesis but as like other EGFR-targeting agents, preclinical studies of panitumumab show synergistic effects when combined with chemotherapy and radiation therapy (Messersmith andHidalgo 2007, Dubois andCohen 2009).…”