Targeting EGFR‐positive cancer cells with cetuximab–ZZ‐PE38: Results of in vitro and in vivo studies

Abstract

Cetuximab-ZZ-PE38 immunocomplex is a highly effective agent in killing EGFR-positive cancer cells and in tumor shrinkage.

Photochemical internalization (PCI) of HER2-targeted toxins

“…EGFR and HER2 are, however, also investigated as delivery portals for cytotoxic agents into the cells (Pastan et al, 2007). EGFR-and HER2-targeted toxins based on the bacterial toxins, Pseudomonas exotoxin (PE) or Diphteria toxin (DT) have demonstrated in vivo antitumor effects in several cancers, including brain cancer (Phillips et al, 1994;Engebraaten et al, 2002;Chandramohan et al, 2013;Liu et al, 2005), pancreatic cancer (Bruell et al, 2005), gastric cancer (Batra et al, 1992) and head and neck cancer (Thomas et al, 2004;Waldron et al, 2012;Barnea et al, 2013;Azemar et al, 2000). Off-target effects with these highly potent targeted toxins, as well as formation of neutralizing antibodies have, however, been demonstrated as obstacles for clinical use (Pai-Scherf et al, 1999;von Minckwitz et al, 2005;Cao et al, 2012;Azemar et al, 2003) and, so far, no targeted toxin has been approved for treatment of nonhematological cancers.…”

“…Targeted toxins are, therefore, clinically not necessarily limited by the same mechanisms as mAbs and TKIs (Lewis Phillips et al, 2008). An extensive number of fusion toxins targeting EGFR and HER2 have been described in the literature and many of them have shown anti-tumor effects in human xenograft models, including breast cancer (Cao et al, 2012), ovarian cancer (Cao et al, 2009), head and neck cancer (Thomas et al, 2004;Barnea et al, 2013;Engebraaten et al, 2002), brain tumors (Liu et al, 2005;Phillips et al, 1994) and pancreatic cancer (Bruell et al, 2005). Dose-limiting toxicity as well as immunogenicity have been demonstrated as limitations for clinical use (Pai-Scherf et al, 1999;Azemar et al, 2000;Azemar et al, 2003) and no EGFR-or HER2-targeted toxin has so far gained clinical approval from the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA).…”

Novel EGFR-specific immunotoxins based on panitumumab and cetuximab show in vitro and ex vivo activity against different tumor entities

“…Cetuximab is a chimeric (mouse/human) mAb indicated for colorectal and head and neck cancer (Barnea et al 2013;Schlessinger et al 2001). Panitumumab is a fully human mAb approved for metastatic colorectal cancer with disease progression after prior treatment and non-mutated wild-type KRAS tumors (Jakobovits et al 2001;Tebbutt et al 2013).…”

Dianthin-EGF is an Effective Tumor Targeted Toxin in Combination with Saponins in a Xenograft Model for Colon Carcinoma

“…Nearly 40% colorectal cancers have mutations (defects) in the KR AS or BR AF genes, which make these antibodies ineffective [40]. EGFR expression is critical for tumor cell growth and is linked to increased resistance to chemoradiotherapy and to poor prognosis [41]. Nevertheless, such a high EGFR differential expression between target cells and normal tissues as present in the applied mouse model is usually not found in humans.…”