Similarly, to further reduce the immunogenicity and side-effects encountered with PE38, the smallest version of PE was engineered (known as PE24), which lacks domain II of PE, with exception of a 11 amino acid length furin cleavage site [163,184] and which might show differences in cytotoxicity dependent on intracellular routing. the first, fully recombinant versions. In this review, we discuss significant advancements in EGFR-targeting immunoconjugates, including ITs and recombinant photoactivable ADCs, which serve as a blueprint for further developments in the evolving domain of cancer immunotherapy. Keywords:epidermal growth factor receptor (EGFR), recombinant immunotoxins (ITs), targeted human cytolytic fusion proteins (hCFPs), recombinant antibody-drug conjugates (rADCs), recombinant antibody photoimmunoconjugates (rAPCs) == INTRODUCTION == Epidermal growth factor receptor (EGFR) belongs to a family of transmembrane proteins that are known as tyrosine kinases (ErbB family) and made of four members known as: EGFR/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4 [14]. EGFR is a 170 kDa glycoprotein, known as HER1 or c-ErbB-1, and was the first member of receptor tyrosine kinase (RTK) to be described [4]. EGFR is characterized by an extracellular ligand binding domain (ectodomain), a single transmembrane Bavisant dihydrochloride hydrate domain (TM), and an intracellular domain with tyrosine function [13]. EGFR activation begins with ligand binding induced ectodomain dimerization (homo- and/or heterodimerization), causing the autotransphosphorylation of tyrosine residues located on the intracellular tyrosine kinase domain [3,4]. This tyrosinase phosphorylation consequently recruits signal transducers and activators of intracellular substrates such as Rat sarcoma (Ras). Once activated, Ras activates downstream signaling cascades such as Bavisant dihydrochloride hydrate RAF/MEK1/2/ERK1/2, and/or PI3k/Akt, regulating cell proliferation, survival, differentiation, and migration [1,2,5]. The EGFR signaling pathway is tightly regulated under normal conditions. However, EGFR has been aberrantly expressed in many cancers due to mutations associated with poor cancer prognosis [4,612]. Hence, developing new therapeutic approaches that target EGFR, becomes very pertinent. So far, two EGFR-targeted therapeutic approaches have been developed using antagonist monoclonal antibodies (mAbs) or small molecule tyrosine kinase inhibitors (TKIs), either blocking ligand binding or inhibiting tyrosinase function by preventing adenosine triphosphate (ATP) binding to the EGFR intracellular domain [13]. Both therapeutic strategies have been clinically approved for treating multiple cancers [1214]. However, compromised efficacy of TKIs is associated PKCA with increased mutations in tyrosine kinase intracellular domains. These mutations were found to drive resistance to TKIs by increasing ATP avidity to the targeted domain or by constitutively activating downstream signaling pathways causing treatment failure [1518]. Conversely Bavisant dihydrochloride hydrate to TKIs, mAbs partly exert their cytotoxic effects by reducing EGFR ectodomain density through induction of receptor mediated endocytosis or by activating antibody-dependent cellular cytotoxicity (ADCC) towards EGFR positive cancer cells [1921]. To date, five mAbs have been clinically approved and target different ErbB family members: EGFR (HER1): cetuximab (2004, head and neck and colorectal cancers), panitumumab (2006, colorectal cancer), necitumumab (2015, non-small lung cancer); and HER2: trastuzumab (1998, breast cancer) and pertuzumab (2012, breast cancer) [14,1926]. Although promising, these naked antibody-based monotherapies have achieved poorer clinical responses, than when combined with conventional chemotherapy, radiotherapy or TKIs [23]. Despite obvious clinical benefits, these combination therapies were associated with undesirable side effects, partly owing to mAbs bulky size limiting tumor penetration or rodent origin, inducing an immune response when used in immunocompetent patients [27,28]. Consequently, mAbs were considered to be armed with cytotoxic drugs to generate so called antibody-drug conjugates (ADCs) which could tilt the toxicity/therapeutic balance towards a more Bavisant dihydrochloride hydrate beneficial specific therapeutic efficacy. These ADCs are able to achieve improved selective cytotoxicity based on their ability to discriminate and exploit the differential cell surface expression of tumor associated antigens (TAA) between diseased and healthy tissues, and use it as a mechanism to specifically deliver the conjugated cytotoxic payloads to the tumor site [2931]..
