While panitumumab is a fully humanized antibody [112], both antibodies bind a similar epitope on the EGFR extracellular domain and function through inhibition of ligand binding [113]. immunotoxins have been developed with the goal of targeting the broad range of cancers reliant upon EGFR overexpression. Many examples demonstrate excellent anti-cancer properties in preclinical development, and several EGFR-targeted immunotoxins have progressed to human trials. This review summarizes much of the past and current work in the development of immunotoxins for targeting EGFR-driven cancers. and inhibition of tumor growth and high dose-tolerability [27,28,29]. A second therapeutic mechanism for targeting EGFR activity is through the use of small molecule tyrosine kinase inhibitors that compete for the kinase active site to inhibit phosphorylation of downstream proteins. Multiple drugs have been clinically-approved, including gefitinib (Iressa?; NSCLC), lapatinib (Tykerb?; breast cancer), and erlotinib (Tarceva?; NSCLC and pancreatic cancers) [30,31,32,33]. However, patients treated with EGFR TKI invariably develop an EGFR kinase domain T790M gatekeeper mutation that blocks inhibitor access, rendering treatment effects only temporary [34]. Second and third generation TKI are being developed in an attempt to circumvent this mutation, and are undergoing human trials [35,36,37,38]. Additionally, while cells expressing EGFRvIII may be sensitive to EGFR TKIs, extended treatment results in downregulation of EGFR expression with no accompanying loss of oncogenic growth [39]. One major issue with using anti-EGFR therapeutics in a clinical setting is the potential for off-target effects of the therapeutic. Many healthy tissues have some level of EGFR expression, with the skin, liver, and gastrointestinal tracts expressing elevated levels of the protein. Inhibition of EGFR signaling in these healthy tissues by either anti-EGFR antibodies or TKI result in adverse effects, most commonly skin rash or gastrointestinal disorders. Between 50% and 100% of patients treated with anti-EGFR antibodies display various skin rashes, while diarrhea is the most common dose-limiting toxicity in patients treated with EGFR TKI [40]. Therefore, while targeting the activation or signaling of therapeutically-relevant proteins is often able to provide Hydroxyfasudil some anti-tumor activity, system-wide inhibition of important signaling pathways is undesirable. Additionally, treatment of the Rabbit Polyclonal to Chk1 majority of cancers is hampered through therapy-driven genetic mutations or upregulation of alternative signaling pathways, suggesting that a mechanism that does not rely on direct inhibition of cellular signaling pathways would be of great use. Antibody-cytotoxin fusions, or immunotoxins, have been under development for the treatment of cancers for several decades [41]. Historically, immunotoxins (IT) consist of an antibody or antibody fragment joined to a cytotoxin, typically a bacterial protein like diphtheria toxin (DT) (Figure 2A) or exotoxin A (PE) (Figure 2B), or a plant-derived ribosomal inactivating protein (RIP) like ricin, gelonin, or saporin (Figure 2C) [42]. Immunotoxins can be engineered through either chemical conjugation of an antibody to the cytotoxin or through recombinant Hydroxyfasudil production of a fusion protein, joining an antibody, single chain Fv (scFv), or Fab to a protein toxin. Recombinant ITs most commonly consist of a gene fusion of the scFv of a relevant cell-targeting domain with the translocation and cell killing domains of DT or PE. As these therapeutics function by killing cells directly rather than through signaling inhibition, the possibility of escape mutation or upregulation of alternative signaling pathways is less of an issue. Open in a separate window Figure 2 Immunotoxin domain organization and trafficking. (A) Immunotoxins derived from diphtheria toxin (DT) consist of cytotoxic ADP-ribosyltransferase domain Hydroxyfasudil I and translocation domain II, with receptor binding domain III replaced by the EGFR-targeting domain of interest. (B) Immunotoxins derived from exotoxin (PE) are constructed in an inverse manner to DT. PE exotoxins consist of replacement of receptor binding domain I with a new targeting domain joined to the translocation (II) and ADP-ribosyltransferase (III) domains of PE. (C) Immunotoxins utilizing plant-derived ribosome-inactivating proteins (RIP; ricin, saporin, gelonin, dianthin) consist of the RNA glycosidase active domain chemically conjugated to the targeting moeity. (D) Upon endocytosis, immunotoxins enter varied trafficking pathways. Once internalized, cellular proteases cleave the peptide chain between active and translocation domains. DT-based immunotoxins are translocated to the cytosol upon endosomal acidification and.
While panitumumab is a fully humanized antibody [112], both antibodies bind a similar epitope on the EGFR extracellular domain and function through inhibition of ligand binding [113]
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a 67 kDa type I transmembrane glycoprotein present on myeloid progenitors
and differentiation. The protein kinase family is one of the largest families of proteins in eukaryotes
Apoptosis
bladder
brain
breast
cell cycle progression
cervix
CSP-B
Cyproterone acetate
EGFR) is the prototype member of the type 1 receptor tyrosine kinases. EGFR overexpression in tumors indicates poor prognosis and is observed in tumors of the head and neck
EM9
endometrium
erythrocytes
F3
Goat polyclonal to IgG H+L)
Goat polyclonal to IgG H+L)Biotin)
GRK4
GSK1904529A
Igf1
Mapkap1
monocytes andgranulocytes. CD33 is absent on lymphocytes
Mouse monoclonal to CD33.CT65 reacts with CD33 andtigen
Palomid 529
platelets
PTK) or serine/threonine
Rabbit Polyclonal to ARNT.
Rabbit polyclonal to BMPR2
Rabbit Polyclonal to CCBP2.
Rabbit Polyclonal to EDG4
Rabbit polyclonal to EIF4E.
Rabbit polyclonal to IL11RA
Rabbit polyclonal to LRRIQ3
Rabbit Polyclonal to MCM3 phospho-Thr722)
Rabbit Polyclonal to RBM34
SB 216763
SKI-606
SNX-5422
STK) kinase catalytic domains. Epidermal Growth factor receptor
stomach
stomach and in squamous cell carcinoma.
TNFSF8
TSHR
VEGFA
vulva