Monoclonal antibodies had the lure of drugs very much since their first description. The ability to bind to a predetermined chemical structure stimulated the imagination of drug discoverers and developers. Nevertheless it took many years before a drug was registered which started to make good on the promise. The complexity of the molecule, made up of four polypeptide chains, its large molecular weight, its multiple and versatile functional domains and its mouse origin initially were obstacles for the production and the utilisation. Also the selection of appropriate target structures on the surface of cells turned out be difficult. Many of these difficulties have been overcome. The replacement of most of the murine sequences with equivalent human sequences and the concomittant decrease in immunogenicity, and the identification of cell surface components which are causative and limiting in cellular transformation have made monoclonal antibodies valuable weapons in the fight against cancer. Multiple mechanisms of monoclonal antibody action are being exploited for this purpose. Antibodies can sequester growth factors and prevent the activation of crucial growth factor receptors. A monoclonal antibody directed against the vascular endothelial growth factor (VEGF) has been shown to be a potent neo-vascularisation inhibitor (bevacizumab). An antibody against the extracellular domain of the EGF receptor prevents the binding of the ligand to the receptor and thereby its activation (cetuximab). EGFR activity, however, is absolutely required for the survival and proliferation of certain human tumour cells. An antibody which interferes with the dimerisation of the ErbB2 and the ErbB3 members of the EGF receptor family prevents the association of a most potent signaling module (pertuxumab). The signals emenating from this dimer determine many phenotypic properties of e.g. human breast cancer cells. A monoclonal antibody also directed against ErbB2 has been most successful, clinically and commercially (trastuzumab). This antibody interferes with signals generated by the receptor and causes the arrest of the cell cycle in tumour cells. In addition, it recruits immune effector cells as cytotoxic agents. Finally, monoclonal antibody derivatives, single chain Fv fragments, have been used as a basis for the construction of recombinant tumour toxins. These molecules harness the exquisite binding specificity of the antibodies and combine them with the toxic principles of bacteria.
These data reveal the presence of a previously unrecognized, high-frequency epitope on the granulocyte Fc gamma receptor III. Luminoimmunoprecipitation proved to be a simple, nonradioactive technique that was useful in identifying the molecule involved.
Epidermal growth factor receptor (EGFR) plays an important role in essential cellular processes such as proliferation, survival and migration. Aberrant activation of EGFR is frequently found in human cancers of various origins and has been implicated in cancer pathogenesis. The therapeutic antibody cetuximab (Erbitux) inhibits tumor growth by binding to the extracellular domain of EGFR, thereby preventing ligand binding and receptor activation. This activity is shared by the single chain antibody fragment scFv(225) that contains the same antigen binding domain. The unrelated EGFR-specific antibody fragment scFv(30) binds to the intracellular domain of the receptor and retains antigen binding upon expression as an intrabody in the reducing environment of the cytosol. Here, we used scFv (225) Epidermal growth factor receptor (EGFR, ErbB) belongs to the family of ErbB receptor tyrosine kinases that also includes the closely related ErbB2 (HER2/Neu), ErbB3 (HER3) and ErbB4 (HER4) molecules.1 These type I transmembrane proteins share a common molecular architecture characterized by a glycosylated extracellular domain to which peptide ligands bind, a single a-helical transmembrane region and a cytosolic domain with tyrosine kinase activity. The EGFR extracellular domain is structurally separated into four subdomains. Subdomains I and III together provide the binding interface for ligands of the EGF-like growth factor family. Ligand binding stabilizes a dimerization-competent state of the receptor by preventing an inhibitory intramolecular contact between subdomains II and IV, thereby exposing a dimerization interface in subdomain II that facilitates the formation of receptor homodimers or heterodimers with other ErbB family members.2 Receptor dimerization stimulates the intrinsic tyrosine kinase activity, which results in autophosphorylation of specific tyrosine residues within the C-terminal tail. These phosphotyrosine residues serve as docking sites for intracellular substrates and adapter proteins that initiate signaling cascades promoting cell survival, migration and proliferation.
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