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The Epidermal Growth Factor Receptor Family

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The epidermal growth factor receptor (EGFR) is a 170kD trans-membrane tyrosine-kinase receptor of the ErbB family. This receptor has an intracellular domain that has tyrosine kinase activity, a trans-membrane domain and an extracellular ligand-binding domain. When its ligands, most notably epidermal growth factor (EGF) and transforming growth factor-alpha (TGFa), bind to the extracellular domain, the EGFR is activated. These ligands are normally produced in the surrounding tissues as local growth factors. The activated EGFR forms homodimers or heterodimers by pairing with other receptors of the ErbB family. This dimerization induces the tyrosine kinase activity of the intracellular domain. The overexpression of EGFR is observed in a variety of epithelial cancers, such as breast cancer, non-small cell lung cancer (NSCLC), and colorectal cancer. This over expression can cause resistance to apoptosis, cancer proliferation, metastatic dissemination and neovascularization. It has been reported that EGFR is over-expressed in 14–91% of breast cancers. Because of these observations EGFR is an interesting target for diagnosis and therapeutic strategies.

Two distinct strategies have been applied to reduce and deactivate EGFR signaling. The first approach is to block the intercellular domain of the receptor by specific tyrosine kinase inhibitors.

These inhibitors bind to the ATP-binding site of the EGFR tyrosine-kinase domain. The literature and the clinical trials of this approach mainly focus on NSCLC because of the promising results. Gefitinib and Erlotinib have resulted in a significant improvement in patients overall conditions. However, after a period of time patients develop tumor resistance due to the emergence of the resistance mutations. Another complication is dose-limiting toxicity in drugs like Afatinib due to simultaneous inhibition of wild-type EGFR. There is one FDA-approved drug Osimertinib which is showing promising results. The second strategy, which is our focus of the current study, is to prevent the binding of the ligands (e.g EGF) to the extracellular domain of the EGFR by monoclonal antibodies (mAbs).

Cetuximab/ErbituxR, is an FDA-approved antibody with these properties in current use in the clinic. Whereas antibodies that bind EGFR and other targets have shown promise in the clinic, there are limitations to their effective application and future development.

One of the drawbacks of mAbs is their large size which limits tumor penetration, and reduces their effectiveness; another problem concerning mAbs is that generation of new or modified mAbs is costly and arduous. Both problems can be solved by exploiting heavy chain only antibodies (HCAbs) from camelids. Whereas the antigen recognition region in conventional antibodies comprises the variable regions of both the heavy and the light chains (VH and VL respectively), the antigen recognition region of HCAbs comprises a single variable domain, referred to as a VHH domain or nanobody. VHHs are thermo- and pH-stable proteins that are well tolerated by the human immune system and can be generated rapidly and cheaply with simple expression systems. Single VHH domains can be powerful diagnostic imaging tools, and are being developed for a range of research applications. For therapeutic use, VHH domains (monomeric or multivalent) can be modified to extend serum half-life and/or functionality.

The clinical success of EGFR-targeted mAbs has caused significant interest in developing VHH domains that bind to and inhibit this receptor. Several EGFR-specific VHH domains have been reported that have the potential to reproduce the clinical efficacy of mAbs such as Cetuximab in an agent that is more stable and far less costly to produce. Moreover, potent multivalent VHH molecules can be generated that bind a number of targets, offering the potential to engineer multivalent agents that combine cetuximab-like EGFR inhibition with other modes of binding to EGFR or to other cancer targets. 7D12, a 133 amino acids VHH domain, is a selected nanobody with the highest affinity binding to EGFR. This VHH domain competes with Cetuximab for EGFR binding (Roovers et al., 2011). Although it is a much smaller VHH domain, it can block both Cetuximab and ligand binding, which makes it a promising nanobody against EGFR.7D12 based nanobodies can also be used for imaging. For example, Gainkam et al. (2008) and van Dongen and Vosjan (2010) used 99mTc-labeled nanobody 7D12 to image the expression of EGFR in mice carcinomas. In another study, bifunctional chelate p-isothiocyanatobenzyl-desferrioxamine (brieflyDf-Bz-NCS) was conjugated with nanobody 7D12 and then labeled by 89Zr (t1/2, 78.4 h). This combination (89Zr-Df-Bz-NCS-7D12) was applied to image the expression of EGFR in carcinomas(8).In another study(8) ,by using molecular dynamic (MD), we have made suitable mutations in the selected key residues of 7D12 and designed a 7D12 based nanobody with high binding affinity to EGFR. In comparison with wild-type 7D12, these high affinity nanobodies are far more effective for therapeutic and bioimaging applications.9G8, a 136 amino acids VHH domain, is another nanobody that binds to a different epitope on EGFR. Interestingly, unlike 7D12, 9G8 do not compete with Cetuximab for binding to EGFR. Instead, this VHH domain binds to an epitope that is inaccessible to Cetuximab and that undergoes large conformational changes during EGFR activation, sterically inhibiting the receptor.

As stated before, the structure of 7D12 bound to EGFR shows how this smaller and readily engineered binding unit can mimic inhibitory features of the intact monoclonal antibody drug cetuximab. Multimerization of 7D12 with other VHH domains generates a potent EGFR inhibitor (Roovers et al., 2011). 7D12 is thus a cassette that can be used to combine cetuximab-like inhibition with modules of synergistic and/or complementary inhibitory properties. In 2011, Roovers et al. showed that the bi-paratopic anti-EGFR nanobody 7D12-9G8 is very potent in inhibiting EGFR signalling.

The length and the composition of the connecting linker are important contributes to the characteristics of the 7D12-9G8 molecule. This linker must provide sufficient space/length and freedom to allow the two nanobodies to bind simultaneously to the same EGFR molecule.

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