Cetuximab for treating Colorectal - Essay Example

CETUXIMAB FOR TREATING COLORECTAL Cetuximab for Treating Colorectal s of the drug Cetuximab is also referred to as mAb anti-EGFRor IMC-225, ErbituxDescription of the drugThe drug is a monoclonal antibody mAb that specifically targets the epidermal growth factor receptor (EGFR). It is a human murine chimeric referred because it was produced from the mammalian cells (murine myeloma) cultures. Therefore, it is a recombinant molecule.Structural protein of the drug (Brand, et al., 2011)The structural domain and the development of cetuximab drug molecule3 Murine antibodies (M579 IgG, M528 IgG, and M225 IgG were developed from mouse and taken to clinical trialsM225 was identified as the most efficacious anti-EFGR and moved for clinical trials Phase 1.

Though M225 was a success in phase1, patients developed HAMA (human-anti-mouse antibodies)M225 was later converted to C225, which is a Human murine Chimera with an IgG1 FC isotype (Brand, Iida and Wheeler 2011)Drug targetThe drug targets extracellular domains of the EGFR receptor and binds to and blocks the natural ligand binding site. The EGFR receptor protein belongs to the member of ErbB receptor family as well as the receptor protein tyrosine kinase (Brand, Iida and Wheeler 2011). Expression of the targetAccording to Brand, Iida and Wheeler (2011) “many human epithelial cancers including head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), breast, pancreatic and brain cancer” (p.778) are the main sites for the expression for EGFR.

The EGFR belongs to EGF receptor family, which also belongs to the family of tyrosine kinase. The receptor is ubiquitously expressed in many cells with epithelial, neuronal and mesenchymal origin (Harding and Burtness 2005). During homeostatic condition the regulation of these receptors are activated when ligand molecules like TGFα (transforming growth factor alpha), EGF and AR (amphiregulin) are available. These ligands have specificity for EGFR. Therefore, the target of the drug is usually expressed in many parts of the body with epithelial, neuronal and mesenchymal cells if there is a ligand molecule to initiate the expression process.

Activation of receptorWhen the ligand binds to the EGFR receptors, activation takes effect, which is manifested by downstream activation of pathways like PLCy/PKC, RAS/RAF/MEK/ERK and P13K/AKT. In the absence of this process the net effect would lead to the activation of cells to proliferate, metastatic and survival of potential cancer cells (Oliveras-Ferraros et al 2008; Chen et al 2012).Figure showing signal pathways involved in drug interaction (Brand, et al., 2011)(Brand, et al., 2011)MOA (mechanism of action) – how drug interact with the targetThe drug has high affinity for EGFR.

Therefore, its affinity out-competes both the EGF and TGFα, whose binding would have initiated proliferation, metastatic and survival of cancerous and tumours cells. The drug binds to the extracellular domain of EGFR to cause lockage of ligand induced EGFR phosphorylation or ligand binding. By hindering HER and EGFR members from binding to the receptor, the drug promoted degradation and internalisation of EGFR, thereby abrogating the downstream cascades of signal pathways (Brand et al 2011).

Cells are arrested and prevented from existing the G1 phase of the cycle. Besides, interaction of the drug with the receptor decreases the expression of factors like pro-angiogenic thereby decreasing angiogenesis. This leads to decreased metastatic spread and invasion of tumor and cancerous cells (Brand, Iida and Wheeler 2011). In summary it causes inhibitory effect by blocking EGF induced phosphorylation that results in reduced proliferation of the potential cancer cells. Those cells later undergo apoptosis as shown in the diagram below.

Diagram showing how the receptor interacts with the drug to bring about apoptosis of metastatic cells.(Brand, et al., 2011)Pharmacological aspect of the drugThe drug has inhibitory effect. It binds to the EGFR extracellular domains of cells with epithelial, neuronal and mesenchymal to prevent binding of TGFa, EGF, and AR from binding the receptor domain, by doing this the downstream process of proliferation, metastatic and survival of malignant cells and tumour cells are inhibited from taking effect (Oliveras-Ferraros et al 2008; Chen et al 2012).

The process is complete inhibition. Side effectsThe drug exhibits intrinsic resistance and the development of acquired resistance. This is the main challenge facing industrial application of this drug to control cancerous conditions.Treatment regime (mode of delivery)The drug was administered as intravenous infusionModels used for Pre-clinical trialsTesting of the pharmacokinetics, toxicity and efficacy of cetuximab was done in mouse model and gave rise 3 Murine antibodies M579 IgG, M528 IgG, and M225 IgG.

These antibodies were tested and one of them (M225 IgG) found to be very efficacious for clinical trial (Oliveras-Ferraros et al 2008; Chen et al 2012).BibliographyBrand, TM., Dunn, EF., Iida, M., Myers, RA., Kostopoulos, KT., Li, C., Peet, CR. & Wheeler, DL. 2011. “Erlotinib is a viable treatment for tumors with acquired resistance to cetuximab”. Cancer Biol Ther. Vol. 112, no. 5, p. 436-46.Brand, TM., Iida, M. & Wheeler, DL. 2011. Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab, Cancer Biol Ther. Vol. 11, no. 9, p. 777–792. Chen, G., Kronenberger, P.

, Teugels, E., Umelo, IA & De Grève J. 2012. “Targeting the epidermal growth factor receptor in non-small cell lung cancer cells: the effect of combining RNA interference with tyrosine kinase inhibitors or cetuximab”, BMC Med. Vol. 21, no. 10, p. 28. Harding, J. & Burtness, B. 2005. “Cetuximab: an epidermal growth factor receptor chemeric human-murine monoclonal antibody”. Drugs Today (Barc). Vol. 41, no. 2, p. 107-27.Oliveras-Ferraros, C., Vazquez-Martin, A., López-Bonet, E., Martín-Castillo, B.

, Del Barco, S., Brunet, J. & Menendez, JA. 2008 “Growth and molecular interactions of the anti-EGFR antibody cetuximab and the DNA cross-linking agent cisplatin in gefitinib-resistant MDA-MB-468 cells: new prospects in the treatment of triple-negative/basal-like breast cancer”. Int J Oncol. Vol. 33, no. 6, p.1165-76.