Production Of The Monoclonal Antibody Cetuximab Biology Essay


Cancer has been studied widely for many decades and is a major part of ongoing research worldwide. During the research a new generation of so-called targeted therapies have been produced to target specific molecular processes that promote cancerous tumour growths. The research lead to development of the drug called Cetuximab which is used to treat head and neck cancers and colon and rectum cancers including large bowel. It is produced under the brand name of Erbitux which is produced by Merck Serono company which is located in Dublin 24 in Ireland. Cetuximab is widely produced in US by several pharmaceutical companies such as Imclone, Bristol Myers Squibb and in UK as well. The treatment with Erbitux is very expensive and the reason for that is because it is a chimeric monoclonal IgG1 antibody which is produced in a mammalian cell line by recombinant DNA technology which requires cost expensive labour and ingredients. ( 2010)

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One of the widely studied areas is molecular targets such as epidermal growth factor receptor (EGFR) which lead to development of Cetuximab which works on these molecular targets. Cetuximab works by inhibiting activation of epidermal growth factor receptor (EGFR). Cetuximab was approved by (FDA) Food and Drugs Administration for the use in the treatment of head and neck squamous cell carcinoma (HNSCC) using the combination of radiotherapy and for metastatic colorectal cancer (mCRC) as single drug or in combination with chemotherapy. (Bruno Vincenzi , Gaia Schiavon, Marianna Silletta, Daniele Santini, Giuseppe Tonini 2008)

Cetuximab is a recombinant chimeric human murine immunoglobulin G1 antibody that binds to the extra-cellular domain of epidermal growth factor receptor with a higher affinity than either endogenous ligand. This binding inhibits receptor

phosphorylation and activation and it leads to receptor internalization and degradation. Several studies have shown that cetuximab is able to inhibit growth of epidermal growth factor receptor (EGFR)-expressing tumour cells in vitro. Moreover, treatment with cetuximab results in a marked inhibition of tumour growth in nude mice bearing xenografts of human cancer cell lines. These results are linked to cetuximab biological effects as inhibition of cell cycle, tumour progression, neo-angiogenesis, invasion and metastatization, as well as increase and activation of pro-apoptotic molecules. Additionally, cetuximab potentiates, in combination, the effects of chemotherapy and radiation therapy in eradicating well-established tumours in nude mice and it may even reverse the resistance to some cytotoxic agents in these xenografts. Moreover, numerous clinical trials demonstrated cetuximab efficacy in different tumour types. It has been approved by Food and Drugs Administration in the treatment of metastatic colorectal cancer as single agent or in combination with chemotherapy, in locally and regionally. (Bruno Vincenzi , Gaia Schiavon, Marianna Silletta, Daniele Santini, Giuseppe Tonini 2008)

Cetuximab is a chimeric human murine derivative IgG1 monoclonal antibody (mAb) that binds extra-cellular domain of the EGFR. This binding inhibits activation of receptor tyrosine kinase and the associated downstream signalling that includes the mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/Akt and the Janus kinases (Jak) signal transducers and activator of transcription pathways.

Furthermore cetuximab induces antibody-mediated receptor dimerization, internalization and degradation leading to receptor down-regulation . In addition, it can determine antibody-dependent cellular cytotoxicity (ADCC) that could contribute to its antitumoural effect. EGFR is expressed on normal and malignant epithelial cells and it plays an important role in tumour biology. In fact, it promotes proliferation, metastatization, angiogenesis and inhibition of apoptosis. (Bruno Vincenzi , Gaia Schiavon, Marianna Silletta, Daniele Santini, Giuseppe Tonini 2008 p. 94)

The most common EGFR alteration in tumour cells is its over-expression that may lead to ligand-independent receptor dimerization. EGFR is frequently over-expressed in human tumours including breast cancer, lung cancer, glioblastoma, bladder carcinoma, head and neck cancer, ovarian carcinoma, colorectal cancer and prostate cancer. Overexpression of EGFR determines the rate of disease progression and aggresivness of cancer. The rate of expression of EGFR can give an overall picture on diagnosis and prognosis of cancer.

Table 1

Rate expression of EGFR in different tumour types

Tumour type Rate of EGFR expression

Head and neck 90â€"100%

Breast Up to 91%

Renal Up to 90%

Cervical Up to 85%

NSCLC Up to 80%

Colon Up to 89%

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Ovarian Up to 77%

Prostate Up to 47%

Glioma Up to 63%

Pancreas Up to 95%

Bladder Up to 72%

EGFR: epidermal growth factor receptor, NSCLC: non-small cell lung cancer.(Bruno Vincenzi , Gaia Schiavon, Marianna Silletta, Daniele Santini, Giuseppe Tonini 2008 p. 95)

The mechanisms through which cetuximab expresses its antitumour activity are numerous and not completely understood yet. Different studies demonstrated that cetuximab mediates cell cycle arrest in various tumour cell lines, leading in some cases to apoptosis (programmed cell death). Numerous studies has proven that cetuximab decreases tumour cell production of angiogenic growth factors such as vascular endothelial growth factor (VEGF), bFGF and interleukin-8 (IL-8). The decrease in angiogenic growth factors, in turn, correlates with a significant decrease in microvessel density and an increase in apoptotic endothelial cells in human tumour xenografts. Angiogenesis is a complex process through which new blood vessels arise from existing vasculature. It is tightly regulated by balance between pro-angiogenic and antiangiogenic factors and it involves autocrine and paracrine signalling.

(Bruno Vincenzi , Gaia Schiavon, Marianna Silletta, Daniele Santini, Giuseppe Tonini 2008 p. 97)

Both in vitro and in vivo experiments have proven that cetuximab inhibits the invasive and metastatic ability of different tumour types.

Tumour invasion is a complex process that needs active interactions between tumour cell, the extra-cellular membrane (ECM) and other stromal elements Different

coordinated events are required for cell invasion: firstly, changes in cellâ€"cell and cellâ€"matrix adhesion, secondly, degradation of ECM, and finally, cell migration, cytoskeletal rearrangement and acquisition of enhanced proteolytic potential. (Maria Luisa Veronese, Peter J. O’Dwyer 2004)

Cetuximab has been shown to inhibit the expression and activity of several MMPs (Matrix Metalloproteinase enzymes related to tissue healing/remodeling and cancer cell metastasis) including the gelatinase MMP-9. Several studies correlated this antibody-mediated reduction in MMP production with both a significant reduction in in vitro tumour-cell invasion and the inhibition of tumour growth and metastasis in nude mice.

Compared with its inhibitory properties, cetuximab immunologic mechanisms have not been extensively studied. Cetuximab may be trigger an ADCC reaction, leading to an indirect antitumour activity by the recruitment of cytotoxic host effector cells such as monocytes and natural-killer cells. Cetuximab ADCC (antibody-dependent cellular cytotoxicity) activity has been described against several tumour cell lines expressing wild-type or mutant EGFR.

(Bruno Vincenzi , Gaia Schiavon, Marianna Silletta, Daniele Santini, Giuseppe Tonini 2008 p. 98)

Cetuximab, the medicinal ingredient of Erbitux, is a recombinant, human/mouse chimeric monoclonal antibody that binds specifically and with high affinity to the extracellular domain of the human epidermal growth factor receptor (EGFR). Cetuximab functions as a competitive antagonist that inhibits the binding of ligands to EGFR which results in the inhibition of growth and survival of tumour cells that express EGFR.

Cetuximab is produced by recombinant DNA technology in a mouse myeloma derived cell line. The manufacture of cetuximab is based on a master and working cell bank system, where the master and working cell banks have been thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with the ICH guidelines. Results of these tests confirmed cell line identity and absence of adventitious agents/viral contaminants. Genetic characterization (restriction endonuclease mapping and copy number analysis) also demonstrated genetic stability of the master cell bank ranging from storage to production at the limit of in vitro cell age. The manufacture of cetuximab comprises a series of steps which include cell culture, harvest, and purification. The purification is performed via a combination of chromatographic and viral inactivation/removal steps. The consistency of the manufacturing process is ensured through defined production procedures, critical quality tests, in-process limits and cetuximab certificate of analysis specifications. Microbial control is maintained throughout the manufacturing process by testing for bioburden as well as for bacterial endotoxins. In-process controls performed during manufacture were reviewed and are considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.

The Erbitux manufacturing process consists of adjusting cetuximab formulated bulk concentration and filling into vials using proper aseptic process techniques, and conventional pharmaceutical equipment and facilities. Erbitux is manufactured within the lab which obeys GMP(Good Manufacturing Practise).

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One-hundred percent of the patients in the pivotal trial experienced an adverse event (AE). Eighty percent of these were grade 3 or 4 in nature. The most commonly reported AEs in order of frequency were asthenia, diarrhea, nausea, abdominal pain and acne. Based on the data from this trial, the AE profile of the combination of irinotecan and cetuximab is the aggregate of the AE profile of each individual agent. There was no evidence that the addition of either agent exacerbated the AE profile of the other agent, nor was there any evidence of frequently occurring new AEs. The most common AEs associated with irinotecan were less frequent than in other trials with irinotecan in CRC. Similar results were observed in the non-pivotal studies. ( 2007)

The treatment with Erbitux is very expensive and the reason for that is because it is a chimeric monoclonal IgG1 antibody which is produced in a mammalian cell line by recombinant DNA technology which requires cost expensive labour and ingredients.

Erbitux is available in injectable form only and contains 5mg/ml solution for infusion. Erbitux is a colourless solution.

Cetuximab is available for injections in different vial sizes:

vial of 10 ml contains 50 mg cetuximab

vial of 20 ml contains 100 mg cetuximab

vial of 50 ml contains 250 mg cetuximab

vial of 100 ml contains 500 mg cetuximab

Cetuximab is used for the treatment on patients with epidermal growth factor receptor (EGFR)-expressing, KRAS wild-type metastatic colorectal cancer in combination with chemotherapy. It can also be used for the the treatment of patients with quamous cell cancer of the head and neck in combination with platinum-based chemotherapy for recurrent metastatic disease.

Patients who receive treatment first time must receive treatment with corticosteroid and antihistamines in order to avoid allergic reaction to the drug and body attacking the drug. It is also recommended to receive treatment with corticosteroids and antihistamines for all subsequent infusions.

For all types of treatments Erbitux is administered once per week. The starting dose is 400 mg of cetuximab per m2 body surface area. All subsequent weekly doses are 250 mg cetuximab per m2 each.

Cetuximab can be used in patients with colorectal cancer as a single drug or in combination with chemotherapy. For patients with squamous cell cancer of neck and head it is used together with radiation therapy.

Allergic skin reactions are very common with Cetuximab patients which occur in more than 80% of patients, the reason for that is because Cetuximab is a chimeric monoclonal antibody drug. The majority of allergic skin reactions will develop within the first 3 weeks of treatment. These include dry skin, skin rash, eczema, nail disorders, in some severe cases skin necrosis. These skin problems generally resolve once the treatment is ceased.

Sometimes Cetuximab can cause skin lesions and patients with sensitive skin may develop superinfections like MRSA, or in other cases cellulites, sepsis, or scalded skin.

( 2010)

Cetuximab works in many different ways : it inhibits cell cycle progression metastatization and invasion, angiogenesis, increase and activation of pro-apoptotic molecules. When cetuximab is used in combination with chemotherapy and radiotherapy its effects are synergic. Effectivenes is much higher if when used in combination rather than separately. Cetuximab is relatively new drug and it is not fully understood its working mechanisms and new types of drugs like cetuximab promise effective treatment against cancer.