Cetuximab Antibody Production

Cetuximab Antibody Production 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. (http://www.medicines.ie/medicine/12082/SPC/Erbitux+5mg+ml+solutio n+for+infusion/ 2010) 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 treatmen t 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 90‚100% Breast Up to 91% Renal Up to 90% Cervical Up to 85% NSCLC Up to 80% Colon Up to 89% 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 cell‚ cell and cell‚ matrix adhesion, secondly, degradation of ECM, and finally, cell migration, cytoskeletal rearrangement and acquisition of enhanced proteolytic potential. (Maria Luisa Veronese, Peter J. ODwyer, 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). 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. (http://www.hc-sc.gc.ca/dhp-ps/prodpharma/sbd-smd/phase1-decision/drug-med/sbd_smd_2007_erbitux_088225-eng.php 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. (http://www.medicines.ie/medicine/12082/SPC/Erbitux+5mg+ml+solution+for+infusion/ 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.

Love and Loss in Poetry Essay -- First Love Remember Christina Walsh E

Love and Loss in Poetry Q. How do the poets convey their attitudes toward love and loss in the poems ‘ a woman to her lover’ ‘first love’ ‘remember’ and ‘ when we two parted’? The poem ‘ a woman to her lover’ was written by Christina Walsh. The poem starts of with a question, ‘do you come to me to bend me to your will?’ throughout the poem, the basic atmosphere of loss is evident. Within the first stanza itself there is marital imagery relating to the sense of power and dominance. ‘ in drudgery and silence’, she tries to portray how she is helpless to protest, she begins the poem with this relationship, the dominance of man over woman, ‘to make of me a bondslave’ in this stanza she is explaining one of the types of relationships between a man and woman. She also gives out a feeling that if the relationship were as what she described she would be wasting her life, and tries to give out women’s point of view to these types of situations. She seems quite certain of what she wants in life and this does not seem to be it, ‘ if that be what you ask, O Lover I refuse you!’And her point is to prove that if that was the man’s view of the relationship, that it would not be possible to commit to that. In the second stanza she does not keep it as long as the first or any of the others as she does not want to dwell on it. The very idea of the man thinking the woman to be perfect and ‘one from heaven sent’ is what she rejects. When she describes women to be perfect her tone is very mocking. ‘ a wingless angel who can do no wrong’ she tries to convey that that would be someone who would have no freedom. ‘Go’ this implies how she rejects him if he wishes the relationship to be anything like this as well. In th... ...ith silence and tears’ there is a different meaning in this now, they do not understand each other now, but in the beginning they knew each other so well because over the years she has changed so much. The pain and sadness seems to intensify, ‘cold kiss, chill on my brow, knell to my ear’, these are all traditional images of rejected love. The poems octave stanza and regular eight lines, show the continuity of his pain. Throughout all these four poems the poets convey all their attitudes towards love and loss by expressing themselves in situations of love with others, of experiencing it and hence showing reactions and feelings that evolve from certain situations. They show that they feel love is a great thing, and for one to really know the true meaning of love, they need to experience loss and pain the be able to value love to its deserved potential.

Carter’s Economic Policies Led to Savings and Loan Failure

The Savings and Loan crisis of the late 1980’s and early 1990’s cost approximately $160 billion, out of which the American taxpayer shouldered in excess of $120 billion in Government bailout measures. The huge budget deficits that resulted can only be compared to the current global economic crisis. However, the genesis of the S & L crisis can be traced back to the failed economic policies of President Jimmy Carter. When Jimmy Carter took over as president in 1979, he inherited an economy in recession. Oil prices were high, unemployment and incomes were low. In order to stimulate the economy, he proposed to increase government spending and introduce tax cuts, but withdrew the former and vetoed the latter when interest rates continued to rise. Instead, when inflation peaked in 1978, the chairman of the Federal Reserve Board, Paul Volcker, initiated policies to tame inflation by reducing the money supply and increasing interest rates. However, these measures had a negative effect and inflation skyrocketed, unemployment reached 11 percent, accompanied by a prime rate of 21. 5 percent (Federal Deposit Insurance Coorporation, 2006). In this climate, the savings and loan institutions could not survive. They were now confronted with asset-liability-mismatches where the costs they were incurring on short term funding were higher than the returns they were getting on fixed-rate-mortgages. Additionally, the passage of the Depository Institutions Deregulation and Monetary Control Act, introduced risks and opportunities which the S & L’S were not qualified to administer. Inevitably, many S & L’s began to go under. In retrospect, Jimmy Carter’s policies should have focused on lowering interest rates and possibly left the money markets as they were. Read also Analyze the Ways in Which British Imperial Policies References Federal Deposit Insurance Coorporation (2006, February). The 1970’s. Retrieved on July 27, 2009 from http://www.fdic.gov/about/learn/learning/when/1970s.html

Gender Roles For White And Black - 1020 Words

Imagine yourself, a proud American starting another chapter in life where your desires and aspirations ahead of you. Then all of sudden undergo dizziness and then wakes up to a time in your ancestry encompassing not a pleasing sight. You walk around the new surroundings, seeking for a form of life to tell you where you are. When revealed to you where and WHEN you landed, your heart races and plummets to the floor at the same time. The one word and time where evil stands necessary and idea of dehumanization is afoot. Slavery: a segment in time surrounding bondage of African slaves under the societal and political supremacy of European America. Yet you pull yourself together, try to adapt to the ways of living hoping to go back to the present. As you learn to know your place in race and gender, you start to realize that your life can be at stake. The gender roles for white and black made an impact distinctively to function in a society on the matter assuring right and just. 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