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Conference Session B9 Chemical Engineering Topics 5 1229 MONOCLONAL ANTIBODIES AND CANCER TREATMENT Deanna Broadwater (email@example.com) and Brittany Givens (firstname.lastname@example.org) Abstract – Monoclonal antibody therapy comprises 33% of monoclonal antibody to be an identical cell to the cells the total biopharmaceutical therapies today . Monoclonal located in the tumor in all aspects, including DNA, not a antibodies (mAbs) offer another component to cancer unique entity. Thus, in order to make the targeting process treatment in addition to radiation and chemo- therapy. of mAbs successful, one must know the process by which There have been several mAbs created in labs that have cancer sustains itself . proven to be effective in treating certain types of cancer and since approved by the Federal Food and Drugs Inside a Cancer Tumor Administration (FDA) for use . These antibodies are becoming more popular and thus must be produced on a Cancer describes diseases in which cells divide large scale . MAbs have many benefits and negative uncontrollably and invade other tissue cells in the body to effects, however, overall they have proven to be a successful form tumors. Cancerous cells migrate through the body by new treatment for cancer. way of the cardiovascular and lymph systems. Healthy cells have genes that control cell growth, and are limited by Key Words – cancer therapy, Cetuximab, colorectal cancer, available space and location. In cancerous cells, however, Epidermal Growth Factor Receptor (EGFR), cell division overrides the normal controls that regulate cell immunotherapy, monoclonal antibodies (mAbs), growth and when this happens, tumors form. There are a Panitumumab, Trastuzumab significant amount of cancer diagnoses each year; for instance, in 2010 there were 1,529,560 new cases of cancer MONOCLONAL ANTIBODIES: DEVELOPMENT in the United States . AND USES In order for engineers to improve the quality of life, their ultimate goal must be to reduce the number of Monoclonal antibodies (mAbs) represent some of the most diagnoses per year. In the short term, as a way to improve promising molecular targeted immunotherapies  and are life in the interim, chemical engineers can develop medicine the most widely used form of cancer immunotherapy at this that is more efficient that has the ability to improve a time . They offer increasingly customized solutions based patient’s health with little effort. This is the current track on the targeting of multiple specific pathways essential for being taken regarding cancer treatment. Engineers are trying cancer development and metastasis . to understand how cancer develops and how it can be Monoclonal antibodies are delivered to patients stopped in order to produce effective medicines. intravenously and are developed in such a way that Cancerous tumors are detected via tumor markers such minimizes the chance for an adverse immune response . as substances that are found in abnormal amounts in blood, Engineers have a responsibility to develop systems and urine, or tissues. Substances that can be tumor markers are: strategies of the future based upon the 14 identified grand alpha-fetoprotein, lactate dehydrogenase, and neuron- challenges for engineers, which includes the call to engineer specific enolase. Tumor markers can be used to diagnose better medicines  and the National Society of Professional cancer as well as assess the patient’s likelihood to respond to Engineers’ code of ethics which includes a statement about certain treatments . This holds great importance because engineers’ duty to improve the quality of life of people . not all treatments work for all cancers. The current drugs Improving the quality of life entails: the production, being produced target different types of cancers because delivery, availability and clinical efficacy of drugs. they work in different ways . Once a patient has begun Chemical engineers focus mainly on the production process treatment, tumor markers can be used to validate a patient’s of mAbs, but they also need to understand how mAbs work response to a certain therapy . . Monoclonal antibodies With Cancer TARGETING PROCESS Clinical monoclonal antibodies get their name because only By definition, a monoclonal antibody is: “an antibody one antibody is made and all others are clones of the original produced by a single clone of cells” . Monoclonal hybridized antibody. The first monoclonal antibodies were antibodies are made to mimic the natural antibodies that are made from mouse antibodies, but since the human immune produced in the human body. Specifically, with cancer does not recognize mouse cells and thus detroys the treatment, they are made to mimic the process by which antiboides, nearly all of the monoclonal antibodies produced tumor cells survive, that is they are made to bind to actively today are fully human, or at least chimeric. Chimeric dividing cells in such a way that the cells perceive the antibodies are hybrids of mouse and human cells. The main University of Pittsburgh Swanson School of Engineering Eleventh Annual Freshman Conference April 9, 2011 1 Deanna Broadwater, Brittany Givens purpose of monoclonal antibodies, no matter how they are tail. This phosphroylation will start a phosphorlyation made, is to attach to specific defects in cancer cells . cascade and this activates a pathway that will induce cell Although the purpose, function, and effects of monoclonal proliferation and growth of the tumor. Monoclonal antibodies are all known, it is still unclear as to what dosage antibodies interact with the receptor protein and stop them is most efficient for patients. In the future, this may be from being able to be activated. In some cases they even solved using the same tumor markers used to identify cause degradation and destroy the receptor . cancerous tumors, however, there is no way to tell. The drugs that we have focused on for our paper all Monoclonal antibodies can work in a multitude of target an EGFR receptor. These drugs are typically the most different ways, depending on what cancer defect they are reliable with the least amount of negative side effects. targeting. Monoclonal antibodies can be used by themselves Though monoclonal antibodies are still a work in process, or combined with radiotherapy. It is possible to attach a some of them have had very positive results in clinical trials. monoclonal antibody to a cell receptor and then have the mAb deliver a dose of radiatoin that effectively kills the SPECIFIC DRUGS cancer cell. Also they can make the cancer cell more visible to the patients immune system by attaching to a defect only There are several monoclonal antibodies that have been the cancer cells possess. It is common for cancer cells to approved by the FDA (Table 1), although mAbs are a have mutations on the cell membrane. For example the relatively new technique for cancer treatment. The efficacy monoclonal antibody drug, rutiximab attaches to CD20, a of many of the drugs presented in Table 1 is still being protein only found on B cells. Lymphomas can occur from determined. In order to determine the efficacy, certain these blood cells so rituximab allows the body to target the B factors must be taken into account such as: the quality of a cells to fight cancer growth. Monoclonal antibodies can also patient’s response to a certain drug, the long term survival of block growith signals the cell sends out to connect it to the drug before administration, which will be discussed in blood vessels. All cells need to be connected to the later sections, and the severity of side effects. Following is circulatory system to recieve nutrients and survive. To an in depth analysis of three specific drugs: Cetuximab connect to the blood vessel system, they send out signals. (Erbitux), Trastuzumab (Herceptin), and Panitumumab There are monoclonal antibodies that can interpet these (Vectibix). Specific research was put into these drugs signals and prevent the tumor from growing . because they are of the most common still being evaluated On of the more succesful versions of monoclonal for their clinical efficacy. Comparing newer drugs to antibody therapy occurs when the antibody blocks the traditional treatments (those which are already being used in growth factors that are being recieved by the cancer cells. cancer treatment) will allow it to be determined if Cancer cells tend to mutated genes that allow them to have monoclonal antibody treatment is a viable source of cancer an abnormal number of growth factor receptors in their cell treatment . membrane. This allows the cancer cells to proliferate faster, but monoclonal antibodies can block certain receptors and Name of Drug Type of Cancer it Treats stop the growth hormones from activating the cell receptors Alemtuzumab (Campath) Chronic lympocytic leukemia . This is also called targeted therapy. One of the major Bevacizumab (Avastin) Brain cancer growth receptor groups is the Epidermal Growth Factor Breast cancer Receptor (EGFR) family. Our paper mainly focuses on the Colon cancer efficacy of EGFR inhibitors. Kidney cancer Growth factor signalling pathways are a major key in Lung cancer regulating cell functions, especially cell growth and proliferation. In tumor cells there are major alterations in the Cetuximab (Erbitux) Colon cancer signaling network. Usually in cancer cells the gene is Head and neck cancers overexpressed and there are many more receptors on the cell membrane than is usual . This allows the tumor cells to Ibritumomab (Zevalin) Non-Hodgkin's lymphoma grow faster. The epidermal growth factor (EGF) family of Ofatumumab (Arzerra) Chronic lymphocytic leukemia receptors are an important mediator in growth factor Panitumumab (Vectibix) Colon cancer signaling. These receptors are all tyrosine kinases and there Rituximab (Rituxan) Chronic lympocytic leukemia are four members: epidermal growth factor receptor (EGFR; Non-Hodgkin's lymphoma also called ERBB1), ERBB2 (HER2), ERBB3 (HER3), and Tositumomab (Bexxar) Non-Hodgkin's lymphoma ERBB4 (HER4) . Trastuzumab (Herceptin) Breast cancer When ligands bind to these receptors, it changes the Stomach cancer shape of the receptor. This change of formation induces the formation of receptor homo and heterodimers which activates the intrinsic kinase domain. When the receptor is TABLE 1 LIST OF FDA- APPROVED MONOCLONAL ANTIBODIES FOR CANCER activated there is phosphorylation in the cytoplasmic protein TREATMENT University of Pittsburgh Swanson School of Engineering Eleventh Annual Freshman Conference April 9, 2011 2 Deanna Broadwater, Brittany Givens Cetuximab common to have to have a wild-type K-ras gene in order to be applicable to use Cetuximab . Cetuximab is a chimeric (mouse/human) monoclonal These results show Cetuximab is useful in cancer antibody marketed under the name Erbitux. It is given to the treatment, but only in epithelial cancers that have an patient via intravenous insertion. It is an EGFR inhibitor that abnormally activated EGFR. It has been approved for use in was approved for use with metastatic colorectal cancer in head and neck cancer, colorectal cancer, and Squamous cell 2004. It can be used with chemoradiotherapy or by itself, carcinoma . depending on what kind of cancer the patient has and how Panitumumab advanced the cancer has become. Cetuximab increases the cytotoxic effects of chemoradiotherapy, as well as blocking Panitumumab is a monoclonal antibody marketed as EGFRs from EGF hormone so the cancerous cells stop Vectibix. It is a human monoclonal antibody that blocks proliferating . It blocks EGFR ligand binding which ligand binding and causes receptor neutralization like causes receptor internalization and degradation . Cetuximab, but not degradation. Due to the fact that Cetuximab was studied in a large meta-analysis of Panitumumab did so well in its phase III clinical trial it was seventeen randomized controlled trials (RCTs) in order to approved by the FDA for colorectal cancer. It is a second determine its clinical efficacy. The trials compared line treatment and used by itself without any other drugs or Cetuximab based therapy versus non-Cetuximab therapy in radiotherapy. It is given intravenously with generally mild advanced cancer. The variables we will measure from the side effects . meta-analysis are progression-free survival (PFS), overall In the phase III trial Panitumumab monotherapy was survival (OS), overall response rate (ORR), and significant compared with best supportive care in patients with side effects . previously treated metastatic colorectal cancer. The trial had In the seventeen controlled trials there was a total of in 463 patients that were randomly assigned to receive either 7,954 patients, 3,965 in the cetuximab group and 3,989 in therapy, 231 patients were in the control group and 232 the non-cetuximab group. The types of treatment besides patients were in the experimental group. The Panitumumab Cetuximab varied for each patient because there are a high therapy resulted in a 46% reduction in risk of tumor number of variations in chemotherapy and treatment progression and a partial response rate of 8%. There was no depending on the patient’s health and what kind of cancer difference in OS, but also there were a large number of they have and many other variables. Therefore there were a patients from the control group that switched to the variety of supporting treatments used with Cetuximab in the experimental group (174 of 231). This causes the form of drugs and radiochemotherapies. Examples of drugs quantitative results to be skewed, and not as truthful. They used were: irinotecan, bevacizumab, carboplatin; and cause it to appear that Panitumumab is less beneficial than it radiochemotherapy . actually is, so we can still these results as proof that The meta-analysis revealed many things about Panitumumab is a beneficial cancer treatment. This clinical Cetuximab. All of the variables that were measured were trial allowed Panitumumab to be approved by the FDA, and significantly higher with the Cetuximab treatment. proves the efficacy of the drug. Like Cetuximab, 90% of the Progression-free survival had an 83% improvement with a patients developed a rash, which was actually more severe in 95% confidence interval 78%-88%. The other variables were patients that responded well to the Panitumumab treatment OS (HR 0.89, 0.84–0.95), and ORR (OR 1.39, 1.22–1.58). . There was some heterogeneity in the results, which indicates In other clinical trials it has been proven that like inconsistency in the separate trials but it is a relatively Cetuximab, Panitumumab does not work effectively if there moderate value, which is expressed by an I-squared value of is a mutation on the K-ras gene. Also in another clinical trial 40.3%. This meta-analysis showed that there are definite (PACCE) it was shown that Panitumumab in combination side effects involved with Cetuximab but most of them are with oxaliplatin or irinotecan-based chemotherapy is mild and easily treated, such as rashes, hypomagnesia, ineffective. These clinical trials allow scientists to discover diarrhea, and a chance of infection in the arm that received problems with the drugs so they can be used more the IV for the Cetuximab. Infection can be serious if it is a effectively and improve more lives . severe case and not taken care of by a doctor . Panitumumab prescribed properly has been proven to be Some efficacy results differed by the type of cancer that an effective use of cancer treatment. Sometimes knowing was being treated. Cetuximab is particularly useful when who can use Panitumumab effectively can be difficult, used to treat colorectal cancer, but there was no decisive therefore the trial and error method is frequently a basis for improvement in pancreatic cancer. An important realization prescribing cancer treatment. that came up during this study is that if the patient has a mutation in the K-ras gene and Cetuximab is being used to Trastuzumab treat colorectal cancer it will not be effective. K-ras is an on/off switch that activates proteins necessary for cell Trastuzumab is a monoclonal antibody that targets the HER2 proliferation, when mutated it is an oncogene. It is now protein and is used to treat breast cancer, marketed under University of Pittsburgh Swanson School of Engineering Eleventh Annual Freshman Conference April 9, 2011 3 Deanna Broadwater, Brittany Givens Herceptin. HER2 is the human EGFR, also known as monoclonal antibodies is increasing, and therefore ERBB2. HER2 is typically overexpressed in human breast production systems must become adequate to meet market cancers and if it is overexpressed there is a correlation with demands. The most efficient way to produce monoclonal reduced survival. Trastuzumab blocks the HER2 receptors as antibodies is from mammalian cells by cell division, because well as alerting the immune system to the cancerous cells so this most accurately mimics the natural production of they can destroy them. In 2006 Trastuzumab was the only antibodies in the human body . New systems must be tyrosine kinase-targeted agent approved for the treatment of suitable for this production type while also being cost solid tumors. It is also given intravenously, though how efficient, readily available and delivered to patients quickly often differs by patient . [6, 7]. Trastuzumab has done very well in its clinical trials. In In all types of production, there are several factors that two clinical trials, patients with HER2-positive breast cancer need to be under constant control. These factors include: were randomly chosen to receive either Trastuzumab therapy temperature, pH level, glucose concentration, osmolarity, for one year or a placebo. There was a 33% increase in OS oxygen and carbon dioxide concentration, and the in the experimental group as well as 52% reduction in risk of concentrations of nutrients and metabolites. Due to high occurrence. Trastuzumab is now approved for metastatic sensitivity to foreign objects, antibodies must be produced in breast cancer . the same environment the human body provides. Trastuzumab is one of the only monoclonal antibodies In order to understand systems of monoclonal antibody that is used in adjuvant breast cancer. This is preventative production, knowledge of biology and chemistry is essential. cancer or decreases the chance of the cancer reappearing. It Production systems are made to mimic natural biological is only used in HER2+ breast cancer though, if there is not processes involving biochemicals. In addition, the time of an overexpression of HER2 than it is not beneficial. In the production and the yield for each run is directly related to study, Trastuzumab, when combined with paclitaxel the chemical reactions involved in the production of mAbs. following AC chemotherapy, reduces the risk of a first The time it takes for a culture to mature depends on the breast cancer event at three years by 52 %. This is kinetic or rate of product formation. Furthermore, in many significant and there are many other trials that support the cultures, there is nothing added or subtracted during the fact that Trastuzumab can be used as a breast cancer process; that is there are no catalysts to speed up the reaction preventative  at any point. This means, a limiting reagent, usually a Unlike Panitumab and Cetuximab there can be serious nutrient, must be identified in order to determine the rate of side effects with Trastuzumab. Serious heart conditions are a production. possible side effect. In one clinical trial 2.6% of patients Each of the factors mentioned above contributes to the stopped trial because of heart problems. There are also the systems used for large and small scale production. Small typical mild side effects, such as diarrhea, nausea and a scale production is no longer adequate for mAbs, but it chance of infection. Trastuzumab is now a standard provides a basis for large scale production . treatment for breast cancer, though it is yet to be determined an exact schedule, duration of therapy, and type of Small Scale Production chemotherapy combination is optimal for treatment. Its efficacy has been proven through numerous clinical trials The systems used for small scale production of monoclonal and can be used in first line or second line, and it is used antibodies are very traditional for producing chemicals. with chemotherapy or by itself . They are well understood and easy to use, and because of this they continue to be used today. Effects on People Small scale production systems grow cell cultures adherently, which is the normal process by which cells grow. The results from clinical trials prove that the previous The most common systems for adherent cell growth use a monoclonal antibodies have the ability to prolong life and humidified carbon dioxide incubator which allows for the sustain it. This allows mAbs to improve the quality of life necessary controlled environment cells need to grow. for people. Also, it allows cancer patients to recover with Adherent cultures are one way to produce drugs on a small fewer long term side effects compared to those treated only scale, however, there is a limited amount of surface area with chemotherapy or radiation therapy. This helps them available for the cells to grow on which greatly limits the maintain the standard of living they had before their amount of antibodies that can be produced . If adherent diagnosis. cultures were the only method, it would be impossible to keep meet demand with the supply that can be produced. Therefore, other methods which build on the same basic PRODUCTION SYSTEMS principles as adherent cultures are more commonly used. Suspension culture is another method used for small Monoclonal antibodies constitute about a third of the total scale production. This is the most common method because biopharmaceutical production today. The demand for the environment in which cells are cultured is independent of University of Pittsburgh Swanson School of Engineering Eleventh Annual Freshman Conference April 9, 2011 4 Deanna Broadwater, Brittany Givens available surface area which allows for higher product compared to the 2 L used in small scale production. The concentration. This method also has a more controlled cellbag rocks, the rocking motion induces undulation to environment than adherent cultures which reduces the risk ensure good nutrient distribution as well as a constantly for cell decomposition. Using this method, in just two renewed surface that increases oxygen transfer without shear months it is possible to produce mAb concentration from 0.7 damage . Cell cultures require a well controlled mg/mL to 2.5 mg/mL, but cannot produce more than 2 liters environment and this is one way that the well controlled per culture . environment is both created and maintained . The yield produced by these systems is only sufficient Disposable wave bioreactors can supply material very for research and diagnostic purposes, but today’s society rapidly, which is beneficial when drugs are in the early stage calls for mAbs to be produced for much more. The systems of clinical trials as well as when drugs are being produced that are traditionally used for small scale production provide for clinical use . the basis for large scale production systems . Large Scale Production While the systems for small scale development are very traditional and have been used for a long period of time the systems used in large scale development are constantly evolving. This continual change is due to the increasing demand for mAbs as well as the current limitations on large scale production systems. As some limitations have been solved, others have arisen, further pushing the production of new systems . Suspension culture is effective for small scale production, but is even more effective for large scale production. Suspension cultures are well understood and easy to use, which makes the transition to large scale FIGURE 1 production smoother. In large scale production, the SCHEMATIC DIAGRAM OF A DISPOSABLE WAVE BIOREACTOR parameters controlling suspension culture are stricter than those used in small scale production. The well controlled For large scale production, suspension cultures are the environment in small scale suspension cultures is not only effective method. Other methods that can be used, such completely maintained when transitioning to large scale as adherent cultures, are completely ineffective because they production, which calls for more maintenance and human have such limited space for cultures and the environment is work on the system, but there are many advantages to too difficult to control. There are other factors that also outweigh this disadvantage . contribute to the negative aspects . Large scale suspension culture allows for great flexibility and variability of working volumes within the system. Flexibility refers to the ability of the system to be DRAWBACKS used for different cell types and in different operation modes. In addition, the aforementioned key parameters can The process of cancer spreading to many parts of the body be easily controlled in this system; they just need more may seem to be well understood, but in actuality there are attention. There are multiple types of suspension culture certain aspects that are still unclear. As researchers work to systems that can be used with ease. Of these, the most decipher these processes, current methods of treatment even commonly used is the disposable bioreactor . with their negative effects must remain in use until better A disposable bioreactor, as the name suggests, is methods can be developed . disposed of after each use. This property is what makes Monoclonal antibodies are truly a developing cancer disposable bioreactors so common. Each time a disposable therapy. Although much progress has been made to make bioreactor is used the environment for cell growth is mAbs efficient and safe, there are still many problems that guaranteed to be completely sterile. This reduces the concern must be solved, such as minimizing the severity of side for cross contamination, which is present in all other systems effects, developing drugs that work independent of that are used for multiple runs with different products . individual differences, and making the drugs cost efficient. The wave bioreactor is a disposable bioreactor that is commonly used today (Figure 1). This bioreactor has a Side Effects disposable, flexible, sterile plastic bag (cellbag) that sits on a rocking thermo-platform. For large scale production, the Side effects are the product of differences in individual maximum capacity of this suspension culture is 1000 L as patients. When drugs are delivered to different individuals, University of Pittsburgh Swanson School of Engineering Eleventh Annual Freshman Conference April 9, 2011 5 Deanna Broadwater, Brittany Givens each person’s body reacts in a unique way. In order for prevent the necessary binding. Another factor that can drugs to be more efficient, engineers must develop drugs influence binding is the location of the antibody. In some independent of individual differences. However, today side tumor cells, the antibodies themselves are not attached to the effects persist and emanate from multiple sources. tumor cells but they are free floating. If a monoclonal Once a monoclonal antibody is present inside the body, antibody binds to a free floating antibody, it will have no there is a risk that there will be an immune response to its effect on the tumor . presence. An immune response decreases the efficacy of monoclonal antibody therapy and eliminates the possibility Economical Effects of re-treatment. If there is an immune response, we know that monoclonal antibody treatment will never work with the Currently, monoclonal antibodies are not economically technology used today . friendly for users. Some factors that are involved include: Other responses from the body due to the presence of cost, availability and drugs that have been approved by the mAbs also cause side effects. These side effects are rare, but Food and Drug Administration (FDA). some can be very serious. The list of side effects includes: Of the mAbs that have been approved by the FDA, not flu-like signs and symptoms, nausea, diarrhea, skin rashes, all of them have shown clear benefits. Some have proven to dangerously low blood cell counts, heart problems, skin only be effective temporarily . problems and bleeding, as was discussed separately for the The cost of monoclonal antibodies used for treatment three specific drugs outlined earlier . and not clinical trials is out of the price range of most There is may also be a response similar to an allergic Americans (on average they are $1000/treatment). The steep reaction. This occurs as a product of the injection itself. price range is a product of the limited availability of the drug These side effects generally only occur when the drug is first as well as the relatively age of therapies. Due to the age of being administered and they are very similar to those of the therapies and the fact that many products are still in the presence of mAbs, however, there are a few minor clinical trial phase, health insurances will not cover the differences. Examples of these side effects are: fever, chills, costs. In contrast, using a drug that is still in the clinical trial weakness, headache, nausea, vomiting, diarrhea, low blood phase can provide drugs at a reduced cost as part of the cost pressure, and rashes . If an allergic reaction occurs in for the drug may be paid for by part of the study . response to the infusion, there is medicine available to block For instance, in 2006 the cost of Trastuzumab was the allergic reaction before monoclonal antibody treatment analyzed. The cost per patient was analyzed using: treatment actually begins, and health will be monitored more closely indications, length of treatments, standard doses/ schedules after early signs of this sort of infection . and local pharmacy data. The average cost of Trastuzumab Monoclonal antibodies may also cause side effects per patient at the time of analysis was $47,278. Other costs when administered in doses that are too high for patients’ for similar mAbs differed from the cost of Trastuzumab by bodies to handle. These side effects are not as severe as 3-6% . those that correspond to an allergic reaction, but they can be MAbs are available in very limited quantities because strong enough to interfere with a patient’s quality of life . supply cannot keep up with demand . Due to the limited quantities available, even those that can afford the product Internal Problems may not have it available to them. Just as with side effects, individual differences have an ANTIBODIES AT THEIR FINEST impact on the efficiency of monoclonal antibodies. One factor that varies in tumor cells themselves is the The use of monoclonal antibodies in cancer treatment presence of antigens, which are foreign substances which overall is proving to be successful. Although there are major trigger reactions from the immune system such as releasing limitations on their use including cost and availability, there antibodies . The distribution of antigens in tumor cells is has been great progress in recent years to make mAbs more heterogeneous; some cells express tumor antigens whereas available to patients and more efficient, thanks to the work others do not. The density of antigens is also inconsistent, of chemical engineers to develop new systems and and the current monoclonal antibodies need a minimum procedures to get the medicine to patients in the best way antigen concentration in order to be effective. possible. In addition to antigens, blood flow is also a major factor. Because most mAbs are administered intravenously, Importance of Monoclonal Antibodies in the 21st they need adequate blood flow in order to reach the tumor. Century Not all tumors have adequate blood flow through them for the antibodies to be delivered to the necessary area. This As stated earlier, there were over one million new cases of makes mAb reliability highly unpredictable. cancer reported in 2010 in the United States. This number Monoclonal antibodies must be bound to the antigens in does not include cases in which cancer redeveloped and the tumor. The interstitial pressure inside the tumor can University of Pittsburgh Swanson School of Engineering Eleventh Annual Freshman Conference April 9, 2011 6 Deanna Broadwater, Brittany Givens nonmelanoma skin cancer . Current cancer treatments  Mayoclinic. http://www.mayoclinic.com/health/monoclonalantibody/CA00082/NSECTI alone and not entirely effective and have serious side effects ONGROUP=2. that greatly inhibit a cancer patient’s ability to function  Lidan L, Yunfei C, Aihua T, Cun L, Feng G. (2010, April). independently . The growing field of mAb production is “Cetuximab-based therapy versus non-cetuximab therapy for advanced due to a large desire to create treatments that are beneficial cancer: a meta-analysis of 17 randomized controlled trials”. Cancer Chemotherapy & Pharmacology [Online]. Available from: Academic to both patients, administrators and manufactorers [3, 4]. Search Premier Chemical engineers are the manufactorers behind  G. Keating. (2010, July). “Spotlight on Panitumumab in Metastatic mAbs, and it is their job to create the systems that will Colorectal Cancer”. BioDrugs [Online]. Available: Academic Search benefit the patient and administrator. As cost for monoclonal Premier  (2010).”Adjuvant Trastuzumab Clinical Trial.” [Online] Available: antibody treatment continues to be out of the budget of many Resultshttp://www.breastcancerupdate.com/sanantonio/2005/SABCS_05_1 American citizens, and health care providers do not take on 3.pdf the cost, not only must the production systems be efficient (January, 2009). “Trastuzumab Injection”. PubMed Health. Available: and produce drugs quickly , but they also must produce http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001048#a699019- otherInformation drugs at a low cost.  M. Bishop. “Monoclonal Antibodies.” [Online]. Available: In addition to the aforementioned restrictions on http://www.meds.com/immunotherapy/monoclonal_antibodies.html production, chemical engineers must ensure that the drugs  A. Drucker, D. Rayson, M. Sellon, C. Skedgel, K. Virik, T. Younis. that they have produced are adequate for delivery to humans. (2006). “2006 ASCO Annual Meeting Procceedings Part 1.” Journal of Clinical Oncology. Vol. 24, No. 18S. [Online]. Available: These drugs must not contain contaminants to the body, for http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_vie example, too much carbon dioxide as a by product of w&confID=40&abstractID=34806 production , as well as an even and sufficient distribution of medicine in each culture . The use of monoclonal antibodies as a method of cancer ADDITIONAL RESOURCES treatment has proven to be effective. The clinical trials have proven the viability of multiple monoclonal antibody Cancernet. Availble: http://www.cancernet.co.uk/herceptin.htm treatments and mAb production systems are now suitable for M. Moroni, S. Veronese, S. Benvenuti, G. Marrapese, A. Sartore-Bianchi, large yield. Although supply can now keep up with demand, F. Di Nicolantonio, F., A. Bardelli. (2005). “Gene copy number for monoclonal antibodies are still very expensive and not epidermal growth factor receptor (EGFR) and clinical response to readily available to many patients for this reason. Even so, antiEGFR treatment in colorectal cancer: a cohort study”. Lancet Oncology. the potential for mAb treatment in the future is promising Available: Academic Search Premier because it is known that the drugs are successful and EUREKA. (2010, May 5). “Manufacturing antibodies”. ScienceDaily. engineers can safely produce them as they are needed. Available: http://www.sciencedaily.com/releases/2010/03/100318132502.htm REFERENCES ACKNOWLEDGMENTS  J. Azeredo, A. Costa, M. Henriques, R. Oliveira, M. Rodrigues. (2009, December 30). "Technological Progresses in Monoclonal Antibody For our paper we had to do a significant amount of research Production Systems." [Online]. Available: http://www.aiche.org/uploadedFiles/SBE/Publications/Technological%20Pr in order to fully understand our topic. Some useful sources ogresses%20in%20Monoclonal.pdf in this process include: Ohio Health, Mayo Clinic and the OhioHealth American Cancer Association. We would also like to thank http://www.ohiohealth.com/body.cfm?id=6&action=detail&ref=3559. our friends, academic advisors, our co-chair Lisa Volpatti  D. Klinke. (2010). “A MultiScale Systems Perspective on Cancer, Immunotherapy, and Interleukin-12.” Molecular Cancer. Vol. 9, pp. 242- and chair Mr. Boback, our writing instructor Nancy Koerbel, 259. [Online]. Available: Academic Search Premier and other members of the University of Pittsburgh who have  (2010, October 12). “Monoclonal Antibodies.” [Online]. Available: offered their help and support in finding reliable information http://www.cancer.org/Treatment/TreatmentsandSideEffects/TreatmentTyp on this topic, especially Steven R. Little and Eric Beckmann. es/Immunotherapy/immunotherapy-monoclonal-antibodies  (2010). “Targeted Therapies for Solid Tumors: Current Status and Future Perspectives.” BioDrugs. Vol. 24, pp. 303-316. [Online]. Available: Academic Search Premier  National Academy of Engineering. (2010). “Engineer better medicines.” [Online]. Available: http://www.engineeringchallenges.org/cms/8996/9129.aspx  National Society of Professional Engineers. (2010, February 10). “Code of Ethics.” [Online]. Available: http://www.nspe.org/Ethics/CodeofEthics/index.html  (2002, March 26) MedicineNet.com http://www.medterms.com/script/main/art.asp?articlekey=4425  Cancernet http://www.cancernet.co.uk/herceptin.htm University of Pittsburgh Swanson School of Engineering Eleventh Annual Freshman Conference April 9, 2011 7
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