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Preparation of Papers in Two-Column Format - DOC 6

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									Conference Session B9 Chemical Engineering Topics 5                                                                           1229


                 MONOCLONAL ANTIBODIES AND CANCER TREATMENT
                 Deanna Broadwater (dmb123@pitt.edu) and Brittany Givens (beg34@pitt.edu)

Abstract – Monoclonal antibody therapy comprises 33% of              monoclonal antibody to be an identical cell to the cells
the total biopharmaceutical therapies today [1]. 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 [2].
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 [2]. These antibodies are
becoming more popular and thus must be produced on a                 Cancer describes diseases in which cells divide
large scale [1]. 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 [9].
                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 [3] 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 [4]. 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 [5].                               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 [4].             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 [6] 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 [9]. This holds great importance because
engineers’ duty to improve the quality of life of people [7].        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 [2]. 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 [9].
[1].
                                                                                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” [8]. 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 [4].            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 [6].
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 [10].                       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 [8].
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
[5]. 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 [5]. 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) [5].                                                       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 [11].
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 [11].
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 [11]. It blocks EGFR ligand binding which               ligand binding and causes receptor neutralization like
causes receptor internalization and degradation [5].                  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 [12].
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 [11].                                                    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 [11].                                               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).                [5].
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 [5].
severe case and not taken care of by a doctor [11].                         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 [1]. 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 [5].                                        [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 [5].                                                   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 [13]                                                    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 [1].
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 [14].                                 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 [1]. 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 [1]. 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 [1].                                                         environment is both created and maintained [1].
     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 [1].
the basis for large scale production systems [1].

                     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 [1].
     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 [1].                                          contribute to the negative aspects [1].
     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 [1].                          with their negative effects must remain in use until better
     A disposable bioreactor, as the name suggests, is                   methods can be developed [8].
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 [1].             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 [15].
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 [1].                                             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 [11].
problems and bleeding, as was discussed separately for the                  The cost of monoclonal antibodies used for treatment
three specific drugs outlined earlier [10].                            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 [4]. If an allergic reaction occurs in            for the drug may be paid for by part of the study [11].
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 [10].                      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% [16].
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 [7].       supply cannot keep up with demand [1]. 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 [9]. 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 [9]. Current cancer treatments                            [10]                                                        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                       [11] Lidan L, Yunfei C, Aihua T, Cun L, Feng G. (2010, April).
independently [4]. 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                               [12] 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
                                                                                  [13] (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                       [14](January, 2009). “Trastuzumab Injection”. PubMed Health. Available:
and produce drugs quickly [1], but they also must produce                         http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001048#a699019-
                                                                                  otherInformation
drugs at a low cost.
                                                                                  [15] 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                         [16] 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 [1], as well as an even and sufficient distribution
of medicine in each culture [3].
     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
[1] 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
[2]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
[3] 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
[4] (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
[5] (2010). “Targeted Therapies for Solid Tumors: Current Status and
Future Perspectives.” BioDrugs. Vol. 24, pp. 303-316. [Online]. Available:
Academic Search Premier
[6] National Academy of Engineering. (2010). “Engineer better medicines.”
[Online].                                                        Available:
http://www.engineeringchallenges.org/cms/8996/9129.aspx
[7] National Society of Professional Engineers. (2010, February 10). “Code
of               Ethics.”               [Online].                Available:
http://www.nspe.org/Ethics/CodeofEthics/index.html
[8] (2002, March 26) MedicineNet.com
http://www.medterms.com/script/main/art.asp?articlekey=4425
[9] Cancernet
 http://www.cancernet.co.uk/herceptin.htm


University of Pittsburgh                                                                                          Swanson School of Engineering
Eleventh Annual Freshman Conference                                                                                                April 9, 2011
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