For the

research article, choose an

immunologically-based disease that is
treated by
monoclonal antibody-based drug. Your article
should be two pages long, single-
spaced. Describe that pathology of the
disease. Describe how the monoclonal
antibody is produce and how it treats the
disease. Include appropriated immune
cells, receptor,
etc.
Crohn disease, also called regional
enteritis or regional ileitis,
chronic inflammation of the digestive tract,
usually occurring in the terminal portion of
the ileum, the region of the small
intestine farthest from the stomach. Crohn
disease was first described in 1904 by Polish
surgeon Antoni Leśniowski. It was later named
for American gastroenterologist Burrill Bernard
Crohn, who in 1932, in collaboration with
fellow physicians Leon Ginzburg and Gordon
D. Oppenheimer, published a thorough
description of a then-unknown intestinal
disorder they called regional ileitis. Today,
Crohn disease is characterized as a type
of inflammatory bowel disease (IBD) and has
been associated with abnormal function of
the immune system and genetic variations.
The disease also has been linked to abnormal
changes in populations of intestinal bacteria.
For example, Faecalibacterium prausnitzii, a
normal inhabitant of the human intestinal tract,
is found in decreased levels in people with
Crohn disease, and Mycobacterium avium
paratuberculosis, found in the intestinal tracts
of ruminants affected by Johne disease, which
is similar to Crohn disease in humans, has
been isolated from the blood of some patients.
However, despite these associations, the
cause of Crohn disease remains unknown.
The most common symptoms of Crohn
disease include diarrhea and abdominal pain.
Rectal bleeding, fever, weight loss, arthritis,
and anemia are indications of moderate to
severe disease. Some patients
develop fistulas, or abnormal passages
connecting the bowel to other organs, such as
the bladder or the vagina. These often lead
to abscesses (pus-filled cavities within
tissues). The formation of fistulas and the
thickening of the intestinal wall—to the point of
obstruction—are the only microscopic findings
that distinguish Crohn disease from ulcerative
colitis, the other type of IBD. In Crohn disease
the maximum damage to the intestine occurs
beneath the mucosa, and lymphoid
conglomerations, known as granulomata, are
formed in the submucosa. In addition, Crohn
disease attacks the perianal tissues more
often than does ulcerative colitis. Crohn
disease is diagnosed by a combination of
methods, including blood and stool analysis
and colonoscopy. Diagnosis may be confirmed
by other methods, such as barium enema,
which uses X-rays to examine the intestine
following rectal insertion of a liquid barium
contrast agent, and capsule endoscopy, which
examines the intestines via a pill-sized video
camera that is swallowed by the patient and
transmits images to sensors attached to the
patient’s body as it passes through the
digestive tract.
A combination of immunosuppressive and anti-
inflammatory drugs, including corticosteroids
and aminosalicylic acid compounds, are used
to treat Crohn disease. The drugs are effective
both in treating acute episodes and in
suppressing the disease over the long term.
Depending on the circumstances,
hematinics, vitamins, high-protein diets,
and blood transfusions are also used. Surgical
resection of the portion of the large bowel
affected is often performed. The
entire colon may need to be removed and the
small intestine brought out to the skin as an
ileostomy, an opening to serve as a substitute
for the anus.

The use of antibodies to treat diseases can be

traced all the way back to the late 1800s with the
advent of diphtheria antitoxin for the treatment
of diphtheria. It wasn't until the 1900s that the
newly emerging class of naturally derived
medications such as sera, vaccines,
and antitoxins began to be referred to as
biologics. The definition for biologics and
biological therapy has changed a lot since. The
development of recombinant DNA technology in
the 1970s shaped the modern understanding of
what constitutes as biological therapy, which
often does not include traditional biological
substances like vaccines. Today, biological
therapy most commonly refers to the use
of proteins, such as monoclonal antibodies, to
regulate the immune system in the treatment of
disease.[9]
In 1975, Georges J. F. Köhler and César
Milstein generated the first monoclonal
antibodies using their own hybridoma
technology.[12] They started the field of
monoclonal antibody development and won
the Nobel Prize for Medicine in 1984 for their
work.[13] Soon after, muromonab-CD3 became
the first fully licensed monoclonal antibody in
1986 for its use in treating kidney transplant
rejection.[14] Since then, over 70 monoclonal
antibodies have been approved by the FDA.[15]
The advancements in biological therapy greatly
changed how IBD is treated. Patients with
Crohn's disease and ulcerative colitis show an
increase in proinflammatory cytokines such
as IL-1, IL-6, IL-8, IL-23, and TNF.[10] In 1988, a
monoclonal antibody called infliximab was
discovered at New York University's School of
Medicine. Infliximab works by binding to TNF,
stopping its inflammatory effects. It was initially
used for the treatment of Crohn's disease and it
became the first FDA approved TNF inhibitor in
1998.[16] Infliximab as well as other TNF
inhibitors like adalimumab, certolizumab,
and golimumab are currently the most common
biologics used in the treatment of both Crohn's
disease and ulcerative colitis. The other main
categories of biologics that treat IBD
are integrin receptor antagonists such
as vedolizumab and natalizumab and interleukin
antagonists like ustekinumab.[11]

Rationale for biological therapy[edit]

Cytokines involved in IBD

Prior to the development of biological therapy as
a modality to treat IBD, other medications that
modulate the immune system—including 5-
aminosalicylates, steroids, azathioprine, and
other immunosuppressants—were primarily
used in treatment.[7] Corticosteroids are effective
in inducing clinical remission in patients with
active IBD, but they can't be used long term due
to the risk of steroid-dependence and harsh side
effects.[17] The other medications like 5-
aminosalicylates and azathioprine are often
used to reduce steroid use while maintaining
remission, but their actual effect on the state of
the disease and the need for surgery remains
unknown.[17] Patients with Crohn's disease that
developed complications, including fistulae (=
abnormal connections to the bowel) were
treated with surgery.[18] Patients with ulcerative
colitis who do not respond to medications are
still treated with colectomy (= removal of
the colon).
However, basic science research showed that
many cytokines were elevated in both Crohn's
disease and ulcerative colitis.[19] Crohn's disease
cytokines are of the type 1 (Th1) cytokines,
which include TNF-α, interleukin-2,
and interferon γ.[20] Ulcerative colitis was less
conclusively linked to the production
of Th2 cytokines.[21]
TNF inhibiting biological therapies were initially
used in IBD patients who weren't responding to
conventional therapy.[17] They proved to be very
effective in some patients, shifting treatment
goals from simply improving symptoms to
actually changing the course of the disease by
reversing mucosal inflammation and preventing
long-term complications and surgery.[22] Although
there are strong initial responses in some
patients, biologic therapies also have their
downsides, and there is still a debate as to what
the most effective treatment strategy is.[17]

TNF inhibitors[edit]

Schematic demonstrating infliximab structure

TNF inhibitors are commonly the first drug
prescribed when a patient begins biologic
therapy. They have the most extensive history of
clinical evidence because they have been
available the longest, are the most accessible,
and are often the least expensive. Initially, it was
thought that TNF inhibitors inactivate the
proinflammatory cytokine by direct
neutralization, but TNF signaling is a very
complex process. Many recent studies suggest
that TNF inhibitors may act with a more complex
mechanism than simple blockade. They are all
administered systemically
either subcutaneously or intravenously.[23]
Infliximab[edit]
Main article: Infliximab
The monoclonal antibody infliximab is a mouse-
human chimeric antibody to TNF-α. The FDA
approved it in 1998, making it the first approved
TNF inhibitor. Infliximab has shown significant
success in treating both Crohn's disease and
ulcerative colitis, but it is also approved for the
treatment of rheumatoid arthritis, ankylosing
spondylitis, psoriatic arthritis, and plaque
psoriasis
Infliximab is a purified, recombinant DNA-
derived chimeric human-mouse IgG monoclonal
antibody that consists of
mouse heavy and light chain variable
regions combined with human heavy and light
chain constant regions.[25] It has a serum half-
life of 9.5 days and can be detected in serum 8
weeks after infusion treatment.[25]
Infliximab neutralizes the biological activity
of TNF-α by binding with high affinity to the
soluble (free floating in the blood) and
transmembrane (located on the outer
membranes of T cells and similar immune cells)
forms of TNF-α, and inhibits or prevents the
effective binding of TNF-α with its receptors.
Infliximab and adalimumab (another TNF
antagonist) are in the subclass of "anti-TNF
antibodies" (they are in the form of naturally
occurring antibodies), and are capable of
neutralizing all forms (extracellular-
, transmembrane-, and receptor-bound) TNF-
α.[26] Etanercept, a third TNF antagonist, is in a
different subclass (receptor-construct fusion
protein), and, because of its modified form,
cannot neutralize receptor-bound TNF-
α.[27] Additionally, the anti-TNF
antibodies adalimumab and infliximab have the
capability of lysing cells involved in the
inflammatory process, whereas the receptor
fusion protein apparently lacks this
capability.[28] Although the clinical significance of
these differences have not been absolutely
proven, etanercept, has been shown to perform
worse than placebo for Crohn's disease. These
differences may account for the differential
actions of these drugs in both efficacy and side
effects.
Infliximab has high specificity for TNF-α, and
does not neutralize TNF beta (TNFβ, also
called lymphotoxin α), an unrelated cytokine that
uses different receptors from TNF-α. Biological
activities attributed to TNF-α include induction
of proinflammatory cytokines (such
as interleukins IL-1 and IL-6), enhancement
of leukocyte movement or migration from the
blood vessels into the tissues (by increasing the
permeability of endothelial layer of blood
vessels), and increasing the release of adhesion
molecules. Infliximab prevents disease
in transgenic mice (a special type of mice
biologically engineered to produce a human
form of TNF-α and which are used to test the
results of these drugs that might be expected in
humans). These experimental mice develop
arthritis as a result of their production of human
TNF-α, and when administered after disease
onset, infliximab allows eroded joints to heal.
Other monoclonal antibodies targeting TNF-α
are golimumab, adalimumab, and certolizumab
pegol. Etanercept also binds and inhibits the
action of TNF-α, but is not a monoclonal
antibody (it is instead a fusion of TNF-
receptor and an antibody constant region).[29]

Adalimumab[edit]
Main article: Adalimumab
Adalimumab was approved by the FDA in 2002,
becoming the first fully human monoclonal
antibody to be approved. It was initially used in
the treatment of rheumatoid arthritis, but it is
now also used in patients with moderate-to-
severe Crohn's disease and ulcerative colitis
who don't respond well to conventional
treatment.[11] Adalimumab showed effectiveness
in patients with Crohn's disease, but less than
that of infliximab.[24] It was the best selling drug in
2017 with sales upwards of $18 billion.[25]
Certolizumab pegol[edit]
Main article: Certolizumab pegol
Certolizumab pegol is a recombinant antigen-
binding fragment antibody that is attached to a
40kDa polyethylene glycol.[11] The addition of
polyethylene glycol, or PEGylation,
increases bioavailability, drug stability, and
plasma half-life.[26] It was found to have efficacy
over placebo medications for 10 weeks in the
treatment of moderate to severe Crohn's
disease in one large trial.[27] It is not used in the
treatment of ulcerative colitis, but it is used in the
treatment of rheumatoid arthritis, active psoriatic
arthropathy, and ankylosing spondylitis.[11]
Golimumab[edit]
Main article: Golimumab
Golimumab is a fully human IgG1 monoclonal
antibody that was first approved by the FDA in
2009 to treat rheumatoid arthritis. Since, it has
been approved to also treat psoriatic arthritis,
ankylosing spondylitis, and moderately to
severely active ulcerative colitis.[11]
Integrin receptor antagonists are different than
TNF inhibitors because they
block transmembrane receptors called integrins
instead of cytokines like TNF. Integrins mediate
adhesion, signaling, and migration in many
different types of cells. During active periods of
disease, cell adhesion molecules on the
vascular endothelium increase in response to
various proinflammatory cytokines. The alpha 4
integrin on inflammatory cells interacts with
these adhesion molecules to allow for migration.
Integrin receptor antagonists block the
interaction and prevent the migration of
inflammatory cells to disease sites.[23]
Natalizumab[edit]
Main article: Natalizumab
Natalizumab is a humanized IgG4 monoclonal
antibody that inhibits the alpha 4 integrin. It was
the first integrin receptor antagonist, receiving
FDA approval in 2004 for the treatment of
Crohn's disease.[11] It was approved for the
treatment of multiple sclerosis as well, but there
have been concerns due to reports of
progressive multifocal leukoencephalopathy.[23]
Vedolizumab[edit]
Main article: Vedolizumab
Vedolizumab is very similar to natalizumab in
that it is a humanized IgG monoclonal antibody,
but vedolizumab is an IgG1 that specifically
blocks the alpha 4 beta 7 integrin that is located
primarily on cells in the gastrointestinal tract. It is
promoted as being gut specific due to the
localization of alpha 4 beta 7 integrin in the
gastrointestinal tract and was the first biologic to
be made specifically for inflammatory bowel
disease.
Maintenance therapy with the drug (versus
intermittent or sporadic therapy) lessens the
likelihood of developing antibodies to infliximab
which are known to reduce the efficacy of the
drug. Combination treatment
with methotrexate (an antifolate drug which
suppresses the immune system) has been
shown to reduce the formation of these
antibodies in patients with rheumatoid
arthritis[24] and combination therapy with other
immunosuppressants has been shown to reduce
the likelihood of these antibodies being formed
in Crohn's disease.[7] The use of
immunosuppressants may not be necessary in
all diseases for which infliximab is indicated, and
indiscriminant uses of these other
immunosuppressants carry their own risks.
Infliximab was studied in monotherapy (without
concomitant immunosuppressants such as
methotrexate or azathioprine)
in psoriasis, psoriatic arthritis, and ankylosing
spondylitis.[12] Only its use in rheumatoid
arthritis requires the concomitant use of
methotrexate by FDA product labeling; however,
the concomitant use of methotrexate in other
disease states may help to reduce the body's
immune response to the infliximab and increase
its duration of efficacy.