monoclonal antibiotics usage in auto immune disorders
TRANSCRIPT
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MONOCLONAL ANTIBIOTICS USAGE IN AUTO IMMUNE
DISORDERS
Praneeth Chandaluri1* and Ramesh Ganpisetti
2
1,2
Department of Pharmacy Practice, Malla Reddy College of Pharmacy (Affiliated to
Osmania University), Hyderabad, Telangana, India-500100.
ABSTRACT
Hybridoma technology is a method for producing large numbers of
identical antibodies (also called monoclonal antibodies). This process
starts by injecting a mouse with an antigen that provokes an immune
response. A type of white blood cell, the B cell that produces
antibodies that bind to the antigen are then harvested from the mouse.
These isolated B cells are in turn fused with immortal B cell cancer
cells, a myeloma, to produce a hybrid cell line called a hybridoma,
which has both the antibody-producing ability of the B-cell and the
exaggerated longevity and reproductively of the myeloma. Once
monoclonal antibodies for a given substance have been produced, they
can be used to detect the presence of this substance. The Western
blot test and immuno dot blottests detect the protein on a membrane.
They are also very useful in immunohistochemistry, which detect antigen in fixed tissue
sections and immunofluorescence test, which detect the substance in a frozen tissue section or
in live cells. Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal
antibodies (mAb) to bind monospecifically to certaincells or proteins. This may then
stimulate the patient's immune system to attack those cells. Monoclonal antibodies used
for autoimmune diseases include infliximab and adalimumab, which are effective
in rheumatoid arthritis, Crohn's disease and ulcerative Colitis by their ability to bind to and
inhibit TNF-α. Basiliximab and daclizumab inhibit IL-2 on activated T cells and thereby help
preventing acute rejection of kidney transplants. Omalizumab inhibits human
immunoglobulin E (IgE) and is useful in moderate-to-severe allergic asthma.
WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
SJIF Impact Factor 6.041
Volume 6, Issue 01, 266-285 Review Article ISSN 2278 – 4357
*Corresponding Author
Praneeth Chandaluri
Department of Pharmacy
Practice, Malla Reddy
College of Pharmacy
(Affiliated to Osmania
University), Hyderabad,
Telangana, India-500100.
Article Received on
24 Oct. 2016,
Revised on 14 Nov. 2016,
Accepted on 04 Dec. 2016
DOI: 10.20959/wjpps20171-8216
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Praneeth et al. World Journal of Pharmacy and Pharmaceutical Sciences
KEYWORDS: Crohn's disease, myeloma, a hybridoma, rheumatoid arthritis,
immunofluorescence test, ulcerative Colitis.
INTRODUCTION
Hybridomas are cells that have been engineered to produce a desired antibody in large
amounts, to produce monoclonal antibodies. (1, 2) Monoclonal antibodies can be produced in
specialized cells through a technique now popularly known as hybridoma technology.[1]
Hybridoma technology was discovered in 1975 by two scientists, Georges Kohler of West
Germany and Cesar Milstein of Argentina (now working in U.K.), who jointly with Niels
Jerne of Denmark (now working in Germany) were awarded the 1984 Noble prize for
physiology and medicine.1 Generally, the production of one MAb, using the hybridoma
technology, costs between $8,000 and $12,000. The average reasonably SK can generate only
15 to 30 hybridoma fusions per year, but in an environment where the focus is on diagnostic-
or therapeutic-quality MAbs, there are additional significant limitations than can further
decrease throughput. Monoclonal antibodies is valuable for the analysis of parasites antigen
and appropriate that WHO should have organized a symposium (held at the national
university of Singapore, October 1981) which brought together those who have establish and
refined the technology and those who are using it, or intending to use it for the study of
organism responsible for some of the major diseases affecting mankind. Such monoclonal
antibodies, as they are known, have opened remarkable new approaches to preventing,
diagnosing and treating disease. Monoclonal antibodies are used, for instance, to distinguish
subsets of B cells and T cells. This knowledge is helpful not only for basic research but also
for identifying different types of leukemias and lymphomas and allowing physicians to tailor
treatment accordingly. Quantitating the number of B cells and helper T cells is all-important
in immune disorders such as AIDS. Monoclonal antibodies are being used to track cancer
antigens and alone or linked to anticancer agents, to attack cancer metastases. The
monoclonal antibody known as OKT3 is saving organ transplants threatened with rejection,
and preventing bone marrow transplants from setting off graft-versus-host disease (immune
system series).
METHODOLOGY
Hybridoma technology is a method for producing large numbers of
identical antibodies (also called monoclonal antibodies). This process starts by injecting a
mouse with an antigen that provokes an immune response. A type of white blood cell, the B
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cell that produces antibodies that bind to the antigen are then harvested from the mouse.
These isolated B cells are in turn fused with immortal B cell cancer cells, a myeloma, to
produce a hybrid cell line called a hybridoma, which has both the antibody-producing ability
of the B-cell and the exaggerated longevity and reproductivity of the myeloma. The
hybridomas can be grown in culture, each culture starting with one viable hybridoma cell,
producing cultures each of which consists of genetically identical hybridomas which produce
one antibody per culture (monoclonal) rather than mixtures of different antibodies
(polyclonal). The myeloma cell line that is used in this process is selected for its ability to
grow in tissue culture and for an absence of antibody synthesis. In contrast to polyclonal
antibodies, which are mixtures of many different antibody molecules, the monoclonal
antibodies produced by each hybridoma line are all chemically identical.
A hybridoma, which can be considered as a harry cell, is produced by the injection of a
specific antigen into a mouse, procuring the antigen-specific plasma cells (antibody-
producing cell) from the mouse's spleen and the subsequent fusion of this cell with a
cancerous immune cell called a myeloma cell. The hybrid cell, which is thus produced, can
be cloned to produce many identical daughter clones. These daughter clones then secrete the
immune cell product. Since these antibodies come from only one type of cell (the hybridoma
cell) they are called monoclonal antibodies. The advantage of this process is that it can
combine the qualities of the two different types of cells; the ability to grow continually, and
to produce large amounts of pure antibody. HAT medium (Hypoxanthine Aminopetrin
Thymidine) is used for preparation of monoclonal antibodies. Laboratory animals (eg. mice)
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are first exposed to an antigen to which we are interested in isolating an antibody against.
Once splenocytes are isolated from the mammal, the B cells are fused with immortalized
myeloma cells - which lack the HGPRT (hypoxanthine-guanine phosphoribosyltransferase)
gene - using polyethylene glycol or the Sendai virus. Fused cells are incubated in the HAT
(Hypoxanthine Aminopetrin Thymidine) medium. Aminopterin in the myeloma cells die, as
they cannot produce nucleotides by the de novo or salvage medium blocks the pathway that
allows for nucleotide synthesis. Hence, unfused D cell die. Unfused B cells die as they have a
short life span. Only the B cell-myeloma hybrids survive, since the HGPRT gene coming
from the B cells is functional. These cells produce antibodies (a property of B cells) and are
immortal (a property of myeloma cells).[2]
The incubated medium is then diluted into
multiwell plates to such an extent that each well contains only 1 cell. Then the supernatant in
each well can be checked for desired antibody. Since the antibodies in a well are produced by
the same B cell, they will be directed towards the same epitope and are known as monoclonal
antibodies.[3]
Once a hybridoma colony is established, it will continually grow in culture
medium like RPMI-1640 (with antibiotics and foetal bovine serum) and produce antibody
(Nelson et al., 2000.)[3]
The next stage is a rapid primary screening process, which identifies
and selects only those hybridomas that produce antibodies of appropriate specificity. The
hybridoma culture supernatant, secondary enzyme labelled conjugate and chromogenic
substrate, is then incubated and the formation of a colored product indicates a positive
hybridoma. Alternatively, immunocytochemical screening can also be used (Nelson et al.,
2000.) Multiwell plates are used initially to grow the hybridomas and after selection, are
changed to larger tissue culture flasks. This maintains the well being of the hybridomas and
provides enough cells for cryopreservation and supernatant for subsequent investigations.
The culture supernatant can yield 1to 60 ug/ml of monoclonal antibody, which is maintained
at 20°C or lower until required (Nelson et al., 2000.) By using culture supernatant or a
purified immunoglobulin preparation, further analysis of a potential monoclonal antibody
producing hybridoma can be made in terms of reactivity, specificity and crossreactivity
(Nelson et al., 2000.).
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(1) Immunisation of a mouse
(2) Isolation of B cells from the spleen
(3) Cultivation of myeloma cells
(4) Fusion of myeloma and B cells
(5) Separation of cell lines
(6) Screening of suitable cell lines
(7) in vitro (a) or in vivo
(b) multiplication
(8) Harvesting
Advancements OR Improvements in Hybridoma Technology
Considerable efforts during the last 10-15 years have been made to improve the yield of
monoclonal antibodies using hybridoma technology.[4,5]
These efforts included the
following:[6,7]
(1) The substitution of a chemical fusion promoter (P.E.G.) for the Sendai virus
initially used to promote fusion and (2) The use of myelomas that do not secrete their own
antibodies and that therefore do not interfere with the production of the required antibody (3)
A continuous cell line (Sp 2/0) was used as a fusion partner for the antibody producing B
cells. (4) Feeder layers consisting of extra cells to feed newly formed hybridomas were used
for optimal growth and hybridoma production. The most common feeder layers consisted
of[6,7]
murine peritoneal cells, marcrophages derived from mouse, rat or guinea pig extra
non immunized spleen cells, human fibroblasts, human peripheral blood monocytes or
thymus cells; these feeder cells had some limitations like depletion of nutrients meant for
hybridoma and contamination, so that other sources of hybridoma growth factors (HGF) like
interleukin-6 (II-6) derived from human cells were used.
Purification of Antibodies Monoclonal antibodies may need to be purified before they are
used for a variety of purposes. Before final purification, the cultures may be subjected to cell
fractionation for enrichment of the antibody protein. In E. coli, the antibodies may be
secreted in the periplasm, which may be used for enrichment of antibody, so that further
purification is simplified. Alternatively the antibodies may be purified from cell homogenate
or cell debris obtained from the medium.[6,7]
Antibodies can be purified by anyone of the
following techniques (I) ion-exchange chromatography; (ii) antigen affinity chromatography.
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Serum Free Media for Bulk Culture of Hybridoma Cells – The media for culturing a variety
of animal cells and discussed the significance of adding serum to basal nutrient media. Serum
is a highly complex and poorly defined mixture of components like albumin, transferrin,
lipoproteins and various hormones/growth factors. Nevertheless, serum makes an essential
component of media for culturing animal cells. The use of serum, however, leads to
difficulties in purification of antibodies. Furthers, it is an expensive technology for large scale
production of hybridoma cells for industrial production of monoclonal antibodies. In view of
these difficulties, serum free media are being increasingly used for culturing hybridoma
cells.[6,7]
Advantages of Serum Free Media in HybridomaCell Culture and Preparation of
Monoclonal Antibodies:[6,7]
1. Greatly simplified purification of antibodies due to increased
1.initial purity and absence of contaminating immunoglobulin. 2. Decreased variability of
culture medium. 3. Reduced risk of infectious agents. 4. Fewer variables for quality
control/quality assurance. 5. Increased control over bioreactor conditions. 6. Potential for
increased antibody secretion. 7. Low or no dependence on animals. 8. Cost effective. 9.
Overall enhanced efficiency.
Disadvantages of Serum Free Media in Hybridoma Cell Culture and Preparation of
Monoclonal Antibodies- 1. Not all serum free media are applicable to all cell lines. 2. Cells
may not grow to as high densities and may be more fragile than cells in serum 3. Media may
take longer to prepare. Bypassing Hybridomas and Cloning of mab Genes – The VH and VL
genes for antibodies can be amplified through polymerase chain reaction (PCR) using
'universal primers' (universal primers will carry conserved sequences for most antibodies). By
building restriction sites in the above primers, the amplified VH and VL genes can also be
cloned directly for expression in mammalian cells or bacteria. The raw material for PCR may
be hybridomas or B cells, which may be homogeneous (if derived from single cells) or
heterogeneous. In the latter case, a variety of VH and VL genes will be amplified and will
combine at random to produce as many as 106 clones for antibody genes (from 1000 different
VH and 1000 different VL genes). These genes will be cloned in a phage and their products
(particularly Fab fragments) can be screened for antigen binding activities. From such a large
number of combinations in a combatorial library, it is very difficult to recover the original
pairs of V genes (e.g. VHa.VLa or VHx.VLx is an original pair: VLy is a new combination
VHa). However, the complexity may be reduced by using antigen-selected B lymphocytes
(filters coated with antigen can be used for screening).[7]
Designing and Building of mab
Genes – The antigen binding sites of antibodies have been studied in some detail in recent
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years. This led to modelling of entirely new antibodies, sometimes for their use as enzymes.
This modelling through computer graphics can be used for alteration of antibody genes or for
synthesis of entirely genes. These genes can be cloned and expressed in bacteria. The
antibodies produced can be tested for their specificity and affinity for specific antigen.[7]
Primary and Secondary Libraries for Antibody Genes – In this method a repertoire of
antibody genes can be prepared by using genes that can be obtained from a number of
different sources including the following (i) Rearranged V genes from animals obtained
through the use of PCR (with universal primers) (ii) New V genes obtained through gene
conversion, a process adopted in birds (iii) Rearranged genes obtained from mRNA through
reverse transcription (iv) Designing entirely new V genes or D segments. The next step is to
allow the expression of library in bacteria and screen antibodies for antigen binding activities.
Thescreening can be done on membrane filters coated with antigen. In future, the screening
procedures may be replaced by methods of selection. In either case the selected VH and VL
genes can be subjected to mutations to increase the affinity of an antibody for a specific
antigen. A variety of methods for the above strategy are being developed, so that in future
monoclonal antibodies will be produced without hybridomas and lymphocytes gens.[6,7]
DIAGNOSTIC TESTS
Once monoclonal antibodies for a given substance have been produced, they can be used to
detect the presence of this substance. The Western blot test and immuno dot blottests detect
the protein on a membrane. They are also very useful in immunohistochemistry, which detect
antigen in fixed tissue sections and immunofluorescence test, which detect the substance in a
frozen tissue section or in live cells.[8,9]
ANALYTIC AND CHEMICAL USES
Antibodies can also be used to purify their target compounds from mixtures, using the
method of immunoprecipitation.
List of therapeutic, Diagnostic and Preventive Monoclonal Antibodies
Antibodies that are clones of a single parent cell. When used as drugs, the International
Nonproprietary Names (INNs) end in -mab. The remaining syllables of the INNs, as well as
the column Source, are explained in Nomenclature of monoclonal antibodies.[9,10,11]
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Types of monoclonal antibodies with other structures than naturally occurring
antibodies.
The abbreviations in the column Type are as follows:
mab: whole monoclonal antibody
Fab: fragment, antigen-binding (one arm)
F(ab')2: fragment, antigen-binding, including hinge region (both arms)
Fab': fragment, antigen-binding, including hinge region (one arm)
Variable fragments:
scFv: single-chain variable fragment
di-scFv: dimeric single-chain variable fragment
sdAb: single-domain antibody
Bispecific monoclonal antibodies:
3funct: trifunctional antibody
BiTE: bi-specific T-cell engager
THERAPEUTIC TREATMENT
Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal
antibodies (mAb) to bind monospecifically to certaincells or proteins. This may then
stimulate the patient's immune system to attack those cells. Alternatively,
in radioimmunotherapy a radioactive dose localizes on a target cell line, delivering lethal
chemical doses.[11]
More recently antibodies have been used to bind to molecules involved
in T-cell regulation to remove inhibitory pathways that block T-cell responses, known as
immune checkpoint therapy.[12]
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It is possible to create a mAb specific to almost any extracellular/ cell surface target.
Research and development is underway to create antibodies for diseases (such as rheumatoid
arthritis, multiple sclerosis, Alzheimer's disease, Ebola[13]
and different types of cancers).
Each antibody binds only one specific antigen.
Immunoglobulin G (IgG) antibodies are large heterodimeric molecules, approximately
150 kDa and are composed of two kinds of polypeptide chain, called the heavy (~50kDa) and
the light chain (~25kDa). The two types of light chains are kappa (κ) and lambda (λ). By
cleavage with enzyme papain, the Fab (fragment-antigen binding) part can be separated from
the Fc (fragment constant) part of the molecule. The Fab fragments contain the variable
domains, which consist of three antibody hypervariable amino aciddomains responsible for
the antibody specificity embedded into constant regions. The four known IgG subclasses are
involved in antibody-dependent cellular cytotoxicity.[14]
STRUCTURE OF ANTIBODY AND ANTIGEN
The immune system responds to the environmental factors it encounters on the basis of
discrimination between "self" and "non-self". Tumor cells are generally not specifically
targeted by the immune system, since tumor cells are the patient's own cells. Tumor cells,
however are highly abnormal and many display unusual antigens.
Some such antigens are inappropriate for the cell type or its environment. Some normally
present only during the organisms' development (e.g. fetal antigens).[4]
Some are rare
or absent in healthy cells and are responsible for activating cellular signal
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transduction pathways that cause unregulated tumor growth. Examples include ErbB2, a
constitutively active cell surface receptor that is produced at abnormally high levels on the
surface of approximately 30% of breast cancer tumor cells. Such breast cancer is known
as HER2-positive breast cancer.[5]
Antibodies are a key component of the adaptive immune response, playing a central role in
both in the recognition of foreign antigens and the stimulation of an immune response to
them. The advent of monoclonal antibody technology has made it possible to raise antibodies
against specific antigens presented on the surfaces of tumors.[15-17]
USES OF MONOCLONAL ANTIBODIES
Cancer
Anti-cancer monoclonal antibodies can be targeted against malignant cells by several
mechanisms. Ramucirumab is a recombinant human monoclonal antibody and is used in the
treatment of advanced malignancies.[18]
Radioimmunotherapy
Radioimmunotherapy (RIT) involves the use of radioactively-conjugated murine antibodies
against cellular antigens. Most research involves their application to lymphomas, as these are
highly radio-sensitive malignancies. To limit radiation exposure, murine antibodies were
chosen, as their high immunogenicity promotes rapid tumor clearance. Tositumomab is an
example used for non-Hodgkins lymphoma.
Antibody-directed enzyme prodrug therapy
Antibody-directed enzyme prodrug therapy (ADEPT) involves the application of cancer-
associated monoclonal antibodies that are linked to a drug-activating enzyme. Systemic
administration of a non-toxic agent results in the antibody's conversion to a toxic drug,
resulting in a cytotoxic effect that can be targeted at malignant cells. The clinical success of
ADEPT treatments is limited.[19]
Immunoliposome therapy
Immunoliposomes are antibody-conjugated liposomes. Liposomes can carry drugs or
therapeutic nucleotides and when conjugated with monoclonal antibodies, may be directed
against malignant cells. Immunoliposomes have been successfully used in vivo to convey
tumour-suppressing genes into tumours, using an antibody fragment against the
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human transferrin receptor. Tissue-specific gene delivery using immunoliposomes has been
achieved in brain and breast cancer tissue.[20]
Checkpoint therapy
Checkpoint therapy uses antibodies and other techniques to circumvent the defenses that
tumors use to suppress the immune system. Each defense is known as a checkpoint.
Compound therapies combine antibodies to suppress multiple defensive layers. Known
checkpoints include CTLA-4 targeted by ipilimumab, PD-1 targeted by nivolumab and
pembrolizumab and the tumor microenvironment.[21]
The tumor microenvironment (TME) features prevents the recruitment of T cells to the
tumor. Ways include chemokine CCL2 nitration, which traps T cells in the stroma. Tumor
vasculature helps tumors preferentially recruit other immune cells over T cells, in part
through endothelial cell (EC)–specific expression of FasL, ETBR and B7H3.
Myelomonocytic and tumor cells can up-regulate expression of PD-L1, partly driven by
hypoxic conditions and cytokine production, such as IFNβ. Aberrant metabolite production in
the TME, such as the pathway regulation by IDO, can affect T cell functions directly and
indirectly via cells such as Treg cells. CD8 cells can be suppressed by B cells regulation of
TAM phenotypes. Cancer-associated fibroblasts (CAFs) have multiple TME functions, in
part through extracellular matrix (ECM)–mediated T cell trapping andCXCL12-regulated T
cell exclusion.[21]
Autoimmune diseases
Monoclonal antibodies used for autoimmune diseases include infliximab and adalimumab,
which are effective in rheumatoid arthritis, Crohn's disease and ulcerative Colitis by their
ability to bind to and inhibit TNF-α.[22]
Basiliximab and daclizumab inhibit IL-2 on
activated T cells and thereby help preventing acute rejection of kidney transplants.[22]
Omalizumab inhibits human immunoglobulin E (IgE) and is useful in moderate-to-severe
allergic asthma.
TNF INHIBITORS OF MONOCLONAL ANTIBODIES
A TNF inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor
necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in
autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing
spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and
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refractory asthma, so TNF inhibitors may be used in their treatment. The important side
effects of TNF inhibitors include lymphomas, infections (especially reactivation of
latenttuberculosis), congestive heart failure, demyelinating disease, a lupus-like syndrome,
induction of auto-antibodies, injection site reactions and systemic side effects.[1]
Tumor
necrosis factor-α (TNF-α) is a cytokine central to many aspects of the inflammatory response.
Macrophages, mast cells and activated TH cells (especially TH1 cells) secrete TNF-α. TNF-α
stimulates macrophages to produce cytotoxic metabolites, thereby increasing phagocytic
killing activity.[23-25]
TNF-α has been implicated in numerous autoimmune diseases. Rheumatoid arthritis,
psoriasis and Crohn’s disease are three disorders in which inhibition of TNF-α has
demonstrated therapeutic efficacy. Rheumatoid arthritis illustrates the central role of TNF-α
in the pathophysiology of autoimmune diseases. Although the initial stimulus for joint
inflammation is still debated, it is thought that macrophages in a diseased joint secrete TNF-
α, which activates endothelial cells, other monocytes and synovial fibroblasts. Activated
endothelial cells up-regulate adhesion molecule expression, resulting in recruitment of
inflammatory cells to the joint. Monocyte activation has a positive feedback effect on T-cell
and synovial fibroblast activation. Activated synovial fibroblasts secrete interleukins, which
recruit additional inflammatory cells. With time, the synovium hypertrophies and forms a
pannus that leads to destruction of bone and cartilage in the joint, causing the characteristic
deformity and pain of rheumatoid arthritis.[26,27]
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Anti TNF agents molecular characteristics
Etanercept (Enbrel): Soluble TNF receptor fusion protein. As you can see in the image,
etanercept molecule consists of 2 extracellular domains of human soluble TNF receptor p75
that binds to TNF and a Fc fragment of human IgG that serves as a stabilizer.
Infliximab (Remicade): chimeric human-mouse anti-TNF alpha. This drug is 25% murinal
(mouse) derived and 75% human. The binding epitope for TNF is of murine origin while the
IgG fragment is of human origin.
Adalimumab (HUMIRA- Human Monoclonal Antibody in Rheumatoid Arthritis-): fully
human anti-tumor necrosis factor alpha monoclonal antibody produced by phage-display
technology.
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Potential mechanisms of action of the TNF-α blockers in immune-mediated
inflammatorydiseases.
MAC: Macrophage; sTNF: Soluble TNF-α; T: T cell; TCD: CD4+ T cell; tmTNF:
Transmembrane TNF-α; Treg: T regulatory cell.
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SIDE EFFECTS OF TNF-α MONOCLONAL ANTIBODIES
Rheumatoid arthritis
The role of TNF as a key player in the development of rheumatoid arthritis was originally
demonstrated by Kollias and colleagues in proof of principle studies in transgenic animal
models.[28,29,30]
Clinical application of anti-TNF drugs in rheumatoid arthritis was demonstrated by Marc
Feldmann and Ravinder N. Maini, who won the 2003 Lasker Award for their work.[31]
Anti-
TNF compounds help eliminate abnormal B cell activity.[17][18]
Skin disease
Clinical trials regarding the effectiveness of these drugs on hidradenitis suppurativa are
ongoing.[31]
The National Institute of Clinical Excellence (NICE) has issued guidelines for the treatment
of severe psoriasis using the anti-TNF drugs etanercept (Enbrel) and adalimumab (Humira) as
well as the anti-IL12/23 biological treatment ustekinumab (Stelara). In cases where more
conventional systemic treatments such as psoralen combined with ultraviolet A treatment
(PUVA), methotrexate and ciclosporin have failed or can not be tolerated, these newer
biological agents may be prescribed. Infliximab (Remicade) may be used to treat severe
plaque psoriasis if aforementioned treatments fail or can not be tolerated.[32]
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Cancer
The U.S. Food and Drug Administration continues to receive reports of a rare cancer of white
blood cells (known as Hepatosplenic T-Cell Lymphoma or HSTCL), primarily in adolescents
and young adults being treated for Crohn’s disease and ulcerative colitis with TNF blockers,
as well as with azathioprine and/or mercaptopurine.[33]
Opportunistic infections
TNF inhibitors put patients at increased risk of certain opportunistic infections. The FDA has
warned about the risk of infection from two bacterial pathogens, Legionella and Listeria.
People taking TNF blockers are at increased risk for developing serious infections that may
lead to hospitalization or death due to certain bacterial, mycobacterial, fungal, viral and
parasitic opportunistic pathogens.[34]
Tuberculosis
In patients with latent Mycobacterium tuberculosis infection, active tuberculosis (TB) may
develop soon after the initiation of treatment with infliximab.[35]
Before prescribing a TNF
inhibitor, physicians should screen patients for latent tuberculosis. The anti-TNF monoclonal
antibody biologics infliximab, golimumab, certolizumab and adalimumab and the fusion
protein etanercept, which are all currently approved by the FDA for human use, have
warnings which state that patients should be evaluated for latent TB infection, and if it is
detected, preventive treatment should be initiated prior to starting therapy with these
medications. dealy the wound healing also may not cause TB.
Fungal infections
The FDA issued a warning on September 4, 2008, that patients on TNF inhibitors are at
increased risk of opportunistic fungal infections such as pulmonary and disseminated
histoplasmosis, coccidioidomycosis, and blastomycosis. They encourage clinicians to
consider empiric antifungal therapy in certain circumstances to all patients at risk until the
pathogen is identified.[36]
CONCLUSION
These antibodies targeted the variable region gene products of T-cell receptors that were
involved in autoimmune disease. It is remarkable that a limited heterogeneity of T-cell
receptors is responsible for autoimmune conditions. However, in certain instances the T-
cell receptor repertoire is more diverse and may require a cocktail of monoclonal antibody
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reagents. Other approaches to treatment of autoimmune disease based on targeting the
variable region of the T-cell receptor involve active molecular vaccination.
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