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The Therapeutic Uses of Antibodies
The use of antibodies to treat disease is an exciting concept, and onethat could
prove vital in the near future. In this essay, the focus will be directed to using
antibodies to treat Alzheimer’s disease (AD), exploring the current monoclonal
antibodies being used or in trials and how they work.
Alzheimer’s disease is a neurodegenerative disease that affects over 24
million people around the world (Robert and Wark, 2012). Current pharmacological
approaches tend to be treatmentsaiming to control symptoms of the disease, rather
than preventing or slowing down the pathological processes that occur in patients
with Alzheimer’s (Prins and Scheltens, 2013).
There are two main methods of immunotherapy to treat AD. Passive
immunotherapy involves administering antibodies to the patient, which have been
manufactured outside the body, whereas active immunotherapy consists of actually
inducing a natural humoral immune response in the individual (Winblad et al., 2014).
To understand the use of antibodies to treat AD, it is important to know the targets
of these monoclonal antibodies (mAb). The main target is amyloid beta (A𝛽), which
is believed to be the root of AD due to the formation of plaques (Cerdernaes et al.,
2014). Different mAbs can be grown against the different epitopes for the A 𝛽40/
42. These varying mAbs are categorised according to the epitope locations. Some of
these locations on the A𝛽 include the N-terminal region, the central region and the
C-terminal region (Robert and Wark, 2012).
The next stage of understanding the immunotherapy of AD is the mAb’s
mechanism of action. Once the mAb is bound to the A 𝛽, the Fc region of the
antibody provides the effector function (similar to many biological processes) and
recruits microglial cells to the complex. This recruitment consequently leads to Fc
receptor-mediated phagocytosis (Bard et al., 2000) and the A𝛽 aggregates are
subsequently internalised by the microglia (Paresce et al., 1997).A problem that
comes with the target protein being in the CNS is the fact the antibodies have to
cross the blood-brain barrier (BBB), which is not known to have specialised receptors
to enable this transport (Spencer and Masliah, 2014).Another mechanism of action
of antibodies (which combats this problem) is the “peripheral sink” hypothesis. This
approach also involves the A𝛽-antibody interaction, but occurs outside of the CNS
(Vasilevko et al., 2007). Due to this, the A𝛽 equilibrium negatively changes, causing
an increased efflux of A𝛽away from the brain, hence the use of the term “sink”
(Robert and Wark, 2012; DeMattos, 2002). Targeting the A𝛽 protein became an
important concept in 1999, when Schenk and collaborators at Elan pharmaceuticals
immunised mice to this peptide. This experiment drew attention when results
showed amyloid deposit reductions and improved memory and learning (Wilcock
and Colton, 2008).
A feature of A𝛽 is that it exists in different forms and research concludes that
the oligomeric form is closely associated with the catastrophic neurodegeneration
that occurs in AD (Harigaya et al., 2000). Due to this, the oligomeric form of
pyroglutamateA 𝛽 is receiving more attention by neurologists. Many anti-A 𝛽
antibodies are produced by the induction of an immune response to the A𝛽1-42
acting as an immunogen. This results in the production of antibodies complimentary
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to the EFRH epitope. Despite this, the epitope is absent in pyroglutamate forms of
A𝛽 and therefore not affected by the antibodies (Perez-Gamendia and Gevorkian,
2013).Truncations occur at N- and C terminals which result in degradation resistance
and ultimately aggregation.To emphasise this, It has also been researched that these
modified A𝛽 forms are more likely to aggregate by up to 250 times than that of
unmodified A𝛽 proteins. This leads to the development of plaques, initiating the
pathogenesis of AD. However, Dr. V. Venkataramani and collaborators at Georg-
August-University have developed the 95D antibody, which can target these
oligomeric and pyroglutamate forms of A𝛽 (Venkataramani, 2012). The 95D antibody
is complementary to only a particular fraction of A 𝛽223, therefore slashes the risk of
potential side effects if administered as a vaccine. Mice that had been passively
immunised with the 95D antibody for 6 weeks actually began to show improved
behaviour, suggesting reduced Alzheimer’s characteristics, which could mean that
this monoclonal antibody could be an essential component for the treatment of AD
(Jawhar et al., 2011).
In 2012 attention was turned to the fully human anti-A 𝛽 antibody
gantenerumab, a new therapeutic prospect,. Investigations carried out by Roche into
this monoclonal antibody saw promising results, such as reduced A𝛽 deposits by
microglia recruitment and phagocytosis, prevention of plaque formation.
Gantenerumab targets both N-terminals and central regions, suggesting a greater
number of complexes and further induction of phagocytic A 𝛽 clearance (Bohrmann
et al., 2012). However, in December 2014, Roche released a statement announcing
the discontinuation of gantenerumab, with reports suggesting that it may be down
to insignificant data between the drug and the placebo. This could be a result of the
low level of antibody delivery across the BBB, as mentioned before, as only 0.1% of
the administered antibodies are successfully transported (Spencer and Masliah,
2014).
Another component of Alzheimer’s disease pathology consists of aggregates
of hyperphosphorylated tau protein (taupathies). The accumulation of this leads to
the disassembly of microtubules and ultimately neurodegeneration (Iqbal et al.,
2010). This principle means that anti-tau antibody therapy could beused in the battle
against Alzheimer’s disease.
A promising example of an anti-tau antibody is the HJ8.5. This antibody was
administered to transgenic mice, which contained the P301S human tau protein. The
HJ8.5 was injectedin these mice for 3 months to see if the hyperphosphorylated tau
and neurodegeneration was affected or not. The results that came back were
astonishing, this IgG antibody had caused a reduction in insoluble tau. Furthermore,
when tau was bound to HJ8.5, there was an increased likelihood of cells similar to
microglia taking up the complex (Yanamandra et al., 2015). Research suggests that
the taupathies and amyloid-beta aggregates are synergistic in the pathogenesis of
Alzheimer’s Disease (Delacourte et al., 2002). This means that targeting both A𝛽 and
tau could be the most effective form of treatment. At present, one promising
vaccine against the tau peptide is AAD-vac1, tests have been conducted to assess its
toxicology and pharmacology safety in which it passed successfully (Kontsekova et
al., 2014). From the journal of Alzheimer’s Research & Therapy, Kontsekova and
colleagues concluded from using transgenic rats that the vaccine proves to be a good
immunogen, inducing antibody production that showed high affinity. It is worth
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noting that this high affinity was particularly concerned the abnormal, pathological
tau, and not the tau peptide used for a physiological purpose. This attribute further
reinforces its potential therapeutic use for Alzheimer’s Disease in the future. The
journal also states that AAD-vac1 has the ability to decrease levels of tau oligomers,
thought to play an important role in early AD pathogenesis (Kontsekova et al., 2014;
Ward et al., 2012).
To conclude the therapeutic uses of antibodies specific to Alzheimer’s
Disease, a definitive course of treatment with immunotherapy still remains a future
concept. However, with current progress and development of promising antibodies
and further understanding on the pathology of Alzheimer’s Disease, it could be
argued that it is just a matter of time before an antibody produces significant results
and passes clinical trials. Hope could rest with AFFiRiS, who have developed Affitope,
which induces an immune response that targets the N-terminus of A𝛽. This is
currently in phase II of clinical trials. Using antibodies to treat AD is only a small
insight into immunotherapy in general, this form of treatment is used for various
other conditions, such as cancer immunotherapy, allergen immunotherapy and for
the treatment of Crohn’s Disease. Advantages with immunotherapy include the
concept of using the body’s own defence mechanism, as opposed to foreign
substances which could lead to toxicity and side effects. As promising developments
with antibodies continue to be made, there is much cause to be optimistic regarding
the future success of their therapeutic use for Alzheimer’s Disease.
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