Therapeutic to tackle various foreign species that cause

Therapeutic antibodies

 

Monoclonal antibodies that are used to
treat disease by targeting specific cells are termed therapeutic antibodies. Monoclonal
antibodies are highly specific and have a high affinity to their target
molecules, antibody therapy aims to manipulate these properties of antibodies
in order to tackle various foreign species that cause disease. This POSTnote
examines the future of therapeutic antibodies and the possible challenges that
may come with the use of monoclonal antibodies in treating disease.

 

Overview

 

§  Antibodies are proteins regulated by the immune system as a means of
distinguish and neutralise foreign species, they may be
manipulated in order to use them to target specific cells to treat certain
types of diseases.

§  As of 2009, 22 therapeutic
antibodies had been approved for clinical use (Chames et al. 2009) and this number had risen significantly since then, as
of 2017 there are 53 monoclonal antibodies that have been approved in both the
EU (by the EMA) and the US (by the FDA) (Animal Cell Technology Industrial
Platform, 2017). it Is estimated that by 2020 approximately 70 monoclonal
antibodies will have been approved for clinical use (Ecker et al. 2014), showing the growing popularity and success of
therapeutic antibodies.

§  In 2013 global sales of
monoclonal antibody products made up half of biopharmaceutical product sales,
it is predicted that by 2020, sales of therapeutic antibodies will reach as
much as $125 billion (Ecker et al.
2014), this shows the vast profit potential of this sector.

§  On account of the fact that
therapeutic antibodies have a long serum half-life, additional safety measures
must be taken which has led to the composition of the European guideline
(Schneider, 2008).

§  As patents for pre-existing
therapeutic antibodies expire, there will be a surge in the production of
biosimilar therapeutic antibodies (Ecker et
al. 2014)

 

Background

Antibiotic
resistance

Antibiotics when initially created were
revolutionary, they had the ability to treat bacterial infections, however over
the decades due to over usage, these bacteria have adapted to the antibiotics
so much so that they are now resistant to the antibiotics. This means that when
these harmful bacteria come into contact with the antibiotics, they are still
able to thrive and multiply, causing illness for the host. These bacterial
infections include Tuberculosis, Pneumonia and Gonorrhoea (WHO, 2017).
Antibiotic resistance is one of the most key issues facing the health sector
and it is now of the upmost importance to find an alternative treatment to
antibiotics otherwise the world may find itself in a crisis very soon. IT is in
the national interest to find a solution as not only is this leading to higher
mortality rates, but it is also leading to longer hospital stays which
subsequently means it is costing the government more. Therapeutic antibodies
could provide an alternative and even more specific treatment.

Antibodies
and monoclonal antibodies

Antibodies are Y-shaped proteins regulated by the Immune system, that bind to specific target
molecules of a complementary shape (antigens) in order to exert their effect
(box 1).

Therapeutic antibodies are genetically
engineered monoclonal antibodies with high specificity and functionality
(Brekke and Sandile, 2003).

In 1975, Kholer and Milstein developed a
method to produce monoclonal antibodies through their mouse hybridoma technique,
this was the first step in the usage
of monoclonal antibodies as therapeutics. The early experiments involved
injecting murine monoclonal antibodies into humans, these were recognised by
the immune system as foreign and were destroyed. Later, antibody
engineering meant that one could produce chimeric antibodies (Figure 2)
consisting of 2 mouse variable domains and 2 human constant domains. These
Chimera are 70% human containing a Human Fc region, allowing them to interact
with human effector cells and decreasing the chances of provoking an Immune response. More recently it has
been possible to further reduce the murine portion of the chimeric antibody.
(Chames et al 2009). Therapeutic
antibodies act in one of 4 ways (box 2); they either block the action of the
molecule of interest or, they target specific cells (which are causing disease),
or they act as signalling molecules or they are used to deliver DNA or antigens
to immune cells which activate a specific Immune response (Brekke and
Sandile,2003).

 

Box
1

 

 

Figure 1. A diagram
showing the structure of a standard antibody molecule.  This diagram highlights the different chains
and domains that make up an antibody molecule. Taken from BioXCell – Guide to
the structure and classification of antibodies.

 

Antibodies
are proteins with a sugar group and so are known as glycoproteins. As shown in figure
1, Each antibody contains two antigen-binding fragments (Fabs) and two constant
(Fc) regions which are joined together by the hinge (flexible) region. The
constant region is responsible for binding to effector molecules of the immune
system. There are also two variable domains which recognize and bind the antigens.
 Antibodies can be grouped into 5 groups;
IgG, IgM, IgA, IgE and IgD, each class has a distinct structure, IgM is the
first to be produced in an immune response (Brekke and Sandile, 2003). Antibodies
are responsible for; neutralizing disease causing microorganisms, activating
other cells responsible for an immune response and activating the complement
system (Institute for Quality and Efficiency in Health Care, 2016) which is a
system which amplifies the antibodies’ ability to destroy disease causing
microorganisms. Antibodies are ideal due to their ability to bind with high
specificity and affinity to a number of molecules (Chames et al, 2009).

 

Figure
2. A diagram showing the formation of a chimeric antibody. The molecule
consists of human and mouse sequences, as you can see the chimera is
predominantly made of human sequences, which reduces the likelihood of the
production of Human Anti-Mouse Antibodies (HAMA) and ultimately destruction by
the immune system. Adapted from absoluteantibody.com – Chimeric monoclonal
antibodies, 2017.

 

 

 

Current
legislation

Currently,
there is no legislation specifically pertaining to therapeutic antibodies,
however the following legislation applies to therapeutic antibodies as they are
covered under the same branch of medicinal products.

In the EU

§  Regulation
(EU) no 1027/2012 of the European Parliament amending Regulation (EC) no
726/2004 as regards pharmacovigilance. This regulation is with regards to the
steps which must be taken in order for a medicine to be authorized and steps
which can be taken to increase safety of medicinal products.

§ 
“new
regulation EU no 536/2014 of the European parliament and of the council on
clinical trials on medical products for human use” which provides guidelines as
to how clinical trials must be carried out

 

 

Outside the EU

In
the USA the FDA have set out guidelines on the use of monoclonal antibodies as
a drugs. The guideline outlines the steps manufacturers need to take in terms
of ensuring safety and drug purification. This guideline provides a framework
for manufacturers to follow prior to applying for drug approval by the FDA
(FDA, 2001).

 

 

Box
2

As
stated earlier, there are 4 main mechanisms in which therapeutic antibodies
destroy or neutralize their targets. The first is that they can block the
action of their target molecule which is causing the disease. This is done by
preventing the growth factors or cytokines from reaching target receptors. The
antibody will bind to the receptor which stops the target molecule itself from
binding to the receptor in order to exert its effects. Alternatively, the antibody
will bind to the growth factor which will also stop it from binding to the
receptor. The second mechanism in which therapeutic antibodies can work is by
targeting specific cells. With this mechanism, the antibodies are directed to
the specific cells of interest, the antibodies will be carrying a particular molecule,
which will somehow aid in the destruction of the target cells (i.e. an enzyme
or toxin or cytokine) which will be delivered to the target cells and will exert
their effects. For example, therapeutic antibodies carrying toxins can eradicate
cancer cells (which would be the target cells in this case). Moreover, the
third mechanism is that therapeutic antibodies can act as signalling molecules,
this will induce cross linking of receptors that are connected to molecules
that regulate cell division or apoptosis, which will result in the termination
of cell division (preventing the diseased cells from multiplying) and will
result in programmed cell death of the pre-existing cells. The final mechanism
in which therapeutic antibodies can act is that they can deliver DNA or
Antigens to Immune cells. The immune cells then activate a specific immune
response against the antigen.

 

Current therapeutic antibodies in use

6
years ago there were a total of 22 therapeutic antibodies approved for clinical
use, most of these were therapeutic antibodies to treat cancers and immune
disorders. (Chames et al 2009). There
are currently 53 therapeutic antibodies approved for clinical use (Animal Cell
Technology Industrial Platform, 2017). Some antibodies were approved for
clinical use but have since been discontinued. As of 2003, 20% of all
biopharmaceutical products in clinical trials were monoclonal antibodies
(Brekke and Sandile, 2003) showing just how popular this particular field of
research medicine is.

One
successful therapeutic antibody has been Rituximab (also known as Rituxan) which
was approved by the FDA in 1997(Dotan et
al 2010). It is used in cancer treatment (Chames et al 2009). Rituximab is used to treat non-Hodgkin lymphoma (NHL),
it targets CD20 proteins which are found on the surface of certain white blood
cells known as B-cells. Rituximab binds to CD20 which the immune system
recognises as a cell that needs to be destroyed. The marked B cells are then
destroyed, destroying both the normal B cells and abnormal NHL B cells (the
normal B-cells then regenerate). Rituximab is given as part of chemotherapy at
the start of each cycle (Macmillan, 2015). B-cell Lymphoma’s make up 85% of all
NHL’s, showing the vast market there is for this drug (Dotan et al 2010). Rituximab can also be used to
treat joint pain and swelling, similarly to cancer treatment, it works by
binding to CD20 ON B-cells which are then destroyed. If the drug has worked its
effects will be evident within 2-16 weeks (Arthritis research, 2017). In 2015,
sales of Rituxan reached $7.32 billion (Gibney, 2017) this shows that not only
is Rituximab a medical success, it is also a financial success.  

 

Challenges

 

Production costs and Dosage

Monoclonal
antibodies are large molecules (~150kDa) this means that in order to administer
them in an active form, is costly. Additionally, large cultures are needed and
a large amount of purification is required which further increases the cost of
production. Moreover, it has been shown that the monoclonal antibodies need to
be injected in rather large doses in order for them to provide an appropriate
level of efficacy (Chames et al. 2009). Murine xenograft models
showed that no more than 20% of the dose of monoclonal antibodies administered
will interact with the tumour (Beckman et
al. 2007), this further exemplifies why a large dosage must be administered
which leads to higher costs for pharmaceutical companies producing these drugs.
Furthermore, another problem faced in the production on therapeutic antibodies
is their ability to penetrate tumours. Tumours have a high fluid pressure,
therefore it is hard for the antibodies to diffuse against this gradient in
order to treat the tumours, especially larger tumours as the pressure is higher
(Chames et al. 2009).

 

Safety

As
with any drugs, there are associated side effects. Due to the fact that the
antibodies used are chimeric, they are made partly from murine antibodies, this
means that the immune system will recognise this and elicit an immune response.
The severity of the immune response varies on the particular therapeutic
antibody in question. However, recently companies have been able to manufacture
therapeutic antibodies which are 85%-90% human by only adding murine hypervariable loops to a fully human antibody (Chames et al. 2009), vastly supressing the
immune response elicited by foreign species. Additionally, the introduction of
part-murine antibodies into the body can lead to the body producing Human
Anti-Chimeric Antibodies (HACAs) which could then destroy the chimeric
antibodies, inhibiting them from achieving their specific objective (Niebecker
and Kloft, 2010). Again this particular
problem can be tackled through decreasing the amount of murine antibody used to
the minimum amount needed for the chimeric antibody to still be effective, as
knowledge in this field increases it is likely that the amount of murine
antibody used shall decrease.

 

Biosimilars

Most
of the monoclonal antibodies on the market today were approved for clinical use
over 10 years ago therefore in the upcoming years, patents for these products
will have expired as a patent both in the UK and US lasts only 20 years. For example,
Rituximab which was approved for use in 1997, meaning its patent will be
expiring in 2018. The expiration of these patents will cause a surge in the
emergence of companies who perhaps did not have the resources or funds to take
part in therapeutic antibodies decades ago producing ‘biosimilars’ which will
be products very similar to the previously patented monoclonal antibodies. One
could argue that that this will be positive thing as it will cost consumers
less to buy these drugs however conversely this will mean that profits of monoclonal
antibodies in the medical sector will decrease making it less lucrative (Ecker et al. 2014) which may result in
pharmaceutical companies reducing funding for research and development in this
sector. Additionally, as patents expire, bogus companies especially in more
deprived countries may start releasing ‘look-alike’ drugs which look similar
but have no effect at all, in order to make money and reduce their costs,
leaving victims of such scams still ill. 

 

 

 

Financial
benefits

The
usage of therapeutic antibodies in treating clinical ailments is emerging as a
very lucrative sector of medicine. In 2013, profits of monoclonal antibodies
and monoclonal antibodies were $75 billion, this made up 50% of the total sales
of all biopharmaceutical products. This shows just how vital monoclonal
antibodies are becoming not only in the treatment of disease but in the
financial stability of pharmaceutical companies and in a larger sense the
financial gain of economies worldwide. It is predicted that by 2020 sales of
monoclonal antibody products will reach a staggering $125 billion.    

 

The
future of antibodies

Monoclonal
therapeutic antibodies have already proved to be both successful and lucrative.
Biopharmaceutical companies are now looking to increase the efficacy of
therapeutic antibodies even further and in particular increase the penetration
ability of therapeutic antibodies which will lower the dosage required and
decrease costs.

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