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Journal of Generic Medicines: The Business

Journal for the Generic Medicines Sector


Biotechnology-Derived Medicines: What are They? A Pharmacological and a Historical Perspective

Fernando de Mora and Rosa Torres
Journal of Generic Medicines: The Business Journal for the Generic Medicines Sector 2010 7: 145
DOI: 10.1057/jgm.2010.10

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Original Article

Biotechnology-derived medicines:
What are they? A pharmacological
and a historical perspective
Received (in revised form):17th February 2010

Fernando de Mora
is Chairman of Department of Pharmacology, Therapeutic and Toxicology of Universidad Autónoma de Barcelona, a Spanish university
with a solid background in biomedicine that focuses on biotechnology as a developing area. Fernando de Mora is consultant for
development and marketing of biosimilars in specific markets, manages Salupharma Biosimilars SA, a Spanish start up company that
operates in the biosimilars arena, and leads a team that specializes in preclinical research of asthma.

Rosa Torres
is a senior postdoc at the research facilities of the Hospital Clínico de Barcelona (Spain). Rosa Torres is experienced in molecular
biology and has a wide expertise in non-clinical research of new therapeutic approaches of immune-mediated diseases.

ABSTRACT Biologicals, that is, medicines obtained from living organisms, are not new.
History provides many examples of animal or human extracts being used to prevent or treat
human diseases. Physicians have thus been aware for centuries of the therapeutic value of
our own molecules. The difficulty laid many times in how to obtain these self or self-like
compounds. Biotechnology – a technology by which manipulated living organisms are utilized
to generate useful products such as drugs – provided a revolutionary answer. We know how
to genetically engineer bacteria, yeast, insect or mammalian cells to synthesize human
molecules, the so-called human recombinant therapeutic proteins. Murine and humanized
monoclonal antibodies against human antigens are also biotechnological products. The number
of biotechnological drugs being marketed, and those in clinical trials or awaiting authorization,
is growing exponentially. We are now still on the beginnings of a new era in pharmacotherapy
of which it is impossible to see the end. Pharmacologists need to keep pace with these changes
and develop new skills. They may even have to challenge old assumptions in order to investigate
new molecules. Using an easy and comprehensible approach, this review article revisits
‘bio-concepts’, and underlines the real dimension of the challenge.
Journal of Generic Medicines (2010) 7, 145–157. doi:10.1057/jgm.2010.10

Keywords: biomedicines; biologicals; biopharmaceuticals; biosimilars; recombinant DNA;

therapeutic proteins

WHAT ARE BIOLOGICALS? seabed, and to design new molecules, more

The search for new drugs has led humans or less successfully, but often quite blindly.
to explore the tropical rain forests and the However, for many of the targeted diseases
or syndromes, we may not have had to make
Correspondence: Fernando de Mora such a huge effort to discover active drugs,
Department of Pharmacology, Therapeutics and Toxicology
(Edificio V), Campus Universidad Autónoma de Barcelona,
as the solution was well within reach, inside
Bellaterra (Cerdanyola del Vallès), Barcelona 08193, Spain our own body, in the form of molecules
E-mail: fernando.demora@uab.cat with a known function that can be converted

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de Mora and Torres

into medicines. The idea is not new. In those small products manufactured by
fact, recent history provides many examples. chemical synthesis and already known as
For instance, since the 1940s, it is known classic, traditional or conventional, drugs,
that the glucocorticoids that we generate, whose production does not involve organisms
when administered as drugs, have an or cells, either as intermediary or source.
anti-inflammatory and an immunosuppressive Technically, biological medicines thus
effect that has proven to be beneficial in included well-known agents such as
autoimmune, allergic and inflammatory gammaglobulins6 (-globulins) – that is,
processes, as well as in preventing rejection antibodies or immunoglobulins isolated
of organ transplants.1 The mystery to be from human blood to prevent or combat
solved, in addition to identifying a potential infections – antibiotics7 (when they were
therapeutic benefit for endogenous molecules, directly obtained from bacteria or fungi),
was how to obtain and purify them. In the vaccines made from extracts of attenuated
case of steroids, we learnt to produce them microorganisms or, more recently,
by chemical synthesis, and today we have low-molecular-weight heparins (LMWH)8
a wide range of agents that more or less (obtained from bovine lung tissue or porcine
mimic their natural counterparts. The case gastric mucosa), and clotting factor VIII
of proteic hormones proved more difficult, when extracted from human plasma.9
and it was often necessary to turn to the What, therefore, is novel about biological
human or animal tissues and organs in which medicines? The novelty, at least in terms
they originate. A well-documented trial with of the agenda for scientific advances, is that
hormone replacement therapy dates back we now have access to more refined and
to 1896, when a woman was efficaciously efficient techniques that enable more reliable
treated with oral bovine ovarian tissue production of specific biologics in the
extract loaded with estrogens.2,3 However, laboratory in sufficient quantity, as we shall
perhaps the most shattering example of the see immediately. In addition, increased
therapeutic use of animal tissue was insulin.4 knowledge of the endogenous activity
In 1922, insulin extracted from bovine of some of these products has led the
pancreas was shown to regulate the pharmaceutical industry to carry out an
concentration of blood glucose in a diabetic enormous amount of research, development
patient who could not synthesize the and/or innovation (R&D&i) projects, thus
hormone (subsequently, given its greater helping to forge the beginnings of a truly
similarity to human hormone, porcine’s new era in pharmacology: the era of
became the main source of insulin until biomedicines (or biopharmaceuticals; a term
the end of the last century). Agents of this coined in 1980, albeit with a slightly different
type are known as biologicals. Yet in meaning). The psychotherapist’s desire to
pharmacology originally the term biologic ‘know thyself ’ has never been as fruitful
applied basically to blood-derivatives and for medicine; such desire places us in
vaccines, it is now used as synonym of a privileged position to expand the frontiers
biological medicine (or biological for that of pharmacological therapy.
matter) and biomedicine, to define, according
to the European Medicines Agency (EMA),5 BIOTECHNOLOGICAL
a drug or medication obtained from a living MEDICINE: A TYPE OF
organism, which is understood to range BIOLOGICAL MEDICINE
from humans to bacteria, and even viruses. A biological medicine is somewhat more
This establishes a fundamental distinction than managing to obtain an endogenous
between biological medicines and currently molecule in the laboratory. The broad
most frequently used medicines, that is, group of biological medicines includes

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Biotechnology-derived medicines

a subgroup – drugs derived from remembering that, by definition, biotechnology

biotechnological processes – that is expanding also includes the process of fermentation
exponentially. These drugs form the subject used to produce foods and drinks such as
of the present article, and we prefer to beer, wine and cheese; however, we shall
simplify by calling them biotechnological not discuss this application here.
products. Biotechnology, that is, technology From the above, it can be inferred that,
based on living organisms or biological as they are generated in living organisms, all
molecules (enzymes or antibodies) that are drugs that are biotechnological in origin are
purposely used or manipulated to obtain biological medicines, but not all biological
useful products,10 had opened up a new medicines are biotechnological drugs. This
area in pharmacology. Biotechnological agents duality between a biotechnological drug
are hence produced from living organisms, and a biological medicine is clearly seen in
as are biologics, but to generate the former, clotting factor VIII. Human factor VIII, given
organisms have had to be manipulated to hemophiliacs to restore hemostasis, can
somehow. For example, the genetic material be obtained in at least two ways. One
of an entity such as Escherichia coli can involves extraction from human plasma (9);
be altered in such a way that, amazingly, the drug is then known as a blood derivative
a human protein can be produced. This is and is considered by definition a biological
known as recombinant DNA (rDNA) medicine, but not a biotechnological one.
technology, which is part of genetic However, if the same factor VIII is produced
engineering, or gene manipulation, which in using rDNA technology,12 it is described
turn belongs to the wider field of molecular as a biotechnological drug. In fact, AIDS,
biology. Although a certain similarity always which appeared at the beginning of the
exists in their chemical structure and 1980s (and whose transmission was attributed
composition, the products obtained using to blood transfusion and, therefore, to
biotechnological techniques are not always therapy involving blood derivatives), was
intended to be exact copies of endogenous one of the greatest boosts to research into
human molecules. Thus, monoclonal the biotechnological production of human
antibodies against self-antigens produced in blood proteins instead of isolating them
mice that have been bred for research purposes from blood. Yet, although it had been
(manipulated) and that have been previously assumed that there would be a shift from
treated (manipulated) are also biotechnological blood extraction procedures to recombinant
agents.11 These are two clear examples of processes to generate blood derivatives such
biotechnological techniques that serve as factor VIII and others, a few companies
pharmacology and, hence, medicine. still successfully market products isolated
The first company to produce a from plasma.13
commercially viable therapeutic molecule
using biotechnology was Genentech, founded RECOMBINANT DNA: PAST,
by Robert Swanson and Herbert Boyer PRESENT AND FUTURE
in 1976. Since then, with the launch of Undoubtedly, the potential of biotechnology
recombinant human (abbreviated in pharmacology is limitless. We are now
as rHu or rh) insulin (1982), recombinant on the threshold of an era of which it is
human growth hormone or rhGH (that is, impossible to see the end, while already
recombinant somatotropin) (1985), and second and third generation agents are
recombinant human erythropoietin, also making their way into the market. Today,
known as EPO or epoetin (1989), an although biotechnological drugs have not
unstoppable race has been in progress in been socially ‘integrated’, not even by
the biopharmaceuticals field. It is worth many health professionals, new-generation

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de Mora and Torres

biotechnological drugs are being developed therapeutic suitability of recombinant proteins

and will be broadly used by the students against severe diseases is beyond doubt. Take,
of today and tomorrow. One area of for example, the advantages offered by rhEPO
biotechnology involves obtaining small in the treatment of anemic patients with
fragments of nucleic acids (oligonucleotides), chronic renal failure,19 the success of
which, by acting on the genome, can curb recombinant filgrastim (granulocyte-colony
or boost the expression of specific genes stimulating factor, or G-CSF) in cancer
to make up what has come to be known patients receiving chemotherapy,20 and the
as gene therapy.14 This area also includes usefulness of engineered interferon (INF)- in
the use of stem cells for therapeutic purposes the treatment of hepatitis.21 Also in use are
(the so-called regenerative medicine).15,16 other cytokines (for example, IFN- or
Experiments are already being carried out interleukin [IL]-2), biotechnological vaccines
in the fields of basic science and clinical such as the recent human papillomavirus
research so that biotechnology can provide vaccine, monoclonal antibodies that require this
even more creative therapeutic options. technology in their production process, clotting
Although biotechnological drugs vary factors, enzymes, and other proteins and
widely in terms of their chemical structure, peptides (often hormonal), such as insulin and
most are proteins, or at least molecules with somatotropin as already mentioned. The
a considerable peptidic component. These increasing interest in these drugs by researchers
therapeutic proteins are expected to dominate and clinicians means that they also receive the
the market for biotechnological drugs in attention of regulatory bodies and health
the coming years. Monoclonal antibodies authorities.
are proteins, irrespective of how they are As is always the case in biomedicine,
produced; however, the driving force behind the state of the art in biotechnological
advances in biotechnological drugs is the pharmacology is the result of decades, even
rDNA technique, which makes it possible to centuries, of efforts by many investigators.
manufacture extremely pure human peptides The principal landmarks became obvious
and proteins (recombinant proteins) for during the twentieth century, with the
therapeutic purposes more efficiently. The award of several Nobel Prizes. The
advances made in this field since the 1970s controversial award of the Nobel Prize in
led to the introduction in 1982 by Eli Lilly of Medicine and Physiology in 1923 to
the recombinant human insulin produced by Banting and McLeod for their discovery of
Genentech. This was the first recombinant insulin22 was followed by the recognition of
molecule to be launched as a drug, and important findings that, in many ways, were
it replaced insulin isolated from porcine the forerunners of today’s biotechnology. In
pancreas, the most widely used until then.17 1945, Fleming, Florey and Chain were
The advantages of rDNA include its ability awarded the Nobel Prize for discovering
to overcome many of the dangers involved that antibiotics could be obtained from
in administering molecules extracted from microorganisms.23 This was a revolutionary
human and non-human tissues. One example glimpse of how biotechnology could grow
can be seen in the treatment of children with to serve pharmacologic therapy. In 1955,
congenital dwarfism, which, until the 1980s Vincent du Vigneaud was awarded the
was treated with cadaver hypophysis – derived Nobel Prize in Chemistry for synthesizing
growth hormone (somatotropin or somatropin). the first peptides using biochemical
This sometimes led to Creutzfeldt-Jacob disease techniques (oxytocin and vasopressin).24
(spongiform encephalopathy),18 a drawback This revealed the interest in, and need for,
that was overcome with the development of laboratory techniques that could be used to
recombinant human somatotropin. The synthesize proteins. In 1959, Severo Ochoa

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Biotechnology-derived medicines

and his disciple Arthur Kornberg were Human DNA to

awarded the Nobel Prize in Medicine and be inserted

Physiology for the discovery of the

Plasmid vector
synthesis mechanisms of the nucleic acids
RNA and DNA,25 a fundamental event
that was to have decisive consequences
for the subsequent development of
genetic engineering. A fitting salute to DNA
pharmacologists, Dr Ochoa held the Chair
of Pharmacology at the Medical School of
New York University. In 1978 Arber,
Nathans and Smith were awarded the Nobel
Prize in Medicine and Physiology for the
discovery of restriction enzymes26 and, in
1980, Berg, Gilbert, and Sanger received
the Nobel Prize in Chemistry for leading
the field in the development of rDNA
technology.27 Sanger’s achievement was
Selection of cells containing recombinant DNA
particularly praiseworthy, because he had
already received the Nobel Prize in 1958
for clarifying the structure of insulin. Other
achievements also deserve recognition, for
example, the discovery of the molecular
structure of DNA by Watson, Crick, and Figure 1: This diagram summarizes the
recombinant DNA technique, which is used in
the often forgotten Wilkins,28 Nobel Prize
the production of recombinant therapeutic
winners in Medicine and Physiology in proteins. Once the protein of interest has been
1962. If we review the list of prizewinners identified, endonucleases are used to isolate the
in Medicine and Physiology or Chemistry, DNA fragment coding for it (in orange). This
beyond the production of protein using fragment is inserted into a plasmid that serves as
rDNA procedures, we can see how many a transfer vector; in other words, it is
other findings are also directly related to recombined with the plasmid (this is the
modern biotechnology. A clear example engineered vector). The plasmid is then
can be seen in Köhler, Milstein and Jerne, inoculated into the bacteria (for example,
who obtained the Nobel Prize in Medicine Escherichia coli) or other producing cell. Some of
and Physiology in 1984 for proposing and the bacteria will accept the new gene and
developing the monoclonal antibody produce the protein, others (most), will not.
Those that contain the recombinant DNA
production technique.29 However, protein
molecule will be selected.
synthesis using the rDNA of different
species has become the basic technique for
producing proteic drugs. Let us examine flourished because the classic procedures
this technique in more detail (Figure 1). for obtaining proteins were many times
Genetic engineering really took off at the unproductive, limited to a few specific
beginning of the 1970s, with the discovery molecules, and often unsafe. Recombinant
of restriction enzymes (or endonucleases), DNA technology is based on the insertion,
‘molecular scissors’ that make it possible by viral vector, of a known human protein –
to obtain a specific fragment of human coding gene into the genome of a prokaryotic
DNA that codes for the protein to be (bacteria) or a eukaryotic cell (mammal, insect
produced.10,30,31 The rDNA technique or yeast). The receptor cell population of

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de Mora and Torres

the human gene is known as the expression changes, far more than chemistry-derived
system. The human gene ‘recombines’ with compounds. This shows just how different
the genetic material of that system, which biotechnological drugs are from synthetic
then produces human protein as if it were drugs, which admit greater flexibility in their
their own. What is relevant is that it produces production process.
protein in large quantities, quickly, and in A well-discussed example that illustrates
a form that is analogous to the natural the relevance of the production protocol
protein, if so desired. In 1977, Eugene of biotechnological agents is the choice of
Goldwasser, a reputable molecular biologist the system for the expression of the human
and biochemist from the University of recombinant protein. Prokaryotic cells
Chicago, famous for his decisive contribution (bacteria) enable more rapid protein
to the isolation and characterization of production, since, as a single bacterium is
erythropoietin, expressed how revolutionary assumed to divide every 20 min, a billion
the technology was by stating that 10 mg cells will form in little more than half a day
of erythropoietin, the dose needed to treat (they are cultured in tanks capable of holding
a dialysis patient for one year, would have thousands of liters). Seemingly, this is an
required 2550 l of urine from anemic patients. advantage of prokaryotic systems. On the
EPO produced by rDNA could finally be other hand, mammal eukaryote cells such as
obtained without the need for so much urine. Chinese Hamster Ovary (CHO) grow more
Producing recombinant molecules is both slowly and, therefore, take considerably
difficult and expensive. Identification of the longer to produce a similar amount of the
gene, choice of the protein-expressing cell biodrug. The resulting protein amino acid
population, and purification of the protein sequence in both expression vectors is the
produced are only some of the complex same, although we know that bacteria cannot
steps necessary for the biosynthesis of glycosylate proteins35 (that is, cannot add
recombinant therapeutic proteins, which also carbohydrates – or sugars – from the Greek
requires monitoring throughout the process.32 glycos, meaning ‘sweet’), whereas mammal
In general, this is infinitely longer and more cells can. For some proteins, glycosylation is
complex than the production of drugs by essential for them to be active.35–37 This is an
chemical synthesis. For example, a traditional extreme example of the importance of
chemical product requires from 100 choosing the production process. Other
to 200 quality control assays, whereas changes, although seemingly insignificant,
a biotechnological drug can require more are sometimes even more decisive for the
than 2000 (including in-process control and therapeutic viability of recombinant biological
product analysis).33 This complexity is medicines, especially in terms of safety. For
extremely relevant: seemingly insignificant instance the formulation of the final product
variations in the production process can will determine stability, conformation, and
lead to structural changes in the final hence biological activity.38,39
molecule that can have a huge impact on Despite the fact that pharmacologists
the pharmacological behavior of the product. are in general still not familiar with this
In the case of biotechnological drugs, it is methodology, we are about to develop
said that ‘the process is the product’, because more sophisticated recombinant proteins, or
the structure, conformation, and, therefore, at least proteins requiring more sophisticated
the pharmacologic properties of the final production processes. Proteins which are
product are closely linked to the procedures created by joining parts of two or more
applied during manufacture.34 This is different genes which originally coded for
understandable since living organisms separate proteins (fusion proteins) are already
behavior is tightly linked to environmental in the market,40 and toxins linked to an

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antibody directed to a specific cell-surface and endogenous molecules. These aspects of

tumor-associated-antigen (immunotoxin) or biotechnological protein drugs considerably
chimeric toxins41,42 already exist. The affect their pharmacological behavior and
situation becomes more complicated, because the methodology necessary for their research
genetic recombination to obtain proteins and development.
can be carried out in plants43 and farm The complexity involved in the
animals that thus become transgenic (the development and study of therapeutic
so-called ‘farm pharmacy’). For example, in proteins, and the impact of this complexity
2006, the EMA approved an anti-thrombin- on pharmacokinetics compared with
produced in the milk of goats into which traditional chemical products, is illustrated
the corresponding gene had been inserted.44 for example by size differences. EPO, for
To conclude on this, compared with instance, is approximately 170 times greater
traditional techniques for obtaining proteic than acetylsalicylic acid (other molecules are
molecules, recombinant DNA methodology up to 1000 and even 10 000 times smaller
enables products to be obtained more rapidly when compared to monoclonal antibodies).
and in greater quantities. These products Size matters in pharmacology. Furthermore,
are purer, less susceptible to contamination, although forms that resist degradation at the
and more similar to the endogenous molecule administration sites have been developed,46
if desired. The success of this technique the bioavailability of these drugs is usually
has an unavoidable ‘arithmetic’ consequence: low and their distribution in, and penetration
the exponential growth in the number of of tissue, is quite limited.47–49 In addition, the
protein drugs produced and expected to fact that the drugs often copy endogenous
reach the market. If we take currently molecules means that the patient’s
authorized recombinant biotechnological pathophysiological status has a considerable
drugs, those waiting for authorization and effect on their activity.47 Not only do
those in the pipeline, the expected market pharmacologists require in-depth knowledge
size is almost unimaginable.45 In 5 years, of the pharmacokinetics and pharmacodynamics
from 2003 to 2008, the global market for of therapeutic proteins for research and
biotech drugs has more than doubled from development, but the technology surrounding
US$38 billion to $83 billion. This, despite these compounds is also considerably different
market share for conventional medicines from that which is habitually used in
is progressively decreasing in favor of chemically synthesized drugs. Manufacturers
biomedicines. This is a particularly relevant often have to design techniques to evaluate
warn for pharmacologists. But, how protein molecules, ensuring that these
does the protein nature of a drug affect its methods discriminate between the biological
pharmacologic behavior? medicine and its endogenous counterpart,50
and to develop methods of detecting
PHARMACOLOGY antibodies against the biological medicine.
OF RECOMBINANT Pharmacologists, for their part, require new
THERAPEUTIC PROTEINS: technical knowledge in order to be able to
IMMUNOGENICITY AND investigate biotechnological drugs.
OTHER ASPECTS Pharmacology should include education of
Other than in the production process, preclinical or clinical ‘biopharmacologists’,
recombinant proteins differ from traditional because the introduction of these drugs will
chemically synthesized drugs in two basic challenge some of the traditional concepts of
ways: in their chemical structure (obviously pharmacology. This can be seen particularly
proteic) and in the structural and functional clearly in the concern raised over adverse
similarity between the recombinant proteins effects resulting from the immune reactions

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that these new compounds generate, that is, be sufficient to generate new structures,
their immunogenicity; anecdotic to date in such as protein aggregates or products
the pharmacology of small molecules. resulting from chemical degradation, which
Why has immunogenicity suddenly become behave like epitopes. In addition, the protein
a cause for concern? It is easy to understand purification process during production
that large, complex and often-unstable often carries impurities from the expression
molecules such as therapeutic proteins and vectors (for example, portions of DNA from
peptides are more likely to express regions bacterial genes), and these impurities may
that behave like epitopes (structures against cause immunogenicity.53
which the immune system reacts). The ability Immunogenicity would not be perceived
of these protein drugs to initiate the immune as an element to be avoided if it had no
response is known as immunogenicity. clinical consequences. Biological medicines
It is even easier to understand the tendency may, and commonly do, generate antidrug
of proteins to become immunogenic if, as antibodies that do not have a clinical impact,
is sometimes the case, these protein molecules but these same antibodies could cause
are not exclusively of human nature. therapy to fail or severe adverse reactions
This is why the potential therapeutic benefit to develop.55,56 Although severe adverse
of the administration of murine monoclonal reactions are not common, an episode that
antibodies was shadowed by the immune occurred at the end of last century and
reaction they generated when identified as beginning of this, forewarned us about the
foreign. These antibodies are known as need to evaluate the potential clinical
human antimouse antibodies (HAMA). consequences of a hypothetical case of
This, triggered the development of chimeric immunogenicity. As stated above, rhEPO
human-mouse monoclonal antibodies (with was a revolutionary molecule that was
the suffix – ximab, for example, rituximab), marketed in the 1980s. It has prevented
followed by ‘humanized’ antibodies with many transfusions, increased the quality of
a greater human content (with the suffix – life of patients with chronic renal failure,
zumab, for example, trastuzumab), and and minimized many of the adverse effects
even the currently available fully human of chemotherapy in cancer patients.19,57
antibodies (suffix – umab, for example, One of the companies that launched rhEPO
adalimumab). Although these agents go a long introduced an apparently insignificant
way towards reducing immunogenicity, they variation – switching albumin for polysorbate
do not solve the problem completely.51 This 80 – in its formulation. From there, very
should come as no surprise, because even severe and sometimes, yet scarce, fatal adverse
recombinant therapeutic proteins with an reactions began to be observed in patients
amino acid sequence that is identical to treated with a specific type of pre-filled
that of a natural counterpart, are not exempt syringe.58 Several hypotheses have been
from carrying antigenic determinants. put forward to explain these reactions.59
It is not easy to explain why a recombinant The most plausible seem to be aggregate
therapeutic protein can be immunogenic, formation or leachates potentiating the
despite such primary structure similarity. production of neutralizing anti-EPO
Nevertheless, some comments can be antibodies that recognized not only the drug,
made.52,53 Recombinant therapeutic proteins but also the patient’s own erythropoietin.60
are three-dimensional compounds and The antibodies that reacted with the
sometimes-complex quaternaries whose endogenous erythropoietin, thus breaking
folding generates a spatial form that may its immune tolerance, caused a type of
be suboptimal and often unstable.54 Its sudden-onset anemia known as pure red cell
instability during storage may occasionally aplasia (PRCA), which had fatal consequences.

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Although the problems highlighted by this consequently, to changes in its safety and/or
case appear to have now been overcome, the efficacy.66 These consequences must be
EMA has strengthened its safety requirements taken into account, for example, when
for the approval of biological medicines. A a company aims to modify the production
similar situation was observed with recombinant protocol of an innovative drug that has
thrombopoietin,61 although luckily this was already been launched,67 but, they also need
detected during clinical development. to be considered when attempting to produce
Finally, regardless of the severity of adverse a copy of a biotechnological medicine whose
reactions, immunogenicity can cause failures patent has expired.68,69 The complexity of
in therapy because the antibodies that interact therapeutic proteins and their production
with external protein drugs neutralize them techniques based on living organisms, and
by attenuating or blocking their activity;62 a the confidentiality requirements of the
phenomenon observed for instance in IFN pharmaceutical companies make it impossible
and Factor VIII preparations.63 Demonstrating for another company to produce a structurally
the existence of neutralizing antibodies during identical copy of the innovative drug.70 Slight
the development of a biological medicine is differences in composition could compromise
an important warning for the pharmaceutical the drug’s safety and efficacy, since it is not
company or regulatory bodies, sometimes sufficient for the amino acid sequence of
against further development. In April 2008, the copy to be the same. As it is neither
the EMA, the agency in charge of possible to generate two identical biodrugs
biotechnological drugs authorization in nor to completely guarantee their molecular
Europe, published the definitive guidelines three-dimensional structure due among
with recommendations that pharmaceutical other things to post-translational modifications
laboratories must adopt to evaluate that lead to microheterogeneity of those
immunogenicity.64 medicines, the development criteria for
a biotechnological drug must be stricter
BIOSIMILARS, NOT than those required for a generic, for which
BIOGENERICS only pharmacokinetic bioequivalence is
The general requirements for the preclinical generally enough to prove identical
and clinical development of an innovative therapeutic behavior.71 Thus, to make them
biotechnological medicine are fundamentally equivalent, the copy of a biotechnological
the same as those of a synthetic drug, in spite medicine must be shown to be as efficacious
of the fact that, on average, the necessary and safe as the innovative reference drug in
investment is much higher for the biodrug. comparative clinical trials that evaluate both
Although we could focus on specific aspects aspects. Preclinical comparisons must also
of drug development (for example, the need be made and post-marketing safety data of the
to evaluate immunogenicity in the case of copy are mandatory. Again, as for the EMA
biological medicines), here we examine why regulation, biopharmaceutical laboratories
is it more demanding to make a copy of producing innovative biotech therapeutics
a biological medicine than of a chemically need also to demonstrate no changes in
synthesized (small) drug, a so-called generic. efficacy and safety when a major change of
We have already seen how even a slight the manufacturing process is applied to the
variation in the production process of a innovator product.
biological medicine can modify the chemical The EMA uses the term ‘biosimilar’
characteristics of the final product (that is, or ‘similar biological medicine’ for the
‘the process is the product’), and that this authorized copy of a biological, hence
could in turn lead to changes in the biotechnological, medicine produced in
biological behavior of the molecule65 and, accordance with specific requirements of

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de Mora and Torres

quality, efficacy and safety.72 In order to It is important to highlight that this ‘non-
avoid confusion, the term biogeneric should automatic substitution’ policy does apply in
not be used since their corresponding some countries to any biotech drug, also
regulatory pathways to reach authorization innovative products, not specifically to
are different. In 2005, the EMA issued biosimilars. This means for instance that the
guidelines on biosimilars,73,74 thus making it pharmacist cannot dispense one innovative
the only regulatory body to date that has EPO if the physician prescribes another
proposed an abridged pathway for their innovator one (there is more than one
development ( Japan and Canada are on the original EPO in the market). The same
way). We shall see what the position of would apply to the two original IFN-1a
the FDA towards biosimilars, or follow-on currently in the market for multiple sclerosis.
biologicals (FOB) as they would presumably It is therefore to say that biosimilars are
be called in the United States, will be. Since drugs that are therapeutically as guaranteed as
the approval in Europe of two biosimilars the corresponding original biomedicines in
of somatotropin in 2006, the EMA has terms of quality, efficacy and safety, and that
granted authorization to 13 biosimilars (in once the molecule has been approved by the
fact really six different molecules). Before EMA it is no longer a copy, but rather
guidelines were issued one copy of a biotech another biotech medicine. Some argue that
product had been rejected, and at least even a biobetter can be produced in some
another one was withdrawn from EMA instances in which modern techniques are used
assessment by the promoter later on. The for their production. Let us finally not forget
demanding exercise of comparing a biosimilar that a copy of a biomedicine that has not
with the innovative drug requires more entered the EMA pathway for authorization,
time and effort, as well as a considerably and yet has been launched in non-European
greater investment (between 5 and 100 times) markets, should not be called biosimilar.
than that required for the development of
a generic medicine. Although biosimilars CONCLUSION.
price is expected to also lead innovators BIOTECHNOLOGICAL
to apply a discount on their products, the MEDICINES (BOTH
demanding regulations will presumably not INNOVATORS AND
allow discounts near those reached on BIOSIMILARS): BOTH
generics. The biosimilars market is expected A NEED AND A CHALLENGE
to grow in the next few years. Luckily, From what has been discussed above, it is
because they cover a ‘social’ need in a world clear that biological medicines are not simply
where health-care expenses are growing at a new drug family, as were for instance
an exponential rate. However, the investment angiotensin-converting enzyme inhibitors,
necessary has generated apprehension and proton pump inhibitors, or leukotriene
doubts concerning the financial viability of receptor antagonists in their day. This new
these agents. It only remains to be seen, generation of therapeutic molecules heralds
therefore, how fast the biosimilars industry a new era in pharmacology, one that will
will develop in Europe and the rest of the require pharmacologists to acquire new skills
world. The growing uncertainty in many to develop and manage these molecules.
companies over the possibility of recouping These new drugs have opened up at least
the original investment is aggravated by the one whole new branch of pharmacology.
fact that, in some countries, national laws Perhaps it is time to begin to use the old
prevent biotechnological drugs from term biopharmacology, now in disuse, with
automatic substitution by pharmacists (unlike a different meaning. We could go even
innovative synthetic drugs and generics).75 further. If we accept, as some thinkers have

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Biotechnology-derived medicines

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