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6 Production ofBiopharmaceuticals onGenetically Modied Organisms
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emerged as an expression system for antibiotics production. To produce G-CSF, the
human g-csf gene was cloned into a periplasmic expression vector. The created
plasmids were then inserted into the P. uorescens chassis strain, which has a spe-
cic phenotype for soluble expression of G-CSF (Wang etal. 2020).
Recombinant Bacillus brevis was used to secrete about 100 mg L-1 of a Fab
against human urokinase-type plasminogen activator. Besides Bacillus brevis,
Bacillus choshinensis, and B. megaterium were employed to produce antibody fragments with high binding afnity to antigens, which also come under the category of
biopharmaceuticals. Growth factors like the human epithelial growth factor (hEGF),
used to treat diseases like cancer, are produced from recombinant Bacillus brevis
HPD31 and B. subtilis. Interferon alpha, beta, and gamma are produced by several
recombinant B. subtilis strains cultured on a complex medium (Lakowitz etal. 2018).
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6.4 Role ofFungi inBiopharmaceuticals
With the rst successful report (1978) on the modication of Saccharomyces cerevisiae by plasmid DNA, the age of genetic engineering in yeasts was launched. It is
used in the production of vaccinations against the human papillomavirus (HPV) and
human serum albumin, as well as therapeutic proteins, peptides, and antibodies. The
hepatitis B vaccine being one of the recombinant vaccines had been produced from
the S. cerevisiae (yeast) unlike the production process of conventional vaccines
which was time consuming and had the risk of pathogenicity (Kulagina etal. 2021).
Also, subunit vaccines and virus-like particle (VLP)-based vaccines prefer using
yeast as the heterologous expression system in their process of production. β-D-
glucose polysaccharides, or β-glucans, are present in the cell walls of yeasts, and
their immunomodulatory and adjuvant properties make them ideal for use in WYB
vaccines. The β-glucans have an afnity to bind to specic receptors of immune
cells like the dectin-1 receptor, the complement receptor 3 (CR3), and toll-likereceptors (TLRs). This property of binding to these specic receptors renders
β-glucans as anticancer agents. Cytotoxic T cell responses against tumours and
enhancement of haemopoiesis also proved β-glucans as anticancer agent in clinical
trials. Human pathogen contamination poses a risk to the labour-intensive, expensive, and time-consuming process of purifying therapeutic human proteins from
blood or tissue extracts and due to the manufacture of human therapeutic proteins in
genetically modied yeast, bacteria, and also cultured mammalian cells, a variety of
recombinant therapeutic proteins are now available for patients, resolving these
concerns. All manufacturing methods, meanwhile, have their limitations. Yeast and
bacteria, for example, are unable to synthesis complex human proteins including
genuine post-translational modications. Although only “simple” proteins are currently produced in yeast and bacteria, efforts are underway to humanise these nonmammal systems (Roohvand etal. 2017).
Pichia pastoris (Komagataella species) is yeast that uses methanol as a carbon
source. It is the rst known methylotrophic yeast that may be used to produce heterologous proteins utilising the methanol-inducible, endogenous AOX1 promoter.
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Also, this species possess comparatively lesser degree of hypermannosylation so
there will be lesser problems of post-translational modications in their products.
These features make it to be a well-enough option to be genetically manipulated in
order to use it as a host to produce biopharmaceuticals (Ahmad etal. 2014). P. pas-
toris was found to secrete biologically active human growth hormone (HGH) efciently, according to a patent application. In addition to HGH, P. pastoris is also
used in producing human calcitonin (hCT) and human alpha-fetoprotein (AFP),
peptide hormones that control blood levels of calcium and phosphate. AFP, or alpha
foetal protein, is a plasma protein that is produced by the liver during foetal development and is used as a tumour marker in cancer therapy.
Genetically modied Y. lipolytica strains have found their application in biophar-
maceuticals production, specically in enzyme replacement therapy, and AzurRx
Biopharma, Inc. (Brooklyn, NY, USA/Langlade, France), INRA and also Mayoly
Spindler (Chatou, France) together developed lipase enzyme from these strains
which were found to overexpress LIP2. Pancreatic insufciency has been treated
with the help of this recombinant lipase enzyme. OXY2810, a recombinant human
acid α-glucosidase produced from Y. lipolytica, is used to treat glycogen build up,
that is, Pompe disease. A GCase decorated with M6P glycans is being developed to
treat neuronopathic Gaucher disease, which is caused by glucocerebroside buildup
in neuronal cells. Recombinant glucocerebrosidase (GCase) is undergoing preclinical testing for the treatment of Parkinson’s disease (Madzak 2021).
S. Jana et al.
6.5 Transgenic Animals asRecombination Protein
Expression Medium
Transgenic animals prove to be quite a good platform for biopharmaceutical production due to the following factors: economically viable, appreciable productivity
of synthesized proteins, and quality of products. Animal bioreactors can create
recombinant proteins that are structurally close to their original forms owing to the
evolutionary link that exists between humans and different mammal species.
Numerous animal species, such as mice, cattle, pigs, goats, sheep, and rabbits, have
been employed as bioreactors (Bertolini et al. 2016). The expression method of
complex recombinant proteins in milk is thought to be the best option currently
available for the production of biopharmaceuticals when it comes to animal platforms. The production of a targeted protein in milk can be directed towards the
mammary gland by using specic promoters for the gland, such as αs1-casein and
whey acid protein (WAP). The technologies related to the purication of recombinant proteins produced from milk have dramatically advanced, enabling the completion of several specialised studies for the synthesis of biopharmaceuticals in
transgenic animal milk (Chaible etal. 2010). The mammary gland’s expression system is the sole animal platform that can produce recombinant proteins for approved
commerce for therapeutic use.
For example, in 2006 the European Medicines Agency (EMA) approved the marketing of the rst recombinant antithrombin drug, Atryn, produced from transgenic
6 Production ofBiopharmaceuticals onGenetically Modied Organisms
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animals in European Union countries. Goats and rabbits collaborated to approve
Ruconest~ (Pharming) which is a recombinant human C1 esterase inhibitor protein
(C1INH), another biopharmaceutical derived from milk which was approved by
European Medicines Agency in 2012 and FDA in 2014 (Bertolini etal. 2016). The
animal platform has been proven to be a very reliable method for producing biopharmaceuticals through testing, approval, and growing convergence.
The production of biopharmaceuticals through animal transgenesis is still being
developed. While signicant progress has been made, convincing advancements
must be made to guarantee efciency in lowering transgenesis costs and allow the
process to be implemented on an industrial scale. Additional advancements in the
eld are provided by novel molecular genetic techniques in conjunction with recent
developments in genome annotation and sequencing, invitro embryo creation, and
reproductive technologies like nuclear transfer. Transgenic animals have a number of
advantages over cultured cells, chief among them being the simplicity with which a
huge number of useful proteins may be created and extracted. This is a result of both
the biology of the producing cell and the “low tech” character of the fundamental
production method, which uses animals in the eld rather than intricate fermentation
containers (Shakweer etal. 2023).
Important sources of production of biopharmaceuticals
Sources Description Reference
Milk • The expression method of complex recombinant proteins in
milk is thought to be the nest option currently available for
the production of biopharmaceuticals when it comes to
animal platforms
• The mammary gland shows great potential to synthesize
proteins and other biochemicals for baby nourishment
during lactation. Milk contains a complex and wealthy
combination of proteins, fats, and carbohydrates. The
primary milk protein is casein, which comes in ve different
forms in mice, four in sheep and also cows, and two in
humans. The milk of transgenic animals can express a vast
array of foreign proteins
• Human α-antitrypsin has been successfully expressed in
sheep to levels of up to 35g/L using the ovine BLG
promoter. Complex multi-chain proteins like brinogen and
transgene combinations intended to enhance the lactating
mammary glands innate capacity for protein processing are
examples of the work that has been done in this area
• In 2006, the European Medicines Agency (EMA) approved
the marketing of the rst recombinant antithrombin drug
produced from goat milk, Atryn, in the European Union
countries. Recombinant proteins such as human IGF-1,
hGH, human lysozyme, human lactoferrin, human
parathyroid hormone, and anti-clotting factors such as
protein C, Antithrombin III, factor VII, factor VIII, factor
IX, brinogen, and tissue plasminogen activator have also
been successfully expressed in transgenic animals
Niemann etal.
(2012), Bertolini
etal. (2016)
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Sources Description Reference
Urine • The urinary system has some advantages over the mammary
gland when it comes to producing certain proteins. Urine is
formed by animals well before the recombinant protein and
lactation can mature more effectively. Membrane-associated
proteins called uroplakins are only expressed in the evolved
uroepithelium of the bladder and urethra
• Scientists have successfully directed human granulocyte
macrophage- colony stimulating factor (hG-CSF) and human
growth hormone (hGH) to express in mice using the mouse
uroplakin II gene promoter. However, a major challenge
with this process of production is the lower capacity for
synthesis in the kidney and bladder compared to the
mammary gland
Blood • Transgenic animal blood is a growing source of human
polyclonal antibodies due to the development of
recombinant human proteins. Improved immune systems in
cattle, pigs, and also rabbits are being developed
• These animals can be vaccinated with a broad range of
antigens to produce a plentiful supply of human polyclonal
antibodies. These antibodies have signicant advantages
over monoclonal antibodies and can be useful in passive
immunotherapy. It is possible to express proteins using
animal blood as a bodily uid
• Examples of recombinant proteins produced in the blood of
transgenic animals include human a1-antitrypsin in the
serum of transgenic rabbits and transchromosomic cattle
producing human polyclonal antibodies
Seminal
uid
• Semen is a bodily uid produced by male sex glands in
signicant amounts (200–300mL each time)
• Studies suggest that porcine seminal uid is a rich source of
bioactive proteins. This is because the protein secretion
process is exocrine, meaning it doesn’t harm the animal’s
health
• Seminal plasma can be a great source for producing
bioactive proteins due to its high capacity for protein
processing, stability, and purication
Niemann etal.
(2012), Bertolini
etal. (2016)
Niemann etal.
(2012), Bertolini
etal. (2016)
Bertolini etal.
(2016)
S. Jana et al.
6.6 Transgenes inProduction ofGenetically
Modied Organisms
Pronuclear microinjection-introduced transgenes are intended to operate upon
insertion into various locations within the host DNA.The number of copies of the
transgenic, the place of insertion into the host genome, and the regulatory elements—that is, the sequences that control transcription, RNA processing, and translation—all affect how the transgene expresses itself. Before a desired gene can be
successfully cloned and put into the organism, it must go through a number of
changes. To enable gene expression, a promoter sequence is inserted. The
6 Production ofBiopharmaceuticals onGenetically Modied Organisms
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transgenes must guide the profuse production and specic protein transport to the
intended organ while preserving the health and welfare of the animal. They also
need to gradually merge into the host genome and be transferred in a Mendelian
fashion (Meyer 1995; Kaundal etal. 2014).
It could be required to modify codons to match those that are most commonly
utilised by the host if the protein originates from progressively distant species.
Additionally, if the protein is not normally released, the generating cell may be
directed to secrete if a signal peptide is inserted at the N-terminus. A lot of genes are
too big to t neatly into plasmid cloning vectors. A “minigene” comprising two or
one introns and 3′ or 5′ anking regions believed to contain +ve regulatory elements
is frequently created by combining cDNA and genomic sequences. Nevertheless,
cryptic splice sites can occasionally result in abnormal RNA splicing when mixing
and matching in this manner. The placement of the transgene within the host genome
has a signicant role in its ability to be expressed. The closeness of activation
sequences, silencers, promoters, and enhancers that are found naturally may also
affect the transgenic expression pattern and intensity. Sometimes anking the transgenic construct with insulator elements improves the level, consistency, and also
specicity of transgene expression. Research has demonstrated that several types of
insulators can keep surrounding natural enhancers and other regulatory components
from inuencing transgenic promoters. They can also stop heterochromatin effects
from extending into the transgene (Niemann etal. 2012).
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6.7 Challenges Faced inProduction
DuetoPost- Translational Modications
inSome Organisms
6.7.1 Glycosylation
One of the main obstacles to yeasts producing viable human therapeutic proteins is
thought to be proper post-translational modication like glycosylation. The low
number of authorised biopharmaceuticals from plant, insect, and yeast platforms is
mostly due to unfavourable glycosylation. Biopharmaceuticals that need highly precise and intricate N-glycans similar to those found in humans must therefore be
created using mammalian expression platforms (Roohvand etal. 2017). Recombinant
human (rh) glycoproteins differ from their endogenous counterparts due to glycosylation, which is species and cell-specic as well as culture-dependent which
affects the accuracy of manufacturing methods. Proper glycosylation is also crucial
for mAbs, the primary product class of biopharmaceuticals. The majority of monoclonal antibodies (mAbs) belong to the IgG class and have a glycosylation site in the
Fc region at amino acid position asparagine (Asn)–297; however a small fraction of
mAbs have an additional site in the Fab region. Cell engineering focuses a lot of
attention on the sugar moieties since they frequently directly affect
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S. Jana et al.
pharmacokinetics, pharmacodynamics, and immunogenicity. The degree of
sialylation and mannosylation can have an effect on the proper functioning of the
mAb (Amann etal. 2019).
6.7.2 Carboxylation
Biopharmaceuticals requiring carboxylation must be expressed on platforms derived
from multicellular species, ideally from mammalian hosts, as carboxylation activity
is only documented inside multicellular organisms, such as mammals and Drosophila
(Amann etal. 2019).
6.7.3 Tyrosine Sulfation
Appropriate tyrosine sulfation appears to affect biological activity and binding in
addition to modulating protein stability and also biopharmaceuticals requiring sulfotyrosine, like recombinant factor VIII (rhFVIII), are produced in mammalian cell
systems because tyrosine sulfation cannot be carried out by E. coli or other prokaryotic expression platforms (Ezban etal. 2014).
6.8 Conclusion
Importance for biopharmaceuticals is rising due to increasing incidence of chronic
diseases. Treatment for autoimmune diseases, genetic problems, and chronic illnesses like cancer has been transformed by biopharmaceuticals. Genetically modied organisms, from microorganisms to transgenic mammals, are characterized to
aid in the development of biopharmaceuticals. They are substantially rich in pharmacological and pharmacokinetic properties. Genetic engineering has proved to be
a boon in the pharmaceutical eld. Despite few limitations in the production process, biopharmaceuticals are being successfully manufactured defying all odds.
Therefore, more and more research should be carried out to contribute to one of the
most pivotal industries in the healthcare arena.
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Chapter 7
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Drug Delivery inBiotechnology:
Present andFuture
SeemaYadav, NarahariNarayanPalei, SubasChandraDinda,
andArghyaKusumDhar
Abstract Nanobiotechnology is the integration of nanotechnology with biotech-
nology, with a specic emphasis on the utilisation of nanoscale techniques in biological systems. Nanobiotechnology signicantly contributes to the eld of drug
delivery by utilising nanoscale materials, such as nanoparticles and liposomes, to
enhance the effectiveness of medications. Nanoparticles possess a reduced size and
altered properties that provide accurate drug localisation, regulated release, and
enhanced bioavailability. This offers distinctive resolutions to challenges encountered in conventional drug administration techniques. Herein we highlight the signicance of achieving optimal drug delivery and subsequently explore the potential
of biotechnology to address these challenges. We explore contemporary methodologies, including the utilisation of nanotechnology for targeted drug delivery.
Additionally, we discuss intelligent drug delivery systems, including those that are
triggered by specic inputs or guided by articial intelligence. The development of
biodegradable implants, the use of articial intelligence for personalised treatment,
and the creation of microbes for the administration of drugs are also discussed. The
chapter includes coverage of cutting-edge technology such as 3D printing for the
customisation of medication forms and continuous monitoring devices, highlighting
the important ethical inquiries and safety hazards linked to these novel methods.
Finally, it provides a concise overview of the key progress made and anticipated
breakthroughs in drug delivery that have the potential to transform healthcare.
S. Yadav · N. N. Palei
Amity Institute of Pharmacy, Amity University Lucknow Campus,
Lucknow, Uttar Pradesh, India
S. C. Dinda · A. K. Dhar (*)
School of Pharmacy, The Neotia University, Sarisa, West Bengal, India
Ltd. 2024
S. Bose et al. (eds.), Concepts in Pharmaceutical Biotechnology and Drug
Development, Interdisciplinary Biotechnological Advances,
https://doi.org/10.1007/978-981-97-1148-2_7
103© The Author(s), under exclusive license to Springer Nature Singapore Pte
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Keywords Nanobiotechnology · Drug delivery · Monoclonal antibody · 3D
printing
S. Yadav et al.
7.1 Introduction
The topic of medication delivery is expanding quickly and attracting the interest of
industry, scientists, and pharmaceutical companies. Pharmaceutical researchers’
“holy grail” is developing efcient drug delivery systems (DDSs) that can deliver a
medication precisely, safely, and to the intended location of action (Morris 2022).
In fact, a plethora of new delivery systems are developed every year, and almost
every bodily region has been investigated as a possible delivery system for both
established and cutting-edge medications. As a result, effective methods for delivering peptides, proteins, and medicines that are poorly soluble have been developed. Furthermore, a great deal of research is now being done on innovative nasal
drug delivery systems, nanodevices, bio-adhesive systems, micro-fabricated systems, implants, transdermal patches, and cell encapsulation devices. These and
other innovations are causing a signicant shift in the drug delivery sector. A new
market for drug delivery is emerging because of increasing demand brought about
by market extension, reduced drug development budgets, and novel formulations
that provide a competitive edge once patents expire. In 2003, the drug delivery
systems market in the US was valued at approximately $43.7 billion. It was projected to experience an average annual growth rate of 11.3% and reach $74.5 billion
by 2008 (Burrows and Lambrix 2022). This information comes from a recent study
from Business Communications Company Inc. Within the broad topic of biotechnology, medication delivery represents an important interface between basic science and therapeutic use (Aslam etal. 2022). The key to increasing the effectiveness
of medications while reducing unwanted side effects is the capacity to precisely and
efciently distribute therapeutic chemicals to target areas within the body. Thanks
to developments in biotechnological research and development, the design and
implementation of DDSs have advanced signicantly over the past few decades
(Aslam etal. 2022). As a multidisciplinary area, biotechnology uses the ability to
manipulate biological systems, cells, and live beings to create novel solutions for
problems in healthcare. Biotechnology goes beyond traditional drug delivery techniques to enhance pharmaceutical substances’ pharmacokinetics, bioavailability,
and targeted delivery. Addressing the intricacies of many diseases, such as cancer,
viral diseases, autoimmune disorders, and hereditary problems, requires a comprehensive approach. The fusion of biology, chemistry, engineering, and material science characterises the current biotechnology drug delivery landscape (Liu etal.
2022). Scholars are presently investigating novel platforms for encapsulating and
delivering medicinal substances, including liposomes, micelles, nanoparticles
(NPs), and biocompatible polymers. With the ability to customise these carriers, it
will be possible to achieve site-specic delivery, sustained activity, and controlled
release with a degree of accuracy that was previously unattainable with traditional
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drug administration techniques. This review addresses new technologies being
researched to get around some of the present challenges with drug delivery and
highlights innovative drug delivery systems that potentially enhance some traditional treatments now available on the market. We also discuss how these difculties should be tackled to develop the profession and offer our perspective on the
drug delivery research policies (Birla etal. 2022).
DDSs have come a long way, but there are still several issues that need to be
resolved, which calls for continued research and development. Overcoming biological barriers to guarantee the secure and efcient delivery of therapeutic payloads to
tissues or cells is one of the main obstacles. A number of complex defence systems
found in the human body, such as blood-brain barrier (BBB) and other physiological barriers, can prevent medications from reaching their intended targets (Mandal
et al. 2023). Nanotechnology has become an increasingly potent weapon in the
medication delivery arsenal as a response to these obstacles. Nanoscale delivery
agents, like NPs, have demonstrated the capacity to get past immunological reactions, cross physiological barriers, and release their payload at the desired location
of action. Additionally, the surface of these nanocarriers can be altered to improve
their targeting efciency, enabling the more accurate delivery of therapeutic medicines. Finding a balance between safety and therapeutic efcacy is a signicant
difculty in drug delivery. At high concentrations, many pharmaceuticals show
strong effects, but this is frequently at the expense of increased toxicity and unfavourable responses. By offering regulated release and long-term maintenance of
therapeutic levels in the body, drug delivery systems seek to address these problems.
This improves patient adherence and quality of life while minimising side effects
and increasing treatment efcacy overall (Awad et al. 2022). Drug delivery has
advanced signicantly in the last several years because of researchers’ exploration
of novel materials and methods to address long-standing issues. Because of their
special physicochemical characteristics, NPs have gained a lot of interest in drug
delivery studies (Park etal. 2022). These submicron-sized carriers provide protection and regulated release for a range of therapeutic substances, like proteins,
nucleic acids, and tiny compounds. Another class of nanocarriers are liposomes,
which are made of phospholipid bilayers and can hold both hydrophilic and hydrophobic medications. Antibiotics, vaccinations, and anticancer medications have all
been delivered effectively using liposomal formulations. The fact that they can
increase drug solubility, increase the duration of circulation, and improve drug
accumulation at the target location has led to their extensive application in preclinical and clinical settings (Hersh et al. 2022). Drug delivery by the formation of
micelles, which are created when amphiphilic molecules self-assemble in aqueous
solutions, is another exciting prospect. These nanostructures can increase the bioavailability of hydrophobic medications by solubilising them. To further increase
their versatility in drug delivery applications, micelles’ amphiphilic nature permits
the integration of both hydrophobic and hydrophilic components. Poly (lactic-coglycolic acid) (PLGA) and polyethylene glycol (PEG), two biocompatible polymers, are now essential parts of DDS designs. Because of the adjustable qualities of
these polymers, carriers with release patterns and degradation kinetics can be
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