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FORMULATION OF
MONOCLONAL
ANTIBODY THERAPIES
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FORMULATION OF
MONOCLONAL
ANTIBODY THERAPIES
FROM LAB TO MARKET
AMAL ALI ELKORDY

School of Pharmacy and Pharmaceutical Sciences, Faculty
of Health Sciences and Wellbeing, University of Sunderland,
Sunderland, United Kingdom
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Contents
Contributors vii
1. Introduction about monoclonal antibodies 1

Amal Ali Elkordy and Mark Carlile
1.1 Introduction 1
1.2 What are therapeutic antibodies? 6
1.3 Classification, types, and structures of mAb-based therapeutics 9
1.4 Nomenclature of therapeutic monoclonal antibodies 14
1.5 Production of monoclonal antibodies using various technologies 14
1.6 Mechanism of mAbs action and examples for mAbs with their
clinical uses 24
References 34
2. Biosimilar antibodies 39
Amal Ali Elkordy and Kamalinder K. Singh
2.1 Introduction 39
2.2 Approval and market availability of biosimilar antibodies-based
medicines 41
2.3 Differences between generic and biosimilar medicines 47
2.4 Importance of biosimilar mAbs 50
References 51
3. Pharmaceutical aspects of mAbs: formulation,

characterization, and current route of administration of
monoclonal antibody therapies 53
Amal Ali Elkordy and Cheng Shu Chaw
3.1 Introduction: pharmaceutical formulations of lyophilized powder
and liquid mAb dosage forms 53
3.2 Formulation of lyophilized mAb powder dosage forms 73
3.3 Formulation/preparation of mAbs in liquid dosage forms 92
References 201
v j
vi Contents
4. Route of monoclonal antibodies administration 209

Amal Ali Elkordy, Amerah Parveen and Rita Haj-Ahmad
4.1 Introduction 209
4.2 Approaches for novel mAbs delivery systems to assist on mAb
delivery by a route/s other than injections 211
4.3 Noninvasive routes for biologics including mAbs 223
References 255
5. Industrial aspects of finished monoclonal antibody therapies 259

Marc Faltes and Amal Ali Elkordy
5.2 Glass vials 262
5.3 Prefilled syringes 275
5.4 Autoinjectors 283
References 284
6. Application of approved and marketed products of

monoclonal antibody therapies 287
Amal Ali Elkordy, Moustafa Elsayed, Sohib Bashier Al-Abdulrazag and
Zeinab Moataz Zarara
6.2 Application of recently approved or in regulatory review mAb
therapies in cancer 288
6.3 Application of recently approved or in regulatory review mAb
therapies in noncancer diseases 293
References 325
Index 329
Contributors
Sohib Bashier Al-Abdulrazag

School of Pharmacy and Pharmaceutical Sciences, Faculty of Health Sciences and
Wellbeing, University of Sunderland, Sunderland, United Kingdom
Mark Carlile
Cheng Shu Chaw
Amal Ali Elkordy
Moustafa Elsayed
Marc Faltes
Rita Haj-Ahmad
Wellbeing, University of Sunderland, Sunderland, United Kingdom; Well Pharmacy,
Nottingham, United Kingdom
Amerah Parveen
Kamalinder K. Singh
School of Pharmacy and Biomedical Sciences, Faculty of Clinical and Biomedical Sciences,
University of Central Lancashire, Preston, United Kingdom
Zeinab Moataz Zarara
Silver and Charlton Dental Practice, Sunderland, United Kingdom
vii j
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CHAPTER ONE
Introduction about monoclonal

antibodies
Amal Ali Elkordy and Mark Carlile
School of Pharmacy and Pharmaceutical Sciences, Faculty of Health Sciences and Wellbeing, University of
Sunderland, Sunderland, United Kingdom
1.1 Introduction
The introduction will cover a brief history of monoclonal antibody
(mAb) therapeutics. Monoclonal antibodies, also known as immunoglobu-
lins, drugs are therapeutic glycoproteins. At least 570 mAbs have already
been progressed to the clinic by commercial companies and to-date 100
mAbs have received approval from the Food and Drug Administration
(FDA) for a range of clinical applications. The first mAb to be approved
was muromonab-CD3, (tradename Orthoclone OKT3) in 1986 as a kidney
transplant immunosuppressant (Liu, 2014; Smith, 1996). Orthoclone OKT3
was latter voluntarily withdrawn from the U.S. market due to the levels of
side effects and the introduction of better-tolerated competitor molecules.
Currently as of August 2, 2021, 100 therapeutic mAbs have been
accepted and therefore approved by the FDA and are currently on the mar-
ket, this is in addition to 17 mAbs under review by the FDA (“Antibody
therapeutics approved or in regulatory review in the EU or US,” 2021).
Also, there are many novel mAbs therapeutics in development. Those pro-
tein therapeutics show high efficacy and good safety profiles hence they
progress through clinical trials very quickly. Accordingly, mAbs are the
most rapidly growing class of biopharmaceutical products. Being complex
quaternary glycoproteins, mAbs have unique structural features that provide
target specificity and downstream cellular signaling activities. They are in use
for treatment of complex and difficult to treat diseases such as rheumatoid
arthritis, cancer, Crohn’s disease, psoriasis, transplant rejection, autoimmune,
asthma, infectious diseases, migraine headaches and most recently they are
used to treat Alzheimer’s diseases (Aduhelm (aducanumab) approved for
the treatment of Alzheimer’s disease, 2021).
Formulation of Monoclonal Antibody Therapies

© 2023 Elsevier Inc.
1 j
ISBN: 978-0-12-823365-8
https://doi.org/10.1016/B978-0-12-823365-8.00002-5 All rights reserved.
2 Amal Ali Elkordy and Mark Carlile
“As the pharmaceutical market in the United States and the rest of the
world continues to expand, biopharmaceutical products have taken on
increasing importance in the treatment of disease. Sales of monoclonal anti-
body products have grown from approximately $50 billion in 2010 to almost
$90 billion in 2015, an approximately 1.8-fold increase and represent
approximately 58% of biopharmaceutical sales. As more and more exciting
monoclonal antibody products for treatment of cancer, autoimmune dis-
eases, cardiovascular disease, and others are introduced, sales from new prod-
ucts approved in the coming years will drive the world-wide sales of
monoclonal antibody products to approximately $150 billion by 2021”
(Insight Pharma Reports, 2020).
There are different laboratory production techniques for mAbs (as will be
explained later in this Chapter); however, each technique presents chal-
lenges in terms of product expression format, yield, purity, complexity,
and heterogeneity. These challenges are compounded at the formulation
stages, wherein, aggregate formation is commonplace and may lead to un-
wanted immunogenicity. For example, muromonab-CD3 and other
early-mAbs were generated via murine models. These purely mouse-
derived proteins were not tolerated by patients for extended administration
periods due to induced immunogenicity. The development of hybridoma
and transgenic “humanized” mouse expression techniques has helped in
the manufacture of more clinically useful antibodies (for recombinant
mAbs production technique refer to Section 1.5 below, and for overcoming
the formulation challenges refer to Chapters 3 and 4).
The immune system is crudely dived into the innate and the adaptive im-
mune response components and is mobilized against foreign agents and in-
fectious organisms through the generation of antibodies from the adaptive
immune system (as shown in Fig. 1.1A and B). The immune system is
constantly responding to all diseases and thus to a wide diversity of pathogens
and antigens. Therefore, part of the body’s normal immune response to an
external toxin or substance is the composition and production of antibodies
(Abs). The Abs production is via B-cells and sustained for later mobilization
via plasma cells (their origin is bone marrowederived B lymphocyte cells
and the process requires help from T cells (Kaunitz, 2017; Kugelberg,
2016) (Fig. 1.1B(ii)).
The power and specificity of the immune system to target specific anti-
gens and select the best antibody candidate generated via unique B cell gen-
eration gave rise to traditional antibody therapies, usually from animal
serum. These “crude” therapies were generated via repeated immunization
Introduction about monoclonal antibodies 3
Figure 1.1a Representation on how immune system works. (i) Cellular immunityd
adaptive immunity part 1: https://www.youtube.com/watch?v¼nqRn5fN22t4. (ii) Hu-
moral immunitydadaptive immunity part 2: https://www.youtube.com/watch?
v¼rAepZG_ChyQ.
Figure 1.1b Link to videos for (i) cellular immunity; (ii) humoral immunity.
of experimental animals with an antigen followed by subsequent purification

of the serum to isolate the antibody fractions (against the antigen) (Fig. 1.2).
However, the administration of purified animals’ sera preparations can pro-
duce allergic reactions in many patients.
The first Nobel Prize in Medicine in 1901 was won by Emil von Behr-
ing. This was for his work on serum therapy (with other scientists in the late
1800s and early 1900s) that not only emphases that “blood is a very unusual
fluid” but also led to discovery of antibodies in protection against diseases
and this discovery denotes the dawn of immunological science (Nunes-
Alves, 2016; Bordon, 2016).
Passive antibody therapy or serum therapy has been used as a preventa-
tive of infection as well as postinfection treatment. Famously, obtaining
serum filled with antibodies from people who have recovered from the
Figure 1.2 Serum therapy steps.
diseasedwas used during the 1918 Spanish influenza pandemic, this was
convalescent serum therapy. More recently serum therapy was used during
the Ebola and SARS epidemics (“First Nobel Prize in Medicine and the
Coronavirus (COVID-19),” 2020). Nevertheless, human serum therapy
can be the only available treatment for some diseases, exemplified by the
2019 global pandemic outbreak. Serum therapy was used recently in 2020
against the SARS2-COVID-19 virus i.e., as a treatment for the coronavirus
(COVID-19), which seems unusual with all the available advanced technol-
ogy to produce medicines. It involves injecting serum from COVID-19
recovered patients into patients with COVID-19 virus.
Due to the complexity of antibodies, biological systems, i.e., cells or
entire organisms capable of immunological response are the only viable op-
tion for generating antibodies against specific targets. However, scientists
have developed laboratory methods (recombinant DNA/gene technologies)
to engineer therapeutic antibodies to finetune and improve their application
to specific diseases. When treating a complex or difficult to treat diseases
(such as cancer, autoimmune diseases) that impair or compromise the im-
mune system, supplementation or augmentation of the immune resposne
is still possible through the use of engineered antibody molecules that may
have been engineered in the laboratory (mAb-based therapeutics).
However, the laboratory production and commercial manufacture of

antibodies is not an easy process and biological systems are still needed for
mass production beyond the initial molecule discovery and screening activ-
ities. Many mAbs used in the clinic originated via the use of hybridoma tech-
nologies for mAb generation and selection (e.g., Fig. 1.3). The expression of
these mAbs is then moved to a recombinant expression system (Fig. 1.3) for
clinical manufacture and commercial supply. More information can be
found here (Frank Lectures, 2017, Hybridoma Technology: Production
of Monoclonal Antibodies (FL-Immuno/55)dYouTube) (Askonas et al.,
1970; Kaunitz, 2017; Köhler and Milstein, 1975). Also for general explana-
tion refers to this link (Khan Academy, 2016 for https://www.youtube.
com/watch?v¼5ffl-0OYVQU).
Therapeutic mAbs are routinely generated in traditional recombinant
expression systems, such as yeast, insect, animal, or human cell lines.
Some modified mAb fragments can be generated using microbial expression
systems. The choice of the system is based mainly on the glycosylation ca-
pacity of the system, the efficiency of expression, the biological efficacy,
and the yield requirements for the mAb. The choice of expression system
can impact the downstream purification process unit operations and the final
formulation of the drug molecule and its application. Kaunitz reported in
detail the dawn of mAbs rule, where the commencing of mAbs revolution
stated (Kaunitz, 2017).
Figure 1.3 Schematic presentation of hybridoma mAb production and recombinant

monoclonal antibody (mAb) technology.
1.2 What are therapeutic antibodies?

Therapeutic monoclonal antibodies (mAbs) are a class of therapeutic
glycoproteins namely immunoglobulins (Igs) that are produced from a single
clonal lymphocyte in response to a foreign agent. Cloning a single lympho-
cyte is very challenging to produce homogenous immunoglobulins in large
quantities. Many of the first therepeutic antibodies have been produced via
the fusion of a single B lymphocyte and a single tumor celldtermed hybrid-
oma technology. This technology has been used successfully against many
disease-causing and diagnostic antigens (Fig. 1.3), also refer to Section 1.5,
Fig. 1.10.
1.2.1 General structure of proteins

Proteins are large molecules (macromolecules), consisting of one or more
chains of amino acid residues joined by peptide bonds. Nature utilizes 20
different L-amino acids for protein generation. The peptide bonds form a
polyamide backbone (known as protein primary structure) with the specific
amino acid side chains contributing to the protein folding, final conforma-
tion, and function of the protein. The final three-dimensional conformation
of a protein is achieved through interactions between the side chains of the
amino acids and the specific physicochemical properties of these side chains
(Fig. 1.4).
The tertiary structure refers to the three-dimensional arrangement of the
folded polypeptide chains. Proteins with the quaternary structures are char-
acterized by a combination of more than two polypeptide chains. Tertiary
and quaternary structures are stabilized by covalent and noncovalent inter-
actions. The interactions include hydrogen bonds, disulfide linkage, van
der Waals forces, and electrostatic interactions. Proteins are unique in their
molecular masses, based on the number of amino acids and any modifica-
tions that are made to the protein (e.g., glycosylation), and in their proper-
ties, more information on basic protein structures and characteristics can be
found in Florence and Attwood (2015), Vella (1992) and Br€andén et al.
(1999); and information on protein therapeutics, in general, can be found
in (Leader et al., 2008).
Proteins carry out a variety of physiological functions, for example, en-
zymes (they are proteins that control the biochemical reactions needed to
sustain life processes); hormones (they are proteins that control cellular phys-
iology, growth, and differentiation); transport and storage proteins (e.g.,
Figure 1.4 The primary, secondary, tertiary, and quaternary structures of proteins (“Pro-
teinStructure.jpg (546 800),” n.d.) ProteinStructure.jpg (546 800) (bu.edu).
serum albumin) and antibodies (they are proteins for the body immune re-
sponses. Accordingly, deficiency or abnormality of the body’s endogenous
proteins can lead to pathophysiology; hence, the therapeutic proteins are be-
ing clinically used to treat various diseases.
Recombinant proteins form the majority of the therapeutic proteins on

the market, and in clinical trials for a variety of intended uses, for example
treating cancers, immune disorders, infections, and other diseases. Dimitrov
(2012) reviewed the types of therapeutic proteins and classified them accord-
ing to their pharmacological activity into five different groups. The first
group is the proteins used to replace a deficiency or abnormalities of the
endogenous proteins e.g., insulin in diabetes mellitus Type I. The second
group encompasses the proteins that augment an existing physiological
pathway such as erythropoietin in anemia caused by renal failure (Dimitrov,
2012). In addition, therapeutic proteins may provide a novel function or ac-
tivity as in the case of Botulinum Toxin Type A when it is used as a drug of
choice for patients suffering from muscle dystonia (Cloud and Jinnah, 2010).
Moreover, some proteins are given to the patients targeted for a particular
activity by interfering with a molecule or organisms such as monoclonal an-
tibodies to treat immunity disorders. Finally, some proteins are being used as
delivering vehicles for other medications or proteins, e.g., gemtuzumab ozo-
gamicin is used as a conjugate for the treatment of de novo CD33-positive
acute myeloid leukemia (AML).
Monoclonal antibodies are complex glycoproteins with distinctive struc-
tural features that contribute to their variable and diverse biological func-
tions. Specific carbohydrates can also have an influence on the biological
activity of mAbs. For example, by looking into Fig. 1.5, insulin (a peptide
Figure 1.5 Schematic presentation to show the large size of the mAbs. Insulin: By
TheislikericedOwn work, CC BY-SA 4.0, mAbs (“Monoclonal antibodiesdall you need
to know about antibody generation | tebu-bio’s blog,” 2018).
hormone) is a small protein that consists of 51 amino acids and its molecular
mass is 5.8 kDa; erythropoietin is a larger protein hormone consists of 165
amino acids and its molecular weight is 30.4 kDa, while mAbs or immuno-
globulins are larger globular proteins, IgG1 has a molecular mass of about
150 kDa with more than 660 amino acids. Also, the hinge region of IgG1
consists of 15 amino acids and is very flexible. IgG2 and IgG4 have shorter
hinges than IgG1, with 12 amino acid residues (Vidarsson et al., 2014). The
hinge region joins the Fab, of the heavy chain, and Fc fragment and allows
some flexibility for the Fab arms (Figs. 1.6 and 1.7). Hence, mAbs are pro-
teins but have different unique features compared to other proteins.
1.3 Classification, types, and structures of mAb-based

therapeutics
Monoclonal antibodies are immunoglobulins (Igs), they present in
five class forms or isotypes (IgA, IgD, IgE, IgG, and IgM) (Figs. 1.6 and 1.7).
IgG is the most clinically used antibodies as therapeutics, mainly due to
their characteristics (Table 1.1) (“Antibody Basics,” n.d.) and because they
are the most common type of antibodies found in the blood and additionally
based on literature they may live longer in the blood. IgGs are globular gly-
coproteins and are highly site specific. IgG contains two identical light chains
of about 25 kDa and two identical g, gamma, heavy chains of about 50 kDa
(Fig. 1.7), thus a tetrameric quaternary structure. The two heavy chains are
Figure 1.6 Class identity that is determined by class-specific sequences in the Fc region
of the heavy chain which are: alpha-IgA, delta-IgD, epsilon-IgE, gamma-IgG, mu-IgM.
Light chains are common among immunoglobulins and occur as two typesdkappa,
k or lambda, l (“Monoclonal antibodiesdall you need to know about antibody gener-
ation | tebu-bio’s blog,” 2018).
Figure 1.7 A schematic representation of a monoclonal antibody (mAb) IgG structure.

The N-terminal domain of an IgG consists of a variable (V) region with the
complementarity-determining region (CDR) that binds to a specific epitope on anti-
gens. CH, constant domain, heavy chain; CL, constant domain, light chain; COO, car-
boxy terminal; Fab, fragment antigen-binding; Fc, fragment crystallisable region,
NHþ3 , amino terminal end; SeS, disulfide bond; VH, variable domain, heavy chain; VL,
variable domain, light chain.
connected to each other and to a light chain each by disulfide bonds

(Fig. 1.7). The resulting tetramer has two similar halves, which together
form the Y-like shape. The Fc regions of IgGs bear a highly conserved
N-glycosylation site (Cobb, 2020; Parekh et al., 1985).
The heavy chain is divided into a Fab portion, which is at the amino ter-
minal (the arm of the Y) and an Fc portion, which is at the carboxyl terminal
(the base of the Y) (Fig. 1.7). Carbohydrate chains are attached to the Fc
portion of the molecule, specific carbohydrate chains are attached to the
Introduction about monoclonal antibodies
Table 1.1 Human immunoglobulin properties.
Property IgG IgA IgM IgD IgE
H chain class G A m D ε
(heavy chain)
H chain g1 g2 g3 g4 a1 a2 None None None
subclasses
H chain MW 50 kDa 50 kDa 60 kDa 50 kDa 55 kDa 55 kDa 70 kDa 62 kDa 70 kDa
L chain MWa 23 kDa 23 kDa 23 kDa 23 kDa 23 kDa 23 kDa 23 kDa 23 kDa 23 kDa
(light chain
k and l)
Total MW 150 kDa 150 kDa 170 kDa 150 kDa 160 kDa 160 kDa 970 kDa 180 kDa 190 kDa
(serum) (serum)
600 kDa 600 kDa
(secretory) (secretory)
Fc receptor Strong Weak Strong Weak Yes Yes Yes No Yes
binding
a
Light chains are present in all Immunoglobulin classes. In humans, k. chains are found 67% of the time, and l chains are found 33% of the time.
Adopted from Antibody Basics, n.d. Sigma-Aldrich. https://www.sigmaaldrich.com/technical-documents/articles/biology/antibody-basics.html. (Accessed 3 May
2021).
11
Fc portion of the molecule and can affect the biological activity of the mAb.
The Fc portion of the Ig molecule, specifically IgG and IgM regions can
bind to receptors on the surface of immunomodulatory cells such as macro-
phages and stimulate the release of cytokines that regulate the immune
response. The Fc region contains determinants unique to the individual clas-
ses (Figs. 1.6 and 1.7) as well as protein sequences common to all Igs. These
regions are known as the constant regions because they do not vary greatly
among different Ig molecules within the same class. The Fab portion of the
Ig molecule contains both light and heavy chains joined together by a single
disulfide bond. One light and one heavy chain pair combine to form the
antigen-binding site of the antibody. Each Ig monomer is able to bind
two antigen molecules (Goebl et al., 2008; Shuptrine et al., 2012).
IgG class (Fig. 1.7) presents in four subclasses (IgG1, IgG2, IgG3, and
IgG4) (Vidarsson et al., 2014) that are differentiated on the basis of the po-
sition of interchain disulfide bonds, size of the hinge region, and molecular
weight. The subclasses also vary in their ability to activate complement.
Hence, each subclass has unique characteristics, e.g., the ability to target
and interfere with cell signaling as well as stimulating the release of CDC
(complement-dependent cytotoxicity), ADCC (antibody-dependent cell-
mediated cytotoxicity), and ADPh (Antibody-dependent cellular phagocy-
tosis) (Hudis, 2007; Schneider-Merck et al., 2010).
Refer to Table 1.1 for human immunoglobulin properties. Fig. 1.5
shows IgG1 mAbs in its intact folded three-dimensional structure and
Fig. 1.7 exhibits the schematic presentation of IgG in some detail.
In cancer therapy, it is becoming increasingly evident that the antitumor
effects of antibodies are driven both by the properties of their Fc domains
and their antigen-binding regions. The Fc domain (Fig. 1.7) can bind
with Fc receptors (FcR) to cause effector functions as will be described later
under the mechanism of mAbs actions, Section 1.6. Posttranslational modi-
fication of the Fc region can also influence the function of antibodies
(Kubota et al., 2009).
Different subclasses of IgG vary in their abilities to facilitate antibody-
dependent cell-mediated cytotoxicity (ADCC) and complement-
dependent cytotoxicity (CDC). An example includes human IgG2 which
can recruit myeloid cells for ADCC but do not activate complement
(Schneider-Merck et al., 2010). Human IgG1 can activate complement
and recruit immune effector cells for ADCC (Hudis, 2007; Weiner et al.,
2010), while human IgG4 does not activate ADCC or CDC.

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AMAL ALI ELKORDY

Copyright Ó 2023 Elsevier Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any

For information on all Academic Press publications visit our website at

Publisher: Stacy Masucci

Typeset by TNQ Technologies

1. Introduction about monoclonal antibodies 1

3. Pharmaceutical aspects of mAbs: formulation,

4. Route of monoclonal antibodies administration 209

5. Industrial aspects of ﬁnished monoclonal antibody therapies 259

6. Application of approved and marketed products of

Sohib Bashier Al-Abdulrazag

Introduction about monoclonal

Formulation of Monoclonal Antibody Therapies

of experimental animals with an antigen followed by subsequent puriﬁcation

Figure 1.2 Serum therapy steps.

However, the laboratory production and commercial manufacture of

Figure 1.3 Schematic presentation of hybridoma mAb production and recombinant

1.2 What are therapeutic antibodies?

1.2.1 General structure of proteins

Recombinant proteins form the majority of the therapeutic proteins on

1.3 Classiﬁcation, types, and structures of mAb-based

Figure 1.7 A schematic representation of a monoclonal antibody (mAb) IgG structure.

connected to each other and to a light chain each by disulﬁde bonds

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