Chinese Journal of Chemical Engineering 30 (2021) 301–307

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Chinese Journal of Chemical Engineering

journal homepage: www.elsevier.com/locate/CJChE

Review

Monoclonal antibody-based cancer therapies

Yingnan Si 1, Arin L. Melkonian 2, Keegan C. Curry 1, Yuanxin Xu 1, Maranda Tidwell 1,
Mingming Liu 3, Ahmed F. Zaky 4, Xiaoguang (Margaret) Liu 1,⇑
1
Department of Biomedical Engineering, University of Alabama at Birmingham (UAB), 1825 University Blvd, Birmingham, AL 35294, USA
2
Department of Medicine, UAB, 1720 2nd Ave S., Birmingham, AL 35294, USA
3
Chinese Medicine Hospital, 98 Shengcheng Street, Shouguang 262700, China
4
Department of Anesthesiology and Perioperative Medicine, UAB, 625 19th Street South, Birmingham, AL 35294, USA

a r t i c l e i n f o a b s t r a c t

Article history: Targeted therapy has been widely demonstrated as an effective strategy to treat cancers, the leading
Received 13 October 2020 cause of death in the world. This minireview summarizes the technical platforms and methodologies uti-
Received in revised form 15 November 2020 lized to develop and engineer therapeutic monoclonal antibodies and antibody-drug conjugates. First, the
Accepted 16 November 2020
USA FDA approved monoclonal antibody (mAb)-based targeted therapies are reviewed. Then the repre-
Available online 27 November 2020
sentative innovative chimeric, humanized and fully human anti-cancer antibodies and antibody-drug
conjugates are described. Finally, the past and predictive market trend of therapeutic antibodies is
Keywords:
discussed.
Monoclonal antibody
Antibody-drug conjugate
Ó 2020 The Chemical Industry and Engineering Society of China, and Chemical Industry Press Co., Ltd. All
Anti-cancer therapy rights reserved.
Market

1. Introduction To develop therapeutic mAbs, hybridoma technology, which

Despite the advances in research, diagnosis, and treatment, can-
cer remains one of the leading causes of death worldwide, with an
estimated 9.6 million deaths in 2018 [1] and an expected rise to
29.5 million new cases and 16.4 million deaths by 2040 (Interna-
tional Agency for Research on cancer). The major obstacles
involved in preventing the success and efficacy of standard
chemotherapies include limited clinical efficacy, development of
drug resistance, severe off-target side effects, and recurrence post
primary treatment. With the intensive efforts for discovering the
cancer-specific antigens or signaling pathways such as HER2, EGFR,
CD20, CD22, CD30, CD33, CD38, CD52, CTLA-4, PD-L1, and others
[2–6], numerous targeted anti-cancer strategies that overcome
these barriers, such as monoclonal antibody (mAb)-based biologics
[7,8], have been developed or are being evaluated in clinical trials.
The mAbs have been demonstrated as effective biopharmaceuticals
that can improve the overall survival of cancer patients via multi-
ple anti-cancer mechanisms, including inhibition of cell prolifera-
tion, induction of apoptosis, antibody-dependent cell-mediated
cytotoxicity (ADCC) [9–12] and complement dependent cytotoxic-
ity (CDC) [13,14] (Fig. 1).
⇑ Corresponding author at: Department of Biomedical Engineering, University of
Alabama at Birmingham, 1825 University Blvd., Birmingham, AL 35294, USA. Fax:
+1 205 996 4701.
E-mail address: mliu@uab.edu (Xiaoguang (Margaret) Liu).
fuses the antibody producing mouse immunized B spleen cells
and reproducing myeloma (an immortal cancer B cells), was estab-
lished by Köhler and Milstein in 1975 [15–17]. The advantages of
hybridoma-based mAbs are the high antigen binding and low
aggregation in vivo [18–22]; however, the generated murine mAbs
have short half-lives, low biological activity, and reduced initiation
of effector function [23,24]. In 1985, Smith et al. developed phage
display technology to develop mAb by screening a pre-
established library of mouse or human antibodies [25,26]. Phage
display screening is fast but the developed mAbs have low antigen
targeting specificity, sensitivity, and affinity.
Antibody engineering is a powerful tool to develop novel ther-
apeutic mAbs for clinical application. For example, after sequenc-
ing and cloning, murine mAbs can be further engineered to
generate either chimeric, humanized, full human, or bispecific
antibodies [7,27–31]. The first humanized mAb (anti-IL2 daclizu-
mab) was developed by grafting the complementary-determining
region (CDR) of murine antibody with the human mAb framework
sequence and was approved in 1997 by the US FDA [32]. The trans-
genic animal technology [33] and phage display [34] enabled the
development of fully human mAb. The first human antibody, pan-
itumumab generated from XenoMouse transgenic mice, treats epi-
dermal growth factor receptor (EGFR) positive metastatic
colorectal cancer and was approved by the US FDA in 2006 [35].
Compared to murine mAb, the constant region in humanized and
human mAbs reduces immunogenicity, improves effector

https://doi.org/10.1016/j.cjche.2020.11.009
1004-9541/Ó 2020 The Chemical Industry and Engineering Society of China, and Chemical Industry Press Co., Ltd. All rights reserved.
302 Y. Si et al. / Chinese Journal of Chemical Engineering 30 (2021) 301–307
Fig. 1. The anti-cancer mechanisms of mAb and ADC. 1. mAb or ADC specifically targets cancer cells by binding the overexpressed surface receptor; 2. ADC internalizes
mediated with receptor; 3.1. Released cytotoxic drug causes cancer cell death; and 3.2. mAb-mediated ADCC or CDC leads to cytolysis.
functions, and significantly extends the serum half-life [36]. More-
over, the affinity maturation, effector function modification, and
pharmacokinetic modulation technologies have been developed
to improve the stability and function of mAbs [27,37].
Since the FDA approved the first anti-cancer chimeric mAb in
1997, anti-CD20 Rituximab, a treatment for non-Hodgkin lym-
phoma [38,39], 32 more mAbs have been approved for cancer
treatment in the USA [40,41] (Table 1). The CD19-targeting
Tafasitamab-cxix and anti-TROP-2 Sacituzumab govitecan were
approved in 2020 for the treatment of adult patients with relapsed
or refractory diffuse large B-cell lymphoma and triple-negative
breast cancer, respectively. There are five additional new antibody
therapeutics undergoing FDA review in 2020 [8]. In addition to
cancer treatment, the mAbs can also be used to diagnose cancers,
construct antibody-drug conjugate, or direct the targeted delivery
of various therapies [42–47].
2. Antibody Structure
Of the five classes of immunoglobin family (IgA, IgD, IgE, IgM,
and IgG), IgG is the most effective antibody for cancer treatment
[48,49]. IgG is comprised of two identical heavy chains (HC,
50000) and two identical light chains (LC, 25000) that are held
together by four interchain disulfide bonds and arranged in a Y
shape (Fig. 2A) [50,51]. The HC consists of one variable domain
(VH), a discrete folded region containing 110 amino acids, three
constant domains (CH1, CH2 and CH3), and a hinge linker. The
LC consists of one variable domain (VL) and constant domain
(CL) with two subtypes, lambda (k) and kappa (j). The domains
of VH, VL, CL and CH1 form the fragment antigen binding (Fab)
region which recognizes and binds a specific antigen. The CH2
and CH3 form the fragment crystallizable (Fc) region that mediates
the recruitment of immune cells through interaction with Fc
gamma receptors (FccR) [52,53]. The four subclasses of IgG
(IgG1-4) are highly conserved and differ in their hinge region
length, the number and location of interchain disulfide bonds,
and the upper CH2 domains [51]. The Fc region of IgG subclasses
leads to their functional difference in ADCC and CDC [40,54,55].
3. Engineering of Therapeutic mAb
Immunogenicity is one of the major factors that hinders the
therapeutic application of murine mAb. For instance, obvious
human anti-murine antibody responses in the circulation can be
detected within one to three weeks post-murine mAb administra-
tion and the serum half-life of murine mAb is only 15–30 h [56,57].
Although chimeric and humanized mAbs have been successfully
developed, their immunogenicity is still challenging [58–60].
Phage display [61–63] and transgenic mice [64–68] have enabled
the development of clinically indistinguishable mAbs (Table 1).
To date, over 500 therapeutic mAbs have been evaluated in clinical
trials worldwide, with more than 80 mAbs (32 of them for cancer
treatment) approved by the US FDA for clinical use (Fig. 3). Here we
use representative FDA-approved mAbs to review a multitude of
advanced antibody engineering technologies.
3.1. Cetuximab (chimeric antibody)
A chimeric antibody can be generated by fusing the variable
region of a murine antibody with the constant region of a human
antibody, containing the consensus sequences for N-linked glyco-
sylation and the N-terminal amino acid cyclized as pyroglutamic
acid [7,27–31,69]. Cetuximab (Erbitux) is a 152000 chimeric mAb
containing a human IgG1 constant region and a murine Fv variable
region, which was developed to treat metastatic colorectal cancer,
metastatic non-small cell lung cancer, and head and neck cancer by
targeting epidermal growth factor receptor (EGFR). Compared to
murine antibodies, Cetuximab showed significantly improved
anti-cancer efficacy, reduced immunogenicity, higher affinity to
antigen, and reduced dosage [70–72]. For example, the combina-
tion of Cetuximab with platinum-based therapy using fluorouracil
has resulted in overall survival (OS), progression-free survival
(PFS), and objective response rate (ORR) of 10.1 months,
5.5 months, and 35.6%, respectively, in the treatment of K-Ras
wild-type and EGFR-positive head and neck cancer patients. In
combination with the chemotherapeutic drug FOLFIRI, the Cetux-
 Y. Si et al. / Chinese Journal of Chemical Engineering 30 (2021) 301–307 303

Table 1
Summary of commercialized mAb-based anti-cancer therapies.

Scientific/ Category Target Cancers Company Ref.

Brand name
Trastuzumab/ Humanized mAb HER2/ HER2-positive breast cancer, stomach cancer Genentech [42]
Herceptin neu (Roche)
Cetuximab/ Chimeric mAb EGFR Metastatic colorectal cancer, metastatic non-small cell lung cancer and head Eli Lilly and Co. [43,44]
Erbitux and neck cancer
Bevacizumab/ Humanized mAb VEGF Colorectal, lung, cervical, renal cell cancers, glioblastoma Genentech [4–6]
Avastin
Rituximab/ Chimeric mAb CD20 Non-Hodgkin’s lymphoma, chronic lymphocytic Leukemia IDEC/ [7,8]
Rituxan Genentech
Pertuzumab/ Humanized mAb HER2 HER2-positive breast cancer Genentech [9,10]
Perjeta
Alemtuzumab/ Humanized mAb CD52 Chronic lymphocytic leukemia Genzyme [11]
Campath
Ipilimumab/ Human mAb CTLA-4 Melanoma Bristol-Myers [12]
Yervoy Squibb
Atezolizumab/ Humanized mAb PD-L1 Urothelial carcinoma, non-small cell lung cancer Genentech [13,14]
Tecentriq
Gemtuzumab Humanized mAb-drug CD33 Acute myeloid leukemia Wyeth/Pfizer [15,16]
Ozogamicin/ conjugate
Mylotarg
Brentuximab Chimeric mAb-drug CD30 Hodgkin Lymphoma Seattle [17,18]
Vedotin/ conjugate Genetics
Adcentris
Nivolumab/ Human mAb PD-1 Melanoma, non-small cell lung cancer, Hodgkin lymphoma, renal cell Bristol-Myers [19]
Opdivo carcinoma Squibb
Elotuzumab/ Humanized mAb SLAMF7 Multiple myeloma Bristol-Myers [20]
Empliciti Squibb
Obinutuzumab/ Humanized mAb CD20 Chronic lymphocytic leukemia Genentech [21]
Gazyva
Daratumumab/ Humanized mAb CD38 Multiple myeloma Janssen Biotech [22,23]
Darzalex
Ibritumomab Mouse mAb CD20 Non-Hodgkin’s Lymphoma Spectrum [24]
Tiuxetan/ Pharm.
Zevalin
Ofatumumab/ Human mAb CD20 Chronic lymphocytic leukemia Glaxo [25]
Arzera
Necitumumab/ Human mAb EGFR squamous non-small cell lung cancer Eli Eilly [26]
Portrazza
Pembrolizumab/ Humanized mAb PD-1 melanoma, non-small cell lung, head and neck squamous cell, gastric, Merck [27]
Ketruda cervical, hepatocellular cancers,
Hodgkin lymphoma, urothelial carcinoma
Dinutuximab/ Chimeric mAb GD2 Neuroblastoma United [28]
Unituxin Therapeutics
Ado-Trastuzumab Humanized mAb HER2 HER2-positive breast cancer Genentech [29]
Emtansine/
Kadcyla
Tositumomab/ Murine mAb CD20 Non-Hodgkin’s Lymphoma Glaxo [30]
Bexxar
Ramucirumab/ Human mAb VEGFR2 Gastric Cancer Eli Lilly [31]
Cyramza
Avelumab/ Human mAb PD-L1 Merkel cell carcinoma EMD Serono [33]
Bavencio
Panitumumab/ Human mAb EGFR Colorectal Cancer Amgen [32]
Vectibix
Blinatumomab/ Murine mAb CD19, Acute Lymphoblastic Leukemia Amgen [34]
Blincyto CD3
Durvalumab/ Human mAb PD-L1 Urothelial Carcinoma AstraZeneca [35]
Imfinzi
Inotuzumab Humanized, drug CD22 Acute Lymphoblastic Leukemia Wyeth/Pfizer [36]
ozogamicin/ conjugate mAb
Besponsa

imab extended the OS, PFS, and ORR to 23.5 months, 9.5 months,
and 57% from 19.6 months, 8.9 months, and 46% respectively [73].
3.2. Trastuzumab (humanized antibody)
A humanized antibody can be generated by substituting the
CDR of a murine antibody with the corresponding CDR graft of a
human antibody, which has a higher proportion of human regions
(90%–94%) and more similarity to fully human antibody than chi-
meric antibody [7,27–31]. Trastuzumab (Herceptin) is a human-
ized mAb utilized to treat the HER2-positive metastatic breast
cancer, stomach cancer and gastroesophageal junction adenocarci-
nomas. The anti-HER2 murine mAb was first developed through
hybridoma technology by immunizing mice with NIH 3T3 cells
that highly express human HER2 receptor. The hybridoma clone
with high anti-HER2 mAb productivity and high HER2 selectivity
was then screened. Finally, the variable region of mouse
anti-HER2 antibody was grafted onto human antibody backbone,
304 Y. Si et al. / Chinese Journal of Chemical Engineering 30 (2021) 301–307
Fig. 2. The structures of mAbs. A. Overall structure of mAb; B. Structures of mouse, chimeric, humanized, and fully human mAbs.
Fig. 3. The USA FDA approved therapeutic mAbs.
generating the humanized Trastuzumab [24,74–77]. Trastuzumab
can be used to treat breast cancer as a monotherapy or in combina-
tion with the thermotherapy paclitaxel.
3.3. Nivolumab (fully human antibody)
A fully human mAb can be generated by display technologies
[25,26], transgenic animals [35,36], and human B cells [78–80].
Nivolumab (Opdivo) is a PD-1-targeted IgG4 human antibody cre-
ated from transgenic mice. In clinical applications, Nivolumab
treats patients with metastatic melanoma, metastatic squamous
cell or squamous non-small-cell lung carcinoma, and advanced
renal cell carcinoma as a monotherapy or in combination with Ipil-
imumab (Yervoy) [80]. The combination of Nivolumab and Ipili-
mumab improved the OS, PFS, and ORR in patients with
metastatic melanoma compared to Nivolumab alone.
3.4. Catumaxomab (bispecific antibody)
A Bispecific Antibody (BsAb) can recognize two distinct antigen
targets or epitopes simultaneously. BsAbs can be constructed by
employing quadroma technology (biological) that somatically
fuses two antibodies producing parent hybridomas into a hybrid-
hybridoma cell [81–84], chemical conjugation that uses a chemical
cross linker to couple different mAbs or fragments at their hinge
cysteine residues [84–87], or recombinant DNA technologies (ge-
netic) such as knobs-into-holes, leucine zippers, minibodies, dia-
bodies, and single chain structures [30,31,82,83]. Compared to
traditional mAbs, BsAbs are advantageous in redirecting immune
cells to tumor cells to maximize tumor killing, simultaneously
blocking two different antigens to prevent activation of deleterious
downstream pathways, increasing binding affinity, and avoiding
potential antigen-loss relapse. Catumaxomab (Removab) is a bis-
pecific antibody containing two binding specificities towards the
epithelial cell adhesion molecule (EpCAM) and the T-cell antigen
CD3 [30,31,88,89]. This BsAb is produced in a mouse-rat quadroma
that contains one mouse IgG2a heavy-light chain and one rat IgG2b
heavy-light chain.
4. Antibody-drug Conjugate (ADC)
In addition to monotherapy, mAbs can be conjugated with
highly potent chemotherapies to construct antibody-drug conju-
gates (ADCs) via the conjugation sites (e.g., free amines and thiols)
and a chemical linker [90,91]. Linkers with high stability in acidic
and protease-rich environments both extracellularly and intracel-
lularly have been developed, such as acid labile, reducible,
enzyme-cleavable, and peptide-based linkers. As effective anti-
cancer biopharmaceuticals, ADCs integrate the advantages of
mAbs, which can specifically bind a tumor associated surface
receptor and mediate cytotoxicity, with the potent cytotoxicity of
small molecule chemotherapeutics. The mAb enables an ADC cir-
culating through the bloodstream to bind the tumor specific sur-
face antigen. After binding, the ADC is internalized via receptor-
mediated endocytosis, a late endosome is formed, and lysosomal
degradation releases cytotoxic drug into the cytoplasm, ultimately
leading to cancer cell death [92]. Multiple ADCs have been devel-
oped to effectively treat cancers in clinics while minimizing side
effects in normal cells [93–99]. Here we use three FDA approved
ADCs as examples to describe the construction, anti-cancer mech-
anisms, and clinical applications of this mAb-directed therapy.
4.1. Gemtuzumab ozogamicin
Gemtuzumab ozogamicin (Mylotarg) has been developed to
treat CD33-positive acute myeloid leukemia (AML) [100–106]. This
 Y. Si et al. / Chinese Journal of Chemical Engineering 30 (2021) 301–307
ADC is composed of a humanized anti-CD33 IgG4 mAb (hP67.6)
and N-acetyl gamma calicheamicin, a DNA-binding cytotoxic
antibiotic, combined through an acid-cleavable hydrazone linker.
The utilization of the lysine attachment site on the mAb can syn-
thesize active hydrazone conjugates without oxidation of the car-
bohydrates. After targeting the surface CD33 receptor and
internalizing, the hydrazone linker is hydrolytically cleaved and
the potent payload is released intracellularly. The released N-
acetyl gamma calicheamicin dimethyl hydrazide induces double-
stranded DNA breaks and further leads to the apoptosis of cancer
cells. The clinical data demonstrated that the gemtuzumab
ozogamicin treatment group achieved event-free survival (EFS),
relapse-free survival (RFS) and OS of 40.8% (32.8–50.8), 50.3%
(41.0–61.6) and 53.2% (44.6–63.5), respectively, without severe
toxicity compared to EFS of 17.1% (10.8–27.1), RFS of 22.7%
(14.5–35.7) and OS of 41.9% (33.1–53.1) in control group [107].
4.2. Brentuximab vedotin
Brentuximab vedotin (Adcetris) is constructed by conjugating a
153-kDa chimeric anit-CD30 IgG1 antibody with monomethyl
auristatin E via a protease-cleavable linker with a drug-antibody
ratio of approximate 4 [108–111]. Brentuximab vedotin was devel-
oped to treat classical Hodgkin lymphoma, systemic anaplastic
large cell lymphoma, and any CD30-expressing peripheral T-cell
lymphomas. The mAb-delivered monomethyl auristatin E induces
cancer cell apoptosis and cell death by binding the microtubule
and disrupting its networks. Significant improvements in objective
response and survival benefit were observed in brentuximab vedo-
tin treated patients compared to conventional therapies [112]. For
instance, a Phase III clinical study with 128 enrolled patients
showed that the objective response rate lasting at least 4 months
(ORR4) was 56.3% in treatment group versus 12.5% in the conven-
tional physician’s choice group. The brentuximab vedotin also
extended the median progression-free survival to 17.2 months
from 3.5 months in control group.
4.3. Trastuzumab emtansine
Trastuzumab emtansine (Kadcyla) is constructed by conjugat-
ing a humanized anti-HER2 IgG1 mAb with a microtubule inhibi-
tory mertansine by a thioether chemical linker with a drug-
antibody ratio of about 3.5 to treat patients with HER2-positive
metastatic breast cancer [108,113–116]. After the initial binding
to the IV sub-domain of HER2 receptor, the ADC undergoes
receptor-mediated internalization and lysosomal degradation.
The cytotoxic small molecule released in breast cancer cells binds
tubulin, disrupts microtubule synthesis, and ultimately leads to
apoptosis and cell death. The clinical data showed that trastuzu-
mab emtansine treatment improved the median progression-free
survival of 6.2 (95% CI 5.59–6.87) with reduced incidence from
3.3 months (2.89–4.14) in control group [117].
5. Market Value and Technical Trend of mAb-based Therapies
With high therapeutic efficacy, mAbs have emerged as a major
targeted treatment strategy of cancers, where the global market
value of therapeutic mAbs was about 150 billion USD in 2019. Con-
sidering the numerous mAbs evaluated in clinical trials, the market
will continue to grow with an estimated value of 300 billion USD
by 2025 [7]. The ADCs-based cancer therapies have made promis-
ing progress over the past decade because of the combined thera-
peutic values. The development and modification of new drugs,
development of novel cancer-targeted mAbs (e.g. humanized
mAbs), and design of new linkers to improve plasma stability
305
and achieve controlled drug release in tumor could further advance
the ADCs technologies.
6. Conclusions
mAb has evolved as an important biopharmaceutical in targeted
anti-cancer delivery as monotherapy or as a conjugated therapy.
Multiple platforms or technologies of therapeutic antibody devel-
opment, including hybridoma technology, phage display, and
transgenic mice, have been developed. Various engineered anti-
bodies, such as chimeric, humanized, and fully human antibodies,
have been developed to overcome the limitation of murine anti-
bodies and are widely used in clinics. The other antibody-
facilitated targeted therapies, such as antibody-drug conjugates
and antibody tagged polymeric nanoparticles for drug delivery,
have also been rapidly developed.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgements
This work was supported by National Institutes of Health
R21CA226491-01A1 (X.M.L.), 1R01CA238273-01A1 (X.M.L.) and
1R01CA242917-01A1 (X.M.L.).
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