Short Communication
Emerging Highlights of Antibody Therapy in Oncology
Chen D*
Research Institute of Biological Medicine, Yiling Pharmaceutical, China
*Corresponding author: Daohong Chen, Research Institute of Biological Medicine, Yiling Pharmaceutical, Shijiazhuang, Hebei 050035, P.R. China
Published: 20 Jul, 2016
Cite this article as: Chen D. Emerging Highlights of
Antibody Therapy in Oncology. Clin
Oncol. 2016; 1: 1026.
Abstract
As a hallmark of biological medicine, monoclonal antibody (mAb) therapy has evolved into the mainstream treatment in clinical oncology at a relatively fast pace. Whereas a therapeutic mAb was traditionally designed to block signaling molecules driving malignant cell growth or tumor angiogenesis, mAb-based agents are currently explored further in comprehensive contexts of disease biology, including immune checkpoint blockade, antibody-drug conjugates, Fc region modification, bispecific antibody, among others. Herein, this article outlines an updated understanding of these emerging avenues derived from mAb platforms, which are coming up with better innovative medicines to fight cancer.
Introduction
Since the first monoclonal antibody (mAb)-bearing hybridoma was invented four decades ago
by Georges Kohler and Cesar Milstein [1], mAb-based therapeutic approaches have been going
through a long evolving journey, and then successfully translated from bench to beside, to play
an unique role in improving clinical outcomes particularly in the field of oncology. To date, more
than sixty mAb-derived drugs have been approved for clinical use of which the majority belongs to
oncology indications (en.wikipedia.org), and of note among the top ten best-selling drugs in 2015,
seven are biomedicines out of which five fell impressively into mAb category (www.biodiscover.com),
reflecting a dominating trend in the medical need-driven pharmaceutical innovation. Accordingly,
the technology of antibody production has been optimized beyond hybridoma generation, taking the
advantages of recombinant DNA engineering, immunoglobulin (Ig) humanization, phage display
and transgenic animals, to circumvent the challenges such as immunogenicity and affinity issues
[2,3]. Interestingly in recent years, mAb-based agents are being explored deeper in comprehensive
contexts of disease biology for delivering further therapeutic benefits to the patients, which appear
opening several avenues of great potentials for better medicines to emerge (Table 1).
Immune checkpoint blockade
Whereas mAb-based approaches have been previously developed to block secreting ligands or
cell surface receptors in the signaling pathways that drive cancer cell growth or tumor angiogenesis,
the renaissance of cancer immunology in recent years dramatically inspires oncology with several
immune checkpoint-targeting antibodies to deliver additional clinical benefits through relieving
immune suppression by the negatively regulatory pathways. The successes of blocking antibodies
(ipilimumab and pembrolizumab/nivolumab) against co-suppressing molecules cytotoxic
T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1),
respectively, in immune cells have validated a novel concept of checkpoint blockade to augment
anti-neoplasm immunity through neutralizing immune inhibitory signaling activities induced by
tumor cells [2,4]. The anti-CTLA-4 antibody ipilimumab was revealed to be able to prolong overall
survival in a fraction of the patients with metastatic melanoma, triggering the curiosity of search for
other immune-modulators as innovative medicines to fight cancer. In this regard, the anti-PD-1
antibody nivolumab has been subsequently demonstrated to confer efficacious clinical responses
in melanoma including some patients free from disease progression for years, while causing less
autoimmunity-associated adverse events than ipilimumab [3-5]. Moreover, nivolumab is also
approved for therapeutic application in non-small cell lung cancer (NSCL) and renal carcinoma,
suggesting extensive anti-tumor roles [5]. Most recently, according to the breaking news from Bio-
World Today, an anti-PD-ligand1 (PD-L1) antibody atezolizumab has just been approved by Food
Drug Administration (FDA) of USA to treat advanced bladder cancer. In this light, it is anticipated
that the above approved antibodies will be tested in a broader spectrum of cancer types to expand
their clinical indications. Meanwhile, following newer immune co-regulatory molecules to be
identified more checkpoint modulating mAbs are going to come forth accordingly.
Antibody-drug conjugate
Historically, cytotoxic medicines played a substantial role in
controlling tumor progression and are particularly efficacious in
certain types of hematological malignancies, through killing rapidly
dividing (cancer) cells by means of inhibiting DNA synthesis or the
related enzymes. Unfortunately, some normal cells, for example
bone marrow and hair cells in the body, also divide very rapidly and
were coincidently affected, resulting in severe adverse effects [3].
One possible solution for this problem is to conjugate certain potent
cytotoxic compounds to tumor-specific antibodies, which has been
termed antibody-drug conjugates (ADCs), thereby directing the
cytotoxic effects to be concentrated on cancer cells while improving
the pharmacokinetic profile of these compounds such as the long halflife
time upon binding to a large protein like Ig. Currently, there are
over fifty ADCs targeting numerous tumors in clinical development
ranging from phase one to phase three, beyond which two of them
have been approved for use in oncologic patients [6,7]. Brentuximab
vedotin was designed to conjugate the anti-CD30 mAb with a highly
potent tubulin inhibitor, for treating conventional drug-resistant
CD30+ Hodgkin lymphoma (HL), and revealed to significantly
improve response rates and progression free duration of the HL
patients [8]. On the other hand, trastuzumab emtansine, consisting
of the anti-Her2 mAb (trastuzumab) conjugated with a tubulin
inhibitor (emtansine), has been demonstrated to be efficacious
against the trastuzumab-resistant Her2+ breast cancer patients with
better progression free and overall survival [3,6]. As such, ADCs can
inhibit the growth of cancer cells expressing a selective antigen at a
lower dosing of cytotoxic agents, and thus result in fewer systemic
adverse events. Upon upgrading the technology such as optimized
molecular linkers and minimized off-target effects, more ADCs will
reach the clinic to deliver further therapeutic benefits to the patients
in oncology, particularly those with refractory cancer.
Third-generation antibody
The first-generation mAbs were produced from mouse B-cell
hybridomas, and can be recognized by human body defensive system
as foreign proteins to mount immune responses against murine Ig,
thus resulting in immunity-associated side effect and short half-life
time in plasma. To deal with these challenges, the second-generation
of therapeutic mAbs has come up with higher target antigen
affinity and lower immunogenicity through genetic engineering
to generate the Ab variants with human or humanized amino acid
sequences. Recently to fully exploit biological potentials of a whole
Ig molecule in the in vivo physiological contexts, there have been
over twenty mAbs of the third generation in development through
Fc region modification or/and glyco-manipulation to augment the
cellular immune activities such as antibody-dependent cell-mediated
cytotoxicity (ADCC). For example, the V158 site of IgGFcRIIIa,
and defucosylated/low fucosylated mAbs have been identified to
bind to the Fc receptor on immune cells such as natural killer cells
with higher affinity which in turn induce stronger ADCC [9,10].
Mogamulizumab, a defucosylated anti-CC chemokine receptor
4 (CCR4) mAb, has achieved the clinical success as evidenced by
conferring an impressive therapeutic response rate and extending the
overall survival in the patients with acute T-cell leukemia/lymphoma.
Later on, a Fc region-modified anti-CD20 mAb obinutuzumab has
also been approved to treat drug-resistant chronic lymphocytic
leukemia/lymphoma, upon delivering much better response rate and
progression free survival than the old generation mAb rituximab
[11]. Thus, being superior to small chemical compounds in this case
therapeutic mAbs can not only block the signaling pathways driving
tumor growth, but also simultaneously motivate several components
of body’s defense system to fight cancer. It is quite plausible that
comprehensive characterization of the functional sites and posttranslational
situations of the IgG Fc region will inspire more third
generation mAbs to overcome resistance to those of the second
generation.
Bispecific antibody
Although in contrast to small chemical compounds therapeutic
antibodies have a few superior properties such as prolonged half-lives
in plasma and highly molecule-targeting specificity with minimized
off-target toxicity, there are several limitations for mAb agents.
A number of severe diseases like cancer usually involve multiple
biological pathways in the pathogenesis, and thus single-targeted
therapy may not be able to deliver the ideal clinical benefits. Even
if certain groups of patients showed an impressive response to
single pathway-blocking-based treatment initially, the majority of
them relapsed due to the drug resistance resulted from target gene
mutation(s) or/and alternative signaling pathway activation [3].
To address this issue, one possible approach is bispecific antibody
(BsAb) therapy which has recently achieved some clinical success
[12]. Blinatumomab, a T-lymphocyte-engaging BsAb simultaneously
binding CD3-positive cytotoxic T cells and CD19-positive malignant
cells, has been approved to treat relapsed/refractory B-acute
lymphoblastic leukemia based on a responsive rate of 43% in a
phase 2 clinical trial after 2 cycles of the treatment [13]. In addition,
catumaxomab, targeting EpCAM and CD3, is clinically available
for the indications of EpCAM-positive tumors with malignant
ascites, and particularly efficacious in treating peritoneal spread
of gastrointestinal or gynecologic neoplasms [12]. Currently there
are over 20 therapeutic BsAbs in the clinical trials [12], which will
hopefully bring fresh waves of therapeutic benefits to the patients
with a variety of tumor types in the coming years.
New strategy of combination
Although the etiology of neoplasm is yet to be precisely
deciphered, it has been well documented that onco-pathogenesis
is orchestrated through complex processes of multiple biological
pathways in a dynamic manner, going beyond malignant cells to
involve stromal components and even systemic factors [14], which
underscores a rationale for combinational regimens-based therapy.
One traditional protocol of combinational therapy was composed of
a cytotoxic medicine plus a therapeutic mAb, such as 5-fluorouracil
plus bevacizumab for colon cancer and doxorubicin plus trastuzumab
for Her2+ breast cancer, in which the mAbs were added to enhance
the direct killing malignant cells by the small chemical compounds.
Interestingly in recent years, combinational strategies are also being
extended to more comprehensive contexts of the disease biology,
to improve the therapeutic efficacy via augmenting anti-tumor
immunity. Combination of nivolumab and ipilimumab for immune
checkpoint blockade in patients with metastatic melanoma raised the
response rate to 61% dramatically, which was much higher than that
of using each mAb alone [15]. Alternatively in case of increased sideeffects
and toxicities resulting from autoimmunity upon combined
blocking of the immune co-inhibitors, one of hopeful options to
circumvent this issue has been proposed to combine nivolumab or
ipilimumab with an immune co-stimulatory mAb such as that of
inducing OX40 receptor [5]. Intriguingly, some cytotoxic compounds
were serendipitously noticed to exert certain positive regulatory effects
on the immune environment at low dosages. Cyclophosphamide and
doxorubicin up-regulate anti-cancer immune responses to eliminate
malignant cells, through enhancing immunogenicity or lowering
Fox3p+/CD8+ ratio in tumor-infiltrating lymphocytes, while
sunitinib blocks STAT3 to diminish myeloid-derived suppressor cell
(MDSCs) and negatively regulatory T (Treg) cells, and bevacizumab
promotes dendritic cell (DC) maturation for antigen-presentation
to prime anti-cancer immune activities [5,16]. In corollary, there
have been several on-going clinical trials that combine immune
checkpoint mAbs with these cytotoxic compounds to boost the antitumor
immunity-resulted therapeutic efficacy [5].
Table 1
Conclusion
The last two decades have witnessed a dramatic translation of mAb platform from a scientific breakthrough to a mainstream therapy in clinical oncology. Whereas the technology of antibody production has been modernized due to a series of impressive progresses in molecular and cellular biology during this period of time to meet the standards of pharmaceutical industry, the emerging waves of efforts are recently being made on further exploiting the functional potentials of a full antibody molecule and its derivates in comprehensive pathobiological contexts in vivo, including immune checkpoint blockade, ADC, Fc region modification, BsAb, new strategies of combinational therapy, among others. It is highly expected that more and better innovational medicines will be developed following the earlier successes from these recently highlighted avenues, to continuously address the unmet clinical needs of oncology in the era of precision medicine.
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