Antibody-Drug Conjugates
Guided
Missiles Deployed To Fight Cancer
They’re here. Antibody-drug
conjugates, target-seeking molecular missiles with lethal payloads, have
arrived.
Introduction
The
advent of modern-day cancer chemotherapy dates back to the mid-1900s when a
chemical warfare agent known as nitrogen mustard was seen to destroy the bone
marrow and lymph tissue of exposed individuals. In the following years,
nitrogen mustard, along with numerous other alkylating agents took center stage
in the treatment of various haematological malignancies including leukaemia,
lymphoma, Hodgkin's disease and multiple myeloma. Several other serendipitous
observations lead to the development of the first primitive classes of cytotoxins.
Despite vast progress in the field of cancer chemotherapy, small-molecule
cancer drugs (although highly potent) continue to be plagued with the problems
of non-specific toxicity (as a result of targeting all rapidly dividing cells),
narrow therapeutic windows and increasing resistance rates. These concerns
emphasize the need to move away from conventional cancer treatments and explore
new ways to tackle the ever-present disease.
What Are Antibody-Drug Conjugates?
Cancer cells differ from
normal cells due to genomic mutations in oncogenes and/or tumour suppressor
genes. Once the integrity of the genome is compromised, cells are more likely
to develop additional genetic faults, some of which may give rise to tumor-specific
antigens (found only on the surface of tumor cells) or tumor-associated antigens
(overexpressed on tumor cells, but also present on normal cells). Ongoing
research has found that several human cancers express unique tumour-specific or
tumour-associated cell surface antigens which are of great value as targets for
large molecule, monoclonal antibody (mAb)-based therapy.
The use of antibodies as
‘magic bullets’ to treat disease was first proposed more than 100 years ago by
the founder of chemotherapy, Paul Ehrlich]. Due to several challenges in the
development of human antibodies, it was only in 1997 that the US FDA (Food and
Drug Administration) approved the first anti-cancer antibody, rituximab, for
the treatment of B-cell non-Hodgkin’s lymphoma. Early mAbs were based on murine
or chimeric antibodies that were modified to target human antigens. As these
were non-human antibodies, they evoked a strong immune response that prevented
the treatment from being successful. The large size of the mAbs also proved to
be problematic as it resulted in reduced tumour penetration and poor
therapeutic effect. Since then, several advances in antibody engineering have
optimized pharmacokinetics and effector function while reducing immunogenicity.
This has resulted in a significant increase in the development of
antibody-based drugs against cancer.
mAbs exert their
therapeutic effect by binding to tumor specific or tumor-associated cell
surface antigens. Once bound, the mAb kills the tumor cell by one or more of
the following mechanisms; abrogation of tumor cell signalllng, resulting in
apoptosis modulation of T-cell function through antibody-dependent cellular
cytotoxicity (ADCC), complement dependent cytotoxicity (CDC) or
complement-dependent cell mediated cytotoxicity (CDCC) and exertion of
inhibitory effects on tumor vasculature and stroma. Despite these various
cell-killing mechanisms, most mAbs display insufficient cytotoxic activity.
Current efforts in cancer treatment have therefore focused on combining the
selectivity of mAbs with the potency of chemotherapeutic small molecules,
giving rise to an entirely new class of anti-cancer drugs known as antibody-drug
conjugates (ADCs).
Antibody-drug
Conjugates or ADCs are empowered
antibodies (mAbs) designed to harness the targeting ability of
monoclonal antibodies by linking them to cell-killing agents. An ideal ADC
has:
- A highly selective monoclonal antibody (mAb)
for a tumor-associated antigen that has restricted or no expression on
normal (healthy) cells;
- A potent cytotoxic agent (generally a small
molecule drug with a high systemic toxicity) designed to induce target
cell death after being internalized in the tumor cell and released;
- A linker that is stable in circulation, but
releases the cytotoxic agent in target cells.
Antibody-drug
Conjugates
- Covalently linked monoclonal antibodies to
small molecule drugs that target the a specific cancer cell reduce
systemic toxicity
- Increase the cell-killing potential of
monoclonal antibodies (mAbs), and
- Confer higher tumor selectivity. As a
result, the tolerability of the drug increases.
- Compared to standard chemotherapeutic drugs
or biologics, there is limited systemic exposure
An Innovative
Therapeutic Application
Antibody-drug conjugates
or ADCs represent an innovative therapeutic application that combines the
unique, high specificity, properties and antitumor activity of monoclonal
antibodies (mAbs) that are tumor-specific but not sufficiently cytotoxic,
with the potent cell killing activity of cytotoxic small molecule drugs that
are too toxic to be used on their own. In linking monoclonal antibodies with
cytotoxic agents, scientists have been able to optimize the features of both
components.
The key components of
antibody-drug conjugates include a monoclonal antibody, a stable linker and a
cytotoxic agent to target a variety of cancers. The cytotoxic (anticancer) drug
is chemically linked (conjugated using disulfide or non-cleavable
thioether linker chemistry) to a monoclonal antibody that recognizes a
specific tumor-associated antigen, making the drug combination very specific.
In simple terms, antibody-drug conjugates deliver “deactivated” cytotoxins to specific cancer cells. Once in the tumor
cell – internalization – the cytotoxin is released after which it regains its
full – cancer killing – cytotoxic activity. In turn, this leads to rapid cell
death.
While the concept of
antibody-drug conjugates is relatively easy to understand and relatively
straightforward, the design and synthesis of a fully functional and effective
antibody-drug conjugate is remarkably challenging, often requiring specialized
development teams.
Although the concept of
ADCs is theoretically simple, it is difficult to combine its various components
into an optimized and functional therapeutic agent. To date, three ADCs have
gained entry into the market, of which only two remain. The first ADC to obtain
FDA approval was gemtuzumab ozogamicin (Mylotarg®), marketed by Wyeth (now
Pfizer), for the treatment of relapsed acute myeloid leukaemia (AML). In 2010,
a decade after its approval, gemtuzumab ozogamicin was withdrawn from the
market when a clinical trial showed that it had little benefit over conventional
cancer therapies and was associated with serious hepatotoxicity. This could
have been due to the fact that the linker technology used was not stable enough
to prevent the drug from being released in the bloodstream.
The two ADCs currently in
the market are brentuximab vedotin (Adcetris® by Seattle Genetics) and
trastuzumab emtansine (TDM1; Kadcyla® by Genentech). The former is the first of
the two ADCs to be approved and is currently being used to treat patients with
relapsed or refractory Hodgkin’s lymphoma or those with relapsed or refractory
systemic anaplastic large cell lymphoma. The more recent approval of T-DM1, in
2014, for use against breast cancer, proved that ADCs were capable of targeting
solid tumors in addition to haematological malignancies. Although there are
only 2 ADCs currently in the market, there are more than 30 ADCs being
developed to target a wide range of blood cancers and solid tumors. In contrast
with small molecules that have a limited choice of drug targets, the diverse
range of ADC targets results in a robust drug pipeline with minimal overlap
between different pharmaceutical companies. With the recent FDA approvals of
brentuximab vedotin and T-DM1, there has been an increase in research investigating
the use of ADCs in the treatment of cancer.
The Make-up of an ADC
Monoclonal antibodies
are attached to biologically active drugs by chemical linkers with labile
bonds. By combining the unique targeting of mAbs with the cancer-killing
ability of cytotoxic drugs, antibody-drug conjugates allow sensitive discrimination
between healthy and diseased tissue. Antibody-drug conjugates are part of
a specialized
and technically challenging type of therapy combining
innovations from biotechnology and chemistry to form a new class of highly
potent biopharmaceutical drugs. The
unique property of antibody-drug conjugates is that these so-called armed
antibodies selectively dispatch highly potent cytotoxic anticancer
chemotherapies directly to cancer cells while, at the same time, leaving healthy
tissue unaffected.
Availability
With the approvals of brentuximab
vedotin (Adcetris®; Seattle Genetics/Millennium Pharmaceuticals)
and ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche) and more
than 50 ADCs in clinical trial pipelines, ADCs are a new drug class.
Owing to improved technology and appropriate targeting, the clinical
application of ADCs is accelerating rapidly.
Conventional
chemotherapy is designed to eliminate fast -growing tumor cells. It can
however, also harm healthy proliferating cells, which causes undesirable side
effects. [In contrast, ADCs are designed to increase the efficacy of therapy
and reduce systemic toxicity, often seen with small molecule drugs.
Linker technology
Advances in linker
technology needed to attach monoclonal antibodies to cytotoxic anticancer
agents to allow control over drug pharmacokinetics and significantly improve
delivery of a cytotoxic agent to cancer cells.
A stable link between
the antibody and cytotoxic (anti-cancer) agent is a crucial aspect of an ADC.
Linkers are based on chemical motifs including disulfides, hydrazones or
peptides (cleavable), or thioethers (noncleavable) and control the distribution
and delivery of the cytotoxic agent to the target cell. Cleavable and
noncleavable types of linkers have been proven to be safe in preclinical and
clinical trials. Brentuximab vedotin includes an
enzyme-sensitive cleavable linker that delivers the potent and highly
toxic antimicrotubule agent monomethyl auristatin E or MMAE, a
synthetic antineoplastic agent, to human specific CD30-positive malignant
cells. Because of its high toxicity MMAE, which inhibits cell division by
blocking the polymerization of tubulin, cannot be used as a single-agent
chemotherapeutic drug. However, the combination of MMAE linked to an anti-CD30
monoclonal antibody (cAC10, a cell membrane protein of the tumor necrosis factoror TNF receptor)
proved to be stable in extracellular fluid, cleavable by cathepsin and safe for
therapy. Trastuzumab emtansine, the other approved
ADC, is a combination of the microtubule-formation inhibitor mertansine (DM-1),
a derivative of the Maytansine, and antibody trastuzumab (Herceptin/
Genentech/Roche) attached by a stable, non-cleavable linker.
The availability of
better and more stable linkers has changed the function of the chemical bond.
The type of linker, cleavable or noncleavable, lends specific
properties to the cytotoxic (anti-cancer) drug. For example, a non-cleavable linker
keeps the drug within the cell. As a result, the entire antibody, linker and
cytotoxic (anti-cancer) agent enter the targeted cancer cell where the antibody
is degraded to the level of an amino acid. The resulting complex – amino acid,
linker and cytotoxic agent – now becomes the active drug. In contrast, cleavable
linkers are catalyzed by enzymes in the cancer cell where it releases the
cytotoxic agent. The difference is that the cytotoxic payload delivered via a
cleavable linker can escape from the targeted cell and, in a process called
“bystander killing,” attack neighboring cancer cells.
Another
type of cleavable linker, currently in development, adds an extra molecule
between the cytotoxic drug and the cleavage site. This linker technology allows
researchers to create ADCs with more flexibility without worrying about
changing cleavage kinetics. Researchers are also developing a new method of
peptide cleavage based on Edman
degradation, a method of sequencing amino acids in a peptide. Future direction in the development of ADCs
also include the development of site-specific conjugation (TDCs) to further
improve stability and therapeutic index and α emitting immunoconjugates and
antibody-conjugated nanoparticles.
How they work
The antibody-drug conjugate is a three-component system including a potent cytotoxic anticancer agent linked via a
biodegradable linker to an antibody. The antibody binds to specific markers
(antigens or receptors) at the surface of the cancer cell. The whole
antibody-drug conjugate is then internalized within the cancer cell, where the
linker is degraded and the active drug released.
The focused delivery of
the cytotoxic agent to the tumor cell is designed to maximize the anti-tumor
effect of ADCs, while minimizing its normal tissue exposure, potentially
leading to an improved therapeutic index.
Mechanism of action
In developing
antibody-drug conjugates, an anticancer drug (e.g. a cell toxin or cytotoxin)
is coupled to an antibody that specifically targets a certain tumor marker
(e.g. a protein that, ideally, is only to be found in or on tumor cells).
Antibodies track these proteins down in the body and attach themselves to the
surface of cancer cells. The biochemical reaction between the antibody and the
target protein (antigen) triggers a signal in the tumor cell, which then
absorbs or internalizes the antibody together with the cytotoxin. After the ADC is internalized, the cytotoxic
drug is released and kills the cancer. Due to
this targeting, ideally the drug has lower side effects and gives a wider therapeutic window than other
chemotherapeutic agents.
An ideal ADC is one that
retains the selectivity and killing capacity of a mAb while still being able to
release the cytotoxic drug in quantities large enough to kill tumor cells. Each
of the steps involved in the mechanism of action is associated with unique
challenges that complicate the design of ADCs.
See Fig. 1 below:
ADCs are administered
intravenously in order to prevent the mAb from being destroyed by gastric acids
and proteolytic enzymes. The mAb component of the ADC enables it to circulate
in the bloodstream until it finds and binds to tumor-specific (or tumor-associated)
cell surface antigens present on target cancer cells. In the interest of
preventing unwarranted release of the cytotoxin and maximizing drug delivery to
cancer cells, an ideal linker would not only have to be stable in the
bloodstream but also capable of releasing the active form of the cytotoxic drug
when required.
Once the mAb component
of the ADC is bound to its target antigen, the ADC–antigen complex should
theoretically be internalized via receptor-mediated endocytosis. The
internalization process finishes with the formation of a clathrin-coated early
endosome containing the ADC–antigen complex. An influx of H + ions into the
endosome results in an acidic environment that facilitates the interaction
between the mAb component of a fraction of ADCs and human neonatal Fc receptors
(FcRns). The bound ADCs are transported outside the cell, where the
physiological pH of 7.4 enables the release of the ADC from the FcRn. This mechanism
acts as a buffer for preventing the death of healthy cells in the case of ADC
mis-delivery. Excessive binding of ADCs to tumor cell FcRns might however
restrict the release of the cytotoxic drug and prevent the ADC from taking
effect. FcRn expression is primarily within the endosomes of endothelial cells.
ADCs
that remain in the endosome without binding to FcRn receptors form the late
endosome. These subsequently undergo lysosomal degradation, allowing the
release of the cytotoxic drug into the cytoplasm. At this stage, it is crucial
to ensure that a sufficient (i.e. threshold) concentration of the drug is
present within the cancer cell for its destruction to be guaranteed. This is
however complicated in practice by the facts that cell-surface antigens are
often quite limited and the process of internalization, rather inefficient.
Assuming all the steps involved in the mechanism of ADC action have an
efficiency of 50 %, only 1 %–2 % of the administered drug will reach tumor
cells. This makes the choice of cytotoxin particularly important, as it is
required to be highly efficacious at very low concentrations. Drugs that are
usually unsuitable for normal chemotherapy (due to excessive toxicity) are
therefore a necessary component of ADCs.
Different classes of
cytotoxic drugs result in cell death using various mechanisms. The common
element between all the classes is interference with critical cell functioning
and, as a consequence, either direct killing of the cell or induction of apoptosis.
As targeted cancer cells die, there is potential for the active cytotoxic drug
to kill neighbouring tumor cells and the supporting stromal tissue. The design
of ADCs with respect to the choice of target, mAb, linker and cytotoxin are all
very important determinants of whether or not the threshold concentration of
the cytotoxic drug is reached within the tumor cell. These factors therefore
determine the overall success of an ADC.
Target Antigen
Selection
Successful development of an ADC is dependent on the selection of an
appropriate target antigen to which the mAb component of the ADC can bind.
Aside from being tumor-specific or tumor associated, cell surface antigens
should also undergo efficient internalization, have high levels of expression
and possess high penetrance, a characteristic whereby a large percentage of
tumour samples test positive for the presence of the antigen. The target of
gemtuzumab ozogamicin, an ADC previously used against AML, was cluster
designation 33 (CD33), a transmembrane cell-surface glycoprotein expressed on
the surface of mature and immature myeloid cells. CD33 has extremely high
penetrance with 90 %– 95 % of all AML patients testing positive for the
antigen. With regard to tumor specificity and sensitivity however, CD33
performed rather poorly as it was found to have only low levels of expression on
not only on mature and immature myeloid cells but also erythroid cells,
megakaryocytes and multipotent progenitor cells. Current ADCs aim to execute
their therapeutic action by identifying target antigens that fulfill all four of
their requirements.
Types of Tumor-Associated
Antigens
Although cell-surface proteins are the most commonly used targets for
ADCs, there are various other categories of tumor associated antigens including
glycoproteins, proteins of the extracellular matrix and aberrant gangliosides
on the tumor cell surface. Apart from antigens found on tumor cells, there is a
growing interest in targeting antigens present on tissues that support the
growth and spread of tumor cells such as neovasculature or extracellular
stromal tissue. This is particularly attractive as these tissues have a stable
genome unlike cancer cells and are therefore less likely to undergo somatic
mutations, reducing the risk of mutation-mediated drug resistance.
Instead, non-tumor tissue targets differentiate themselves from healthy
tissue by being in an undeveloped state as a result of their rapid formation
and turnover rate.
ADCs that bind to neovasculature destroy the tumor blood supply and cause
tumor cell death via nutrient deprivation and hypoxia. Potential targets in
tumor vasculature include vascular endothelial growth factor (VEGF) and its
receptors integrin and endoglin. ADCs that target and destroy extracellular
stromal tissue cause tumor cell death by reducing the concentration of growth
factors produced by stroma. Similar to tumor vasculature, these growth factors
are critical in promoting tumor cell survival. Examples of anti-tumour stromal
targets include fibroblast activation protein (FAP) and protein tyrosine kinase
7 (Ptk 7), a pseudokinase enzyme commonly found on many cancer and stromal
cells. Since all tumours depend on angiogenesis and stromal factors for their
survival and growth, ADCs that target such tissues have a wider efficacy.
Choosing Monoclonal
Antibodies
mAbs allow ADCs to have high target-specificity, target-affinity and prolonged
drug exposure at the tumor site. Based on these features, antibody selection
should ideally ensure minimal cross reactivity with healthy tissues,
sub-nanomolar affinity to the target antigen and a long pharmacokinetic
half-life combined with minimal immunogenicity. Over time, these features
result in the accumulation of the ADC at the tumor site and allow it to have an
increased therapeutic effect. In addition, it is beneficial for the mAb to
possess intrinsic anti-tumor activity resulting from either direct modulation
of the biological activity of the target antigen (e.g., anti-HER2 mAbs) [80]
and/or via immune effector functions such as ADCC, CDC and CDCC. When
constructing the ideal ADC, it is important to maximally preserve the favorable
properties of the mAb. With regard to tumor specificity and target affinity, it
is important to choose a mAb that does not lose these features through
non-specific binding to normal cells. Apart from being toxic to healthy tissue,
an antibody lacking tumor specificity may be eliminated from the circulation
due to immunogenicity, leading to sub-optimal target exposure and decreased
therapeutic effect. The complementarity-determining regions of an antibody
(i.e. the antigen-binding sites) should have extremely high (preferably
sub-nanomolar) target affinity in order to guarantee efficient internalization.
A major benefit of using mAbs and mAb-based drugs, such as ADCs, is their
favorable pharmacokinetics with respect to distribution, metabolism and
elimination in comparison with small molecule cancer therapies. Once mAbs are
administered into the bloodstream, they can distribute into cancer tissue
either via extravasation through pores in the endothelium or via pinocytosis
through endothelial cells following a diffusion gradient [89]. The distribution
of the ADC (and hence the cytotoxic drug) into tumor tissues is limited by the
size of the antibody, which represents more than 90 % of the mass of an ADC.
Specificity and
efficacy
The efficacy of
antibody-targeted chemotherapy greatly depends on the specific binding of the
targeting antibody-drug conjugate to the specific tumor antigen and on the
internalization of the antigen-antibody complex to ensure focused delivery of
the conjugated cytotoxic agent inside tumor cells.
The focused delivery of
the cytotoxic agent to tumor cells maximizes the antitumor effect. It also
minimizes normal tissue exposure that results in an improved therapeutic index
and less damage to the surrounding, healthy tissue.
Antibody affinity
The monoclonal antibody
affinity, the strength with which an antibody binds to an epitope (antigenic
determinant), to the selected antigen is an important factor in ADCs. So-called
high-affinity antibodies may have a greater uptake, increasing the therapeutic
advantage. However, while the uptake by
the ‘outer layer’ of antigen-positive cells may be higher, the penetration and
distribution throughout a ‘bulky tumors’ may be reduced.
Conjugation Chemistry
In recent years, a great
deal of research has been conducted in order to develop novel conjugation
techniques for use in future ADCs. Traditionally, cytotoxic drugs have
undergone chemical conjugation to mAbs, whereby reactive portions of native
amino acids are made to interact and bind a specific part of the linker
molecule. Examples of reactive groups include the epsilonamino end of lysine
residues (used in the conjugation of T-DM1) and the thiol side chains present
in the partially reduced form of cysteine residues (used in brentuximab
vedotin). As this technique relies on native amino acids, conjugation of the
drug is limited by the peptide sequence of the antibody, which therefore
restricts control over the number and position of attached cytotoxic drugs. The
resulting heterogenous ADC mixture is a major drawback to the chemical
conjugation technique as it impacts the toxicity, stability and potency of the
ADC. Heterogeneity, with respect to the number of cytotoxin molecules attached
per antibody (Figure 5), results in only a small portion of the prepared ADC
solution being therapeutically active. This is because a subset of ADCs will
contain too few cytotoxin molecules to retain their cell-killing capacity
whereas others will have too many to maintain their stability in the
bloodstream. Furthermore, inactive ADCs directly decrease ADC potency by
binding the limited number of target antigens available on tumor cells and
blocking the binding of therapeutically-active ADCs.
Cytotoxic drugs
There are thousands of
cellular toxins from either natural sources or chemical synthesis, but only a
very few are suitable as components for use in an Antibody-drug Conjugate
(ADCs). In the development of early ADCs, researchers used clinically
approved chemotherapeutic drugs. One reason is that these agents were
readily available and their toxicological properties were well known.
However, these early
ADCs were only moderately potent and generally less cytotoxic for the
targeted tumor cells than the corresponding unconjugated agents.
To solve this problem,
scientists started to look at compounds found to be too toxic when tested
as a stand-alone chemotherapeutic agent. But the number of these high potent
toxins, generally 100 to 1,000 times more toxic than traditional anticancer
agents, and are stable, is quite limited.
As ADCs are most often
prepared in an aqueous solution and administered intravenously, it is important
that the cytotoxic drug has prolonged stability in such environments to prevent
damage to healthy cells and increase the availability of the drug at the tumor
site. Similarly, it is important that the molecular structure of the cytotoxin
allows for its conjugation to the linker while avoiding immunogenicity,
maintaining the internalization rate of the mAb and promoting its anti-tumor
effects.
Typically, the
cytotoxins used in ADCs are a 100–1000 times more potent than regular
chemotherapeutics and preferably have sub-nanomolar potency. Most classes of
cytotoxins act to inhibit cell division and are classified based on their
mechanism of action. Since many ADCs utilize cytotoxins that target rapidly
dividing cells, there is a decreased risk of unwanted toxicity if the ADC
mistakenly delivers the drug to a non-replicating cell. As the cytotoxin is
most commonly released in the lysosome following cleavage of the linker
molecule, it is important to ensure that the cytotoxin remains stable in low pH
environments and has the capacity to move into the cytosolic or nuclear
compartments of the cell within which it takes effect. The choice of the
specific cytotoxin to be used in an ADC depends on its mechanism of action and
the type of cancer.
Among these are highly potent, biologically active anti-microtubule agents,
alkylating agents and DNA minor groove binding agents are being used in
combination to humanized mAb targeting agents. These drugs are biologically
active at the ng/Kg level placing them in the most potent class of advanced
cancer drugs.
ADCs in Development
Many lessons have been
learnt since the FDA withdrawal of gemtuzumab ozogamicin regarding the design
and development of ADC components. Pharmaceutical companies investing in ADC
research have made significant advances in linker technology, conjugation
chemistry, antibody engineering and the identification of potent cytotoxins,
resulting in rapid evolution of the field. This has not only led to the recent
approvals of brentuximab vedotin and trastuzumab emtansine but has also driven
the clinical development of ADCs. Currently approved ADCs and those in advanced
clinical development are listed in the table below:
Antibody-drug Conjugates
combine the unique targeting capabilities of monoclonal antibodies (mAbs) with
the specific cancer killing ability of cytotoxic drugs. By attaching
biologically active chemotherapeutic drugs, radioactive isotopes, cytokines or
cytotoxins via chemical linkers with liable bonds to a monoclonal antibody
directed to antigens differentially overexpressed in tumor cells, ADCs
significantly improve sensitive discrimination between healthy and diseased
tissue. Anitibody-drug Conjugates are part of a specialized subset of highly
potent active pharmaceutical ingredients (APIs).
Over the past decade
pharmaceutical companies have started to commercialize antibody-drug
conjugates. Today, about 50 molecules are in clinical development. Of these,
approximately 25% are in Phase II or Phase III of development, leading to a
rapidly expanding pre-clinical pipeline. With nearly 190+ active clinical
trials, antibody-drug conjugates are gaining acceptance across the globe as
they offer superior pharmacological efficiency along with minimized side
effects.
Manufacturing
In order to be effective naked, unconjugated, therapeutic monoclonal antibodies
or TMAs used in the treatment of human disease, require significant quantities
as well as multiple treatments. Clinical evidence shows that antibody-drug
conjugates require a lower doses to be effective.
Both
naked antibodies as well as antibody-drug conjugates are approved for
manufacture in mammalian expression and bioreactor systems, which require
expensive upstream and downstream processes. In addition, the production of
antibody-drug conjugates involves additional, specialized, technologies –
including chemical conjugation steps – complicating production streams. These
factors result in the outsourcing of 70%-80% of all ADC manufacturing to a
limited number of specialized contract manufacturers or CMOs capable of
manufacturing monoclonal antibodies, linkers and cytotoxins. In addition,
even fewer CMOs have the ability to provide specific conjugation services
required to manufacture the actual ADC.
Global Antibody-Drug Market
The global
next-generation antibody therapeutics market was worth $ 1,328.3 million in
2014, and it is expected to grow at a CAGR of 44% during 2015-2020.
Next-generation antibody therapeutics market is escalating with high growth
rate due to growing prevalence of chronic diseases. Some of the major reasons
leading to increase in number of chronic disease cases include unhealthy
lifestyle, poor diet, and addictions, such as smoking, and others. In addition,
various pharmaceutical and biotechnology companies are collaborating with other
companies and organizations for R&D of next-generation antibody
therapeutics which further drives the market of next-generation antibody
therapeutics.
The next-generation
antibody therapeutics industry has made huge growth in the recent years. The
growing healthcare expenditure has increased the overall research and
development investment by various organizations. This leads to the growth of
global next-generation antibody therapeutics market. The
Autoimmune/Inflammatory market is growing at an average annual growth rate of over
46.4%. The Fc Engineered Antibodies market on the other hand grew at a CAGR of
56.8% during 2015-2020.
The restraints
associated with next-generation antibody therapeutics market include high cost,
stringent regulatory requirements and time consuming approval process of drugs.
A significant capital investment is required for the research and
manufacturing of next-generation therapeutics. The manufacturing process of
next-generation antibody therapeutics is very complex, as it requires
specialized equipment and careful handling techniques. Next-generation antibody
therapeutics is a biologic product, and thus requires specific downstream
process for their production. This leads to the high cost of manufacturing
next-generation antibody therapeutics.
Different countries have
distinct regulatory requirements for launching a product in the market. Strict
regulatory requirements and extended approval time hinders the market for
next-generation antibody therapeutics.
The key companies
operating in the global next-generation antibody therapeutics market include F.
Hoffmann-La Roche Ltd, Seattle Genetics Inc., Pfizer Inc., ImmunoGen Inc.,
Amgen Inc., Biogen, Kyowa Hakko Kirin Co. Ltd., Xencor Inc., Bristol-Myers
Squibb Company, AstraZeneca PLC., Dyax Corp., Takeda Pharmaceuticals Company
Limited and Bayer AG.
Conclusion
The major challenges
associated with the development of ADCs arise from factors that interfere with
ADC efficacy and/or those that result in ADC-mediated non-target cell toxicity.
All three components of an ADC contribute to these challenges and need to be
optimized to create a successful conjugate. Once the therapeutic effect of an
ADC has been maximized, it is also desirable to prolong these effects by
avoiding resistance mechanisms that decrease the duration of ADC efficacy. All
targeted cancer therapies (including ADCs) are prone to resistance mechanisms
that alter the function of the target antigen and render the treatment
redundant. The future of ADCs will mainly depend on our ability to tackle these
challenges.
Despite
complexities in designing ADCs, the promise of this therapeutic class has
generated intense interest for decades. A robust clinical pipeline and the
recent FDA approvals of Adcetris1 and Kadcyla1 suggest that the potential
benefit of ADCs may finally be realized. Evolving clinical data will continue
to drive technological advancements in the field. Current methods for
preclinical lead selection typically rely on systematic in vitro evaluation of
a matrix of various mAbs, linkers and cytotoxic payloads. Whether in vitro
models are sufficient to predict response remains to be seen; until further
understanding of ADCs is realized, early in vivo studies might be crucial.
Progress in site-specific conjugation modalities, optimization of linkers with
balanced stability and identification of novel, potent cytotoxic agents should
pave the way for greater insight into the contribution of these various factors
to ADC efficacy, PK and safety. Challenges in target tumor selection will be
addressed as the roles of antigen expression, heterogeneity and internalization
rate are further elucidated. Guiding principles for the selection of an ideal
antibody Fc format are, as of yet, lacking and prompt validation of current
assumptions regarding antibody-dependent properties, such as specificity and
immune effector functions. Ongoing efforts to address these issues will
continue to broaden the impact of ADCs as targeted therapeutics for the
treatment of cancer and potentially other diseases.
