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Chemotherapeutic treatment of both hematologic and solid tumours
has changed dramatically in the last 20 years with the introduction
of monoclonal antibodies (mAb) directed against tumour-associated
or tumour-specific antigens. Classical mAbs mediate antitumour
effects through antibody-dependent cellular cytotoxicity (ADCC),
complement-dependent cytolysis (CDC), antibody-dependent
phagocytosis, direct induction of apoptosis, or interference with
cellular signalling.1 While mAbs such as the anti-CD20 rituximab or
anti-HER2 trastuzumab result in modest efficacy when used alone,
significant improvements in overall survival have resulted from
combining mAbs with cytotoxic chemothera-py. A growing area of
interest is the development of immu-noconjugates, whereby a
cytotoxic “payload” is directed to the tumour by mAb
conjugation.
The different types of immunoconjugates include:
radio-immunoconjugates, such as ibritumomab tiuxetan, which
contains a CD20-specific antibody that delivers yttrium-90 to its
target, and is approved for refractory follicular lymphoma; toxin
immu-noconjugates, such as moxetumomab pasudotox, a CD22 antibody
linked to an exotoxin from Pseudomonas, now in phase III trials for
relapsed or advanced hairy cell leukemia; and antibody-drug
conjugates (ADC), the focus of this article.2,3
MechanisM of actionThere are 3 essential components in an ADC:
the mAb, linker, and cytotoxic “payload” to be delivered
intracellularly to the tumour (Figure 1). After intravenous
injection, the mAb binds the target antigen, forming an ADC-antigen
complex, which is internalized via endocytosis, forming a
clathrin-coated endosome that undergoes lysosomal degradation and
proteolysis. The cytotoxin, typically 100–1000x more potent than
regular chemotherapeutics, is then released intracellularly,
resulting in DNA damage or interference with mitosis.4
When designing the mAb, consideration must be given to the
antigen target, immunoglobulin type and antibody size. Antigens
should be selected for tumour specificity, down-stream anti-tumour
effects, degree and homogeneity of expression, lack of shedding,
and internalization efficiency.4 Because mAbs have long half-lives,
stable linker technology is extremely important to prevent release
of the “payload” in the circulation. The linker forms the bond
between mAb and drug, and can be either cleavable (disulfides,
hydrazones or peptides) or noncleavable (thioethers). In older
ADCs, the linker was bound to the mAb by hydrazone or disulfide
bonds. However, these are sensitive to reductive and oxidative
environments other than those found inside tumour cells. Currently,
most linkers are selectively cleaved from the anti-body by
tumour-associated proteases or esterases that are only present
inside a lysosome. One of the 2 currently approved ADCs is
brentuximab vedotin, a chimeric CD30 mAb linked to
Antibody-drug conjugatesGwynivere A. Davies, MD, FRCPC, and
Douglas A. Stewart, MD, FRCPC, University of Calgary
Gwynivere a. Davies, MD, fRcPc, Hematology Fellow, PGY5,
University of Calgary
Douglas a. stewart, MD, fRcPc, Medical Oncologist, Tom Baker
Cancer Centre; Professor, Oncology and Medicine, University of
Calgary; Leader, Provincial Hematology Tumour Team, AHS
CancerControl
monomethyl auristatin E for treatment of relapsed/refractory
Hodgkin and anaplastic large cell lymphoma. Brentuximab vedotin
employs a spacer between the bond to the antibody and the peptide
portion of the linker, to provide room for the enzyme to recognize
and bind to the cleavable portion of the linker.5 The other ADC is
trastuzumab emtansine, a humanized anti-HER2 mAb linked to
mertansine (DM-1), approved for relapsed HER2+ breast cancer
previously treated with trastuzumab. Trastuzumab emtansine utilizes
a non-cleavable linker, wherein the mAb is degraded to the level of
an amino acid inside the tumour cell.6 The remaining amino
acid-linker-cytotoxic agent becomes the active drug, mini-mizing
drug efflux and bystander effects on neighbouring cells.
Cytotoxins currently in use include: auristatins, which are
mitotic inhibitors similar to taxanes; maytansines that interfere
with microtubule assembly similar to vinca alkaloids; and
calicheamicins, which target the minor groove of DNA, similar to
anthracyclines.4
futuRe DeveloPMentThere are currently more than 30 ADCs in
development. Future challenges include optimizing linker structures
to improve stability in peripheral blood, finding alternatives to
improve component conjugation specificity, using drug-carrying
nanoparticles conjugated to mAb, and developing improved cytotoxins
that overcome tumour resistance mech-anisms such as transport by
multidrug resistance proteins.3 Though expensive and complex to
develop and manufac-ture, ADCs represent a large step forward in
maximizing antitumour effects with minimal off-target toxicity.
References1. Adams GP, Weiner LM. Monoclonal antibody therapy of
cancer. Nat Biotechnol.
2005 Sep;23(9):1147-57.2. Schrama D, Reisfeld RA, Becker JC.
Antibody targeted drugs as cancer
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Redman JM, Hill EM, Al Deghaither D, Weiner LM. Mechanisms of
action of
therapeutic antibodies for cancer. Mol Immunol. 2015 Apr 23.
[Epub ahead of print]4. Peters C, Brown S. Antibody-drug conjugates
as novel anti-cancer
chemotherapeutics. Biosci Rep. 2015 Jun 12;35(4).5. Francisco
JA, Cerveny CG, Meyer DL, et al. cAC10-vcMMAE, an anti-CD30-
monomethyl auristatin E conjugate with potent and selective
antitumor activity. Blood. 2003 Aug 15;102(4):1458-65.
6. Lewis Phillips GD, Li G, Dugger DL, et al. Targeting
HER2-positive breast cancer with trastuzumab-DM1, an
antibody-cytotoxic drug conjugate. Cancer Res. 2008 Nov
15;68(22):9280-90.
Disclosure: Dr. G. Davies has no conflicts to declare. Dr. D.
Stewart has received honoraria from Seattle Genetics and
Hoffmann-La Roche for ad hoc advisory boards.
Figure 1. representation of antibody drug conjugate mechanism of
action
Binding and endocytosis
Toxin release
Apoptosis (cell death)
DNA disruption and cell cycle arrest
Antibody
Cytotoxic agent
Linker
DISCLAIMER: This supplement was supported by a third-party
contribution from Seattle Genetics.
