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Page 72 Shek et al. Cancer Drug Resist 2019;2:69-81 I http://dx.doi.org/10.20517/cdr.2018.20

treatment from 12 h to several weeks. They vary from maculopapular rash to severe adverse events (Steven
Johnson Syndrome, erythema multiforme), and are thought to be primarily T-cell mediated reactions, which
[15]
explains the delayed onset of such toxicities .
Prediction of immune-related adverse events and their prevention are essential milestones for the
development of personalised cancer treatment. Pharmacogenetic studies will likely be crucial in the near
future to understand individual adverse responses to mAb treatment and how they can be avoided. In spite
of the fact that this problem is very topical for modern medicine, there are currently no published studies
that have examined the association between individual genetic variations and the development of adverse
reactions to mAb treatment.

Therapeutic significance of pharmacogenetic study
Pharmacogenetics is a multidisciplinary research area that aims to predict and personalise modern
treatment protocols by understanding the influence of genetic variation on drug efficacy and toxicity.
Millions of genetic polymorphisms have thus far been identified in the human genome, many of which
can affect pharmacokinetics and pharmacodynamics of antineoplastic drugs [16,17] . Understanding these
genetic polymorphisms is particularly important in cancer research, as cancer cells possess an increased
number of genetic mutations, some of which may influence drug transport, metabolism, toxicity and
[18]
cellular response . For non-mAb cancer treatments, the majority of these polymorphisms lie within genes
responsible for drug transport and metabolism, and likely underlie inter-individual differences in drug
[19]
response . Genetic polymorphisms in genes, encoding enzymes TPMT (thiopurine methyltransferase),
CDA (cytidine deaminase), and CYP2D6 (cytochrome P450 2D6) can lead to severe changes in the
metabolism of non-mAb treatments such as mercaptopurine, azathioprine and tamoxifen respectively, but
[20]
differ significantly from gene polymorphisms responsible for mAb metabolism and response . Due to the
immunological nature of mAbs, their efficacy can be affected by variations in genes responsible for antibody
recognition, presentation and metabolism. This review will summarise the existing data concerning the
influence of genetic variations on cancer treatment with mAbs.

PART 1. THE INFLUENCE OF GENETIC POLYMORPHISMS ON THE METABOLISM OF
MONOCLONAL ANTIBODIES
All current clinically available mAbs are IgG (immunoglobulin G) proteins, consisting of two heavy chains
(50 kDa) and two light chains (25 kDa) composed of constant domains (C and C ) and variable domains
H
L
[21]
(V and V ) [Figure 1]. The variable regions and C domain comprise the Fab, which is specific for the
H1
H
L
target antigen. Together, C and C comprise the fragment crystallizable region (Fc), which can bind to cell
H3
H2
surface receptors present on immune cell populations . These membrane proteins known as Fc receptors
[22]
are expressed on B lymphocytes, natural killer cells, macrophages and play role in the recognition of foreign
antigens and neoplasms, as well as the activation of phagocytic and cytotoxic cells . The half-life of mAbs
[23]
[21]
is dependent on their structure: murine IgG have the shortest half-life of 1-2 days . Chimeric IgG half-
life is equal to 8-10 days and humanized or fully human half-life is 20-30 days [24,25] . This is significantly
longer than traditional chemotherapies that possess half-lives ranging from hours (methotrexate) to 1-2 days
(doxorubicin) [26,27] .
mAbs can be administered via intravenous (IV) infusion or subcutaneous (SC) and intramuscular (IM)
injections. Due to the higher risk of infusion-related reactions following IV administration of mAbs, SC
and IM are more preferable. Systemic absorption of mAbs from the injection site is slow, and a maximum
[28]
concentration is usually reached in 1-8 days after SC or IM injection . mAbs are distributed from the blood
to tissues via convection, which is determined by the blood-tissue hydrostatic gradient, as well as by the
[29]
sieving effect of the vascular epithelium . Absorption of SC and IM administered mAbs is also dependent