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Figure 1. Structure of a monoclonal antibody

on factors such as gender, age, weight, blood pressure, respiratory rate and disease stage, and of course,
[30]
genetic background .
Metabolism of mAbs does not involve the cytochrome P450 enzyme system that is critically important for
[31]
the hepatic metabolism of many cancer drugs . Instead, due to their large molecular size, elimination of
mAbs occurs mostly via endocytosis and pinocytosis followed by proteolytic catabolism [32,33] . Moreover,
[34]
clearance can occur specifically (Fab or Fc receptor binding) or non-specifically . Importantly, target
mediated clearance is triggered by the interaction of the mAb with its antigen, and can therefore depend
on specific tumour characteristics including the amount of antigen expressed. More frequently uptake
of mAbs occurs via receptor-mediated endocytosis in response to binding of the antibody Fc domain
[35]
to FcγR expressed on immune cells, such as monocytes, macrophages, dendritic cells . This effect was
emphasised in a 2008 study examining a polymorphism in the FcgR3A gene (rs396991 T/G) that results in a
change of amino acid phenylalanine (F) to valine (V) at position 158. The valine substitution was shown to
[36]
increase binding affinity and improve antibody-dependant cell-mediated cytotoxicity . As a result, human
epidermal growth factor receptor (HER) 2-positive breast cancer patients with the V/V genotype have higher
[36]
response rate to treatment with anti-HER2 drug trastuzumab . This mutation also increases the response
rate and progression-free survival (PFS) of patients with colorectal cancer and B-cell lymphoma treated by
cetuximab and rituximab, respectively [36-38] .

The expression of another Fc receptor termed the neonatal Fc receptor FcRn is also subject to genetic
influence based on a variable number of tandem repeats (VNTR) in the promoter region of FCGRT, the
[39]
FcRn gene. An increased number of tandem repeats has been shown to increase its expression , and has
subsequently been linked to increased serum infliximab and adalimumab in patients with inflammatory
[40]
bowel disease . As FcRn is responsible for salvaging IgG, reduced expression is thought to result in lower
[21]
serum concentration and increased clearance via alternative mechanisms . This polymorphism was also
examined in patients treated with the anticancer epidermal growth factor receptor (EGFR) mAb cetuximab,
where VNTR3 homozygotes possessing three repeats demonstrated a reduced distribution, clearance and a
[41]
trend towards increased half-life (P = 0.058) of the mAb when compared to heterozygotes .