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INTRODUCTION
The evolution of monoclonal antibodies in cancer treatment
Over the last 20 years, immunotherapy has become established as one of the most promising and effective
therapeutic strategies targeting cancer. Monoclonal antibodies (mAbs) in particular have revolutionized the
[1]
treatment of hematologic and solid malignancies . In 1997, the first chemotherapeutic mAb (Rituximab)
[2]
was approved by the FDA for clinical use , and was quickly followed by numerous other mAbs for a range
of malignancies [Table 1]. The generation of therapeutic mAbs began over 20 years previous, where the first
mAbs were synthesized using hybridoma technologies from murine sources (-omab). The method consisted
of mouse immunisation against a specific antigenic epitope, followed by extraction of splenic B-lymphocytes
and their fusion with immortal myeloma cells. The resulting cell clones produced antibodies towards a
single epitope, hence the name monoclonal (single clone) antibodies. Unfortunately, the use of such mAbs
was restricted due to the development of an immune response against the mouse derived antibodies, termed
[3]
HAMA (human anti-mouse antibody response) . The development of mAbs has since evolved quickly,
resulting in subsequent generations of mAbs that were chimeric (-ximab), humanised (-zumab) and fully
human (-umab). Chimeric mAbs are composed of variable regions derived from mice, and the remainder
[constant domains of heavy chain - C H (1-3) ] from human or other animals. Humanised mAbs are engineered
from human sources and contain only a mouse derived antigen-binding fragment representing ~5% of the
mAb. Human mAbs are the gold standard, and are generated from hybridomas of human or humanised
mouse origin . mAbs with the strongest affinities/biological response are selected using phage display
[4]
[5]
[6-8]
systems , or high throughput immunoassays .
Monoclonal antibodies have been developed to target cancer cells using a number of distinct and fascinating
mechanisms. Naked antibodies that lack any type of drug conjugation work by either: (1) stimulating
the immune system by binding to an antigen present on a cancer cell (alemtuzumab); (2) boosting the
immune response via interaction with immune-checkpoint proteins (CTLA-4 inhibitors (ipilimumab)/
PD-1 inhibitors (pembrolizumab); or (3) blocking growth factor receptors on cancer cells (trastuzumab). In
contrast, conjugated (tagged, labelled, loaded) mAbs work by carrying radioactive elements [radiolabelled
antibodies - ibritumomab tiuxetan (Zevalin)] or chemotherapeutic drugs [chemolabeled antibodies -
brentuximab vedotin (Adcetris)]. An additional group of mAbs, called bispecific mAbs, possess two different
antigen binding fragments (Fabs) whose function is to bring cells in proximity to one another. For example,
blinatumomab binds CD19 on lymphoma cells and CD3 on T cells, thus prompting T cell cytotoxicity
[9]
against leukemic B cells .

Adverse events and monoclonal antibody treatment
While mAbs are a promising new therapy for the treatment of a growing number of cancers, they can
cause various systemic and cutaneous adverse events, including a wide range of hypersensitivities: antibody
mediated type I reactions (anaphylaxis), cytotoxic type II (neutropenia, thrombocytopenia, haemolytic
anaemia), immune complex type III (vasculitis), T cell mediated type IV (delayed mucocutaneous
[10]
reactions, cardiac events, progressive multifocal encephalopathy (PML) . Type I hypersensitivities are
most common, with a recent study showing that among 901 patients treated with rituximab, 9% (n = 79)
faced type I hypersensitivity reactions. The absence of IgE against rituximab, however suggested that the
patients developed pseudo-allergic reactions, which manifest with the same clinical symptoms as true
type I hypersensitivities (flushing, hypotension, mucous secretion, rash, rhinitis, conjunctivitis) but less
severe [11,12] . Cytotoxic (type II) reactions manifest as neutropenia, anaemia, thrombocytopenia, and are
common for rituximab and trastuzumab. This is perhaps due to their antitumor mechanism of action,
[13]
which occurs via antibody- and complement-dependent cell cytotoxicity . Type III reactions occur due
to the formation of antibody-antigen complexes and are relatively rare in response to mAb treatment, with
the exception of chimeric antibodies such as rituximab, where serum sickness-like reaction occur in up to
[14]
20% of individuals . T-cell mediated type IV hypersensitivity reactions occur following cessation of mAb