Page 94 - Bio Engineering Approaches to Cancer Diagnosis and Treatment

92 CHAPTER 4 Immunotherapy

targeting unique antigens (antibodies binding site, allows them specific cell type
selection) [59] that has caused researchers to keep them as novel cancer therapeu-
tic methods [67]. Historically, IgG (immunoglobulin G) is known as the most used
form in antibody construction. However, while IgG is still prominent, scientists have
also attracted to other forms of antibodies; over 30 antibodies have considered for
oncology usage differing in solid tumors and hematological tumors [55]. It is worth
emphasizing that antibodies targeting solid tumors require a deep penetration in
order to thoroughly reach the tumor, so the usage of antibody fragments instead of
whole antibody is recommended.
There are many different forms of antibodies with different uses, including those
conjugated with drugs, radioisotopes (like heavy metals), and PEG (polyethylene
glycol) or antibody fragments [55] and monoclonal antibodies, having been used in
ADCs production. Due to the fact that antibodies must induce minimal antigenicity,
monoclonal antibodies are mainly produced from humans or murine which is being
humanized [66].

4.5.3 Linkers and conjugates
The function of linkers is to bond the payloads with the antibodies, and the physio-
chemical characteristics of linkers demonstrate the ADCs’ pharmacokinetics [58]. In
order to design a successful ADC, the linkers need to fulfill some special character-
istics. First, linkers’ stability in plasma is one of the crucial factors which helps them
with better circulation and tumor targeting. Unstable linker causes drug leakage and
systemic toxicity, resulting in damage to healthy cells. To produce stable linkers:
payload, the type of cancer and antigens must be carefully studied. Despite stability
in circulation, the linker should be capable of rapid drug release once ADC enters the
tumor cells [62,63]. The final key criteria in designing the linkers are based on their
hydrophobic bounds. Linkers with a hydrophobic manner along with hydrophobic
drugs may trigger the accumulation of ADCs which have the ability in immune unde-
sired alertness and liver removing effect. Hence, manufacturing hydrophilic linkers
coupled with negative sulfonate, PEG and pyrophosphate diester groups would be
demanding [63].
There are two general classes of linkers: cleavable and noncleavable. The former
cleaves once ADC encounters the tumor cell and the latter group is not cleavable
during the process [62].
• Cleavable

This group of linkers are produced to break when faced environmental changes.
Hence, these linkers cleave when they move from an extracellular matrix into intra-
cellular milieu by feeling the alternation in pH, redox potency (hydrolysis) or some
determined enzymes (proteolysis), etc. once the linker breaks and the drug releases
[58,63]. Those antibodies whose function is on the basis of proteolysis recognized by
specific enzymes like cysteine proteases due to existing determined sites [58].
• Noncleavable