Page 95 - Bio Engineering Approaches to Cancer Diagnosis and Treatment

4.5 Antibody-drug conjugate 93

This class of linkers include stable and degradation-resistant bonds resulting in
whole ADC degradation in the lysosome [63].
A huge gamut of ADCs is constructed by accidental connection of residues
of lysine or cysteine to the antibody which resulted in ADCs with different DAR
(drug-antibody ratios) [66]. Although many ADCs such as Mylotarg and Kadcyla
(gemtuzumab ozogamicin and trastuzumab emtansine, respectively) are produced
by lysine conjugation (this modification on the surface of antibodies is of the most
common conjugation strategies), this method would provide heterogeneous mixture
with divergent DAR leading to a low therapeutic window. Hence, novel ADC con-
struction approaches have focused on site-specific strategies that provide ADCs with
the exact DAR, better therapeutic windows, and many advances on developing less
heterogeneous conjugation in lysine modification [66,67].

4.5.4 Drugs
Cytotoxic drugs are characterized in two groups: drugs which inhibit the microtu-
bule and those which damage DNA. Early ADCs were included in classic chemo-
therapy payloads like methotrexate or doxorubicin due to the known toxic effects
of these drugs, however their low instability/limited payload efficiency caused
them to be ineffective. Then the second generation of ADCs came through, and
the potency of the drugs used in this group was about 100–1000 folds higher
[58,60].

4.5.4.1 The most important drugs used in ADCs are discussed further
Auristatins are the most common group of drugs in ADCs inhibiting tubulin gather-
ing and lead to G2/M cell cycle discontinuing. Maytansinoids are the other micro-
tubulin blockage drugs which are well recognized and both Kadcyla (trastuzumab
emtansine) and Adcetris (brentuximab vedotin) are approved ADCs and fall into the
Maytansinoids and Auristatins categories, respectively. One of the novel tubulin sup-
pressor payloads which leads to microtubules instability and mitotic discontinuing
is Tubulysins that forms stable ADC along with trastuzumab. It is worth noting that
this group of drugs are efficient on cells with high proliferation rates such as most
cancer cells.
The second group of drugs which damage the DNA are more effective in solid
tumors. A number of famous DNA damaging ADCs include Duocarmycin and Cali-
cheamicin [60,61]. It is conventional to add that these ADCs have the ability to kill
cancer stem cells, however it also runs the risk of killing normal cells that express
a low amount of tumor antigens [61]. Current ADC payloads are extremely toxic
if they were freely used, as conjugation with antibodies reduce drug potency [61].
Mitotic inhibitor drugs prevent mitosis by chromosome division and the changing of
the cytoskeleton structure as to promote cell death like Vinca alkaloids and taxoids
[56]. Some prominent drugs in ADCs include: pertuzumab, rituximab, trastuzumab,
and cetuximab [60].