Over the last years, a novel class of anti-cancer drugs named antibody-drug conjugates
(ADCs) has been developed. Due to their limited off-target toxicity but highly potent cytotoxicity at
tumor sites, ADCs have proven to be a good alternative to ordinary cancer treatment, such as chemotherapy
or combination therapy. Numerous enhancements in antibody-drug engineering led to
highly potent tumor targeting drugs with a wide therapeutic window. Two ADCs (Brentuximab
vedotin and Trastuzumab emtansine) are already on the market and many others are in clinical trials.
However, unstable linkers, low drug potency and unwanted bystander-effects are only some of
the drawbacks of ADCs. Enzymes used in combination with prodrugs happen to be a promising
alternative. The glyco-enzyme horseradish peroxidase (HRP) has proven to activate the hormone
indole-3-acetic acid (IAA) to a highly potent cytotoxic drug. This combination of IAA and HRP has
been investigated for the use in strategies such as gene-directed enzyme prodrug therapy (GDEPT)
and antibody-directed enzyme prodrug therapy (ADEPT). This article reviews the current state of
research in ADC engineering and describes the potential major enhancements through use of glycoenzymes
in combination with a prodrug.
Keywords: Antibody-drug conjugates, linker, cytotoxic payload, horseradish peroxidase, indole-3-acetic acid, antibodydirected
enzyme prodrug therapy.
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