Antibody-drug conjugates (ADCs) have been developed as one of the effective drug delivery systems, which combine the specificity of mAbs and the cytotoxicity of payloads. Among which, antibody directed enzyme prodrug therapy (ADEPT) employs antibody-enzyme conjugates to achieve selective tumor cell death.
Figure: DOS47 mode of action (Bioconjug Chem. 2015)
Generally, ADEPT employs a two-step strategy, prodrug and antibody-enzyme conjugates, in various researches. Antibody-enzyme conjugates are administrated followed by the prodrug and then the enzyme portion of antibody-enzyme conjugates converts prodrugs to active cytotoxic form to kill tumor cells. For instance, the glucuronide prodrug/β-glucuronidase antibody system can selectively generate cytotoxic drug at specific tumor cells. In this system, BHAMG (tetra-n-butyl ammonium salt of HAMG, a glucuronide prodrug) acts as prodrug that can be converted to HAM (p-hydroxyaniline mustard) by the β-glucuronidase moiety of conjugates. HAM has cytotoxicity to cells. Novel enzyme-based therapy approaches with no administration of prodrugs needed have also been developed and studied, such as anti-CEACAM6 antibody-urease conjugate known as L-DOS47. L-DOS47 is one of the ADCs that have been in clinical trials. The urease moiety of L-DOS47 can convert endogenous urea into ammonia, hydroxyl ions, and CO2 to induce cytotoxicity as increasing pH in the normal acidic tumor microenvironment will be harmful to the tumor cells and ammonia taken up by tumor cells will upset their metabolism (shown in the figure). Enzymes, as one type of payload candidates in ADC strategy, can modify the biochemistry of the targeted microenvironment, resulting in tumor cytotoxicity. Additionally, some immune-detection enzymes, e.g. HRPO (horseradish peroxidase) and ALP (alkaline phosphatase), can be conjugated to a primary antibody to detect antigens or conjugated to a secondary antibody to detect antibodies.
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