Antibody-directed enzyme prodrug therapy was conceived as a means of restricting the action of cytotoxic drugs to tumor sites. Since antigenic targets were a central component of the approach, colonic cancer, with its virtually universal expression of carcinoembryonic antigen at the cellular level, presented an obvious starting point. The principle of antibody-directed enzyme prodrug therapy is to use an antibody directed at a tumor-associated antigen to vector an enzyme to tumor sites. The enzyme should be retained at tumor sites after it has cleared from blood and normal tissues. A nontoxic prodrug, a substrate for the enzyme, is then given and, by cleaving an inactivating component from the prodrug, a potent cytotoxic agent is generated. One of the potential advantages of such a system is that a small cytotoxic agent, generated within a tumor site, is much more diffusible than a large antibody molecule. Moreover, failure to express the target antigen by cancer cells does not protect them from the bystander action of the cytotoxic agent. This review will primarily consider the studies of the London group since this is the only group that has so far reported clinical trials and it is only through clinical trials that the requirements of a successful antibody-directed enzyme prodrug therapy system can be identified.

Antibody-Directed Enzyme Prodrug Therapy (ADEPT) for Cancer

Antibody-directed enzyme prodrug therapy (ADEPT) aims to restrict the cytotoxic action to tumour sites. The obstacles to achieve this were recognised at the outset, but time and experience have given these better definition. The development of fusion proteins has provided the means of making consistent antibody-enzyme constructs on an adequate scale, and glycosylation has provided the means to control the clearance of enzyme from non-tumour sites. Human enzymes have yet to be tested in a clinical setting, and there are pointers indicating that the immunological response to foreign enzymes can be overcome. The relatively small number of purpose-designed prodrugs tested so far leaves this an area ripe for further development. The ongoing iterative process between preclinical and clinical studies is critical to achieving the objective.

Antibody-directed enzyme prodrug therapy (ADEPT) for cancer.

MFECP1 is a mannosylated antibody-enzyme fusion protein used in antibody-directed enzyme prodrug therapy (ADEPT). The antibody selectively targets tumor cells and the targeted enzyme converts a prodrug into a toxic drug. MFECP1 is obtained from expression in the yeast Pichia pastoris and produced to clinical grade. The P. pastoris-derived mannosylation of the fusion protein aids rapid normal tissue clearance required for successful ADEPT. The work presented provides evidence that MFECP1 is cleared by the endocytic and phagocytic mannose receptor (MR), which is known to bind to mannose-terminating glycans. MR-transfected fibroblast cells internalize MFECP1 as revealed by flow cytometry and confocal microscopy. Immunofluorescence microscopy shows that in vivo clearance in mice occurs predominantly by MR on liver sinusoidal endothelial cells, although MR is also expressed on adjacent Kupffer cells. In the spleen, MFECP1 is taken up by MR-expressing macrophages residing in the red pulp and not by dendritic cells which are found in the marginal zone and white pulp. Clearance can be inhibited in vivo by the MR inhibitor mannan as shown by increased enzyme activities in blood. The work improves understanding of interactions of MFECP1 with normal tissue, shows that glycosylation can be exploited in the design of recombinant anticancer therapeutics and opens the ways for optimizing pharmacokinetics of mannosylated recombinant therapeutics.

/pdf/clearance-mechanism-of-a-mannosylated-antibody-enzyme-fusion-43wg93g40j.pdf

Clearance mechanism of a mannosylated antibody-enzyme fusion protein used in experimental cancer therapy.

Clearance mechanism of a mannosylated antibody-enzyme fusion protein used in experimental cancer therapy (vol 17, pg 36, 2007)

Strategies in the designing of prodrugs, taking into account the antiviral and anticancer compounds.

A phase I/II trial of antibody directed enzyme prodrug therapy (ADEPT) with MFECP1 and ZD2767P

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A phase I/II trial of antibody directed enzyme prodrug therapy (ADEPT) with MFECP1 and ZD2767P