Content area
Full Text
Figure 1. Basic principle of ADEPT. In stage 1, an AEC is administered and allowed to localize at tumor sites. After blood clearance (stage 2), a nontoxic prodrug is administered in stage 3. The enzyme cleaves the protective moiety to generate a cytotoxic drug within tumors. The drug, being a small molecule, can diffuse throughout the tumor to kill antigen-negative cells, as well as the cells expressing the antigen, thus providing a bystander effect. ADEPT: Antibody-directed enzyme prodrug therapy; AEC: Antibody-enzyme construct.
(Figure omitted. See article PDF.)
Antibody-directed enzyme prodrug therapy (ADEPT) was proposed in the mid-1980s as a means of restricting the action of cytotoxic drugs to tumor sites, thereby increasing their efficacy and reducing their normal tissue toxicity [1]. It was suggested that this could be achieved in a multistep procedure [2,3]. In the first step, an antibody directed at a tumor-associated antigen is used to vector an enzyme to tumor sites. The second step allows the antibody-enzyme complex (AEC) to clear from the blood while it is retained at tumor sites. Next, a prodrug that bears an inactivating component cleavable by the chosen enzyme is administered intravenously, resulting in the generation of a highly cytotoxic agent at cancer sites (Figure 1).
One potential advantage of such a system would be the ability to deliver a much higher concentration of drug to treat cancer. Low-molecular-weight drugs diffuse better than large AECs in solid tissues. However, it was also recognized that the active drug could leak out of tumors and be carried to normal cell renewal tissues via the blood. So it was thought that the drugs generated in such a system should have short half-lives. It would also overcome the problem of heterogeneity of tumor marker expression within tumors so that cells that do not express the target antigen would be killed through the so-called bystander action.
For some years prior to testing the ADEPT concept, radiolabeled anti-carcinoembryonic antigen (CEA) antibodies had been used in the imaging technique of radioimmunolocalization of colonic tumors and their metastases. Initially, this had been performed with intact immunoglobulin (Ig)G and these molecules were slow to accumulate in tumors and clear from the blood. It was then shown that F(ab)2 antibodies that lack the Fc component of...