Pretargeted radioimmunotherapy of cancer: progress step by step.

Abstract

To enhance the therapeutic efficacy of radioimmunotherapy of cancer, several pretargeting strategies have been developed. In pretargeted radioimmunotherapy, the tumor is pretargeted with an antibody construct that has affinity for the tumor-associated antigen on the one hand and for a radiolabeled hapten on the other. The radiolabeled hapten is administered in a later phase, preferably after the antibody construct has cleared from the circulation. In pretargeted radioimmunotherapy, 2 main approaches can be distinguished: pretargeting strategies based on the avid interaction between streptavidin (SA) or avidin and biotin, and pretargeting strategies based on the use of bispecific antibodies. In pretargeting strategies based on biotin and SA or avidin, the use of a clearing agent that could remove the pretargeting construct from the circulation markedly improved the targeting of the radiolabeled biotin to the tumor. Thus, multistep injection schemes in which 3-5 different agents are subsequently injected were developed. In bispecific antibody-based pretargeting strategies, the use of bivalent haptens improved the efficacy of the tumor targeting, and a 2-step pretargeted radioimmunotherapy strategy is now being tested in cancer patients. Preclinical studies as well as studies on cancer patients have shown that these pretargeting strategies can result in higher radiation doses to the tumor than can directly radiolabeled antitumor antibodies. Here, the development and state of the art of the most effective approaches for pretargeted radioimmunotherapy are reviewed.