Abstract
Selective delivery of radionuclides to tumors may be accomplished using a two-step approach, in which in the first step the tumor is pretargeted with an unlabeled antibody construct and in the second step the tumor is targeted with a radiolabeled small molecule. This results in a more rapid clearance of the radioactivity from normal tissues due to the fast pharmacokinetics of the small molecule as compared to antibodies. In the last decade, several pretargeting approaches have been tested, which have shown improved tumor-to-background ratios and thus improved imaging and therapy as compared to directly labeled antibodies. In this review, we will discuss the strategies and applications in (pre-)clinical studies of pretargeting concepts based on the use of bispecific antibodies, which are capable of binding to both a target antigen and a radiolabeled peptide. So far, three generations of the bispecific antibody-based pretargeting approach have been studied. The first clinical studies have shown the feasibility and potential for these pretargeting systems to detect and treat tumor lesions. However, to fully integrate the pretargeting approach in clinic, further research should focus on the best regime and pretargeting protocol. Additionally, recent developments in the use of bioorthogonal chemistry for pretargeting of tumors suggest that this chemical pretargeting approach is an attractive alternative strategy for the detection and treatment of tumor lesions.
Highlights
The use of radiolabeled monoclonal antibodies directed against tumor-associated antigens to visualize, characterize, and/or treat tumor lesions has been widely studied in preclinical and clinical studies [1,2,3]
Several pretargeting systems have been developed including the avidin/streptavidin-biotin pretargeting system [4, 6] exploiting the extremely high binding affinity between biotin andavidin (K d = 4 × 10−14 M) [7], the DNA-complementary DNA binding pretargeting system, which relies on the high affinity interaction between complementary oligomers [8,9,10,11], pretargeting systems based on the use of bispecific antibodies, and recently a novel pretargeting approach has been reported based on highly selective bioorthogonal chemical reactions [12, 13]
Clinical studies revealed that the pretargeting approach based on bispecific antibodies (bsAb) directed against a tumor-associated antigen and against HSG in combination with radiolabeled peptides containing the HSG residue resulted in high contrast images
Summary
The use of radiolabeled monoclonal antibodies (mAbs) directed against tumor-associated antigens to visualize, characterize, and/or treat tumor lesions has been widely studied in preclinical and clinical studies [1,2,3]. Only a small fraction of the injected activity will localize in the tumor Despite this inefficient targeting, in various clinical settings this approach can be effective: especially radiosensitive tumors, like Non-Hodgkin’s lymphomas, can respond to treatment with radiolabeled anti-CD20 antibodies [5]. Molecular engineering techniques made it possible to produce antibody formats that clear faster from the blood This is the central dilemma in antibody targeting of tumors: on one hand, the high level of mAb in the circulation is the driving force for the accumulation of the mAb in the tumor; on the other hand, the clearance from normal tissues should be rapid. The pretargeting concept based on the use of bsAb directed against both a target antigen and a radiolabeled hapten is carried out in the following www.frontiersin.org van de Watering et al
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