Development of Dual Receptor Enhanced Pre‐Targeting Strategy—A Novel Promising Technology for Immuno‐Positron Emission Tomography Imaging

Abstract

Positron emission tomography (PET) imaging has become an important diagnostic tool. Various pre‐targeting systems have been reported to address limitations associated with traditional immuno‐PET. However, the application of these mono‐receptor based pre‐targeting (MRPT) strategies is limited to non‐internalizable antibodies, and the tumor uptake is usually much lower than that in the corresponding immuno‐PET. To circumvent these limitations, the first dual‐receptor enhanced pre‐targeting (DRPT) system is developed through entrapping the tumor‐receptor‐specific radioligand by the pre‐administered antibody. Besides the similar ligation pathway happens in MRPT, incorporation of a tumor‐receptor‐specific peptide into the radioligand in DRPT enhances both concentration and retention of the radioligand on tumor, promoting its ligation with pre‐administered antibody on cell‐surface and/or internalized into tumor‐cells. In this study, 64Cu‐based DRPT shows superior performance over corresponding MRPT and immuno‐PET using internalizable antibodies. Besides, the compatibility of DRPT with short‐lived and generator‐produced 68Ga is demonstrated, leveraging its advantage in reducing radio‐dose exposure. Furthermore, the feasibility of reducing the amount of the pre‐administered antibody is confirmed, indicating the cost saving potential of DRPT. In summary, synergizing advantages of dual‐receptor targeting and pre‐targeting, it is expect that this DRPT strategy can become a breakthrough technology in the field of antibody‐based molecular imaging.

Recent Advances in Bioorthogonal Click Chemistry for Enhanced PET and SPECT Radiochemistry

“…(D) DRPT leads to greatly enhanced tumor uptake compared with MRPT. Adapted with permission from ref . Copyright 2021 John Wiley and Sons.…”

“…Several studies reported that tetrazine analogues bearing various imaging modules, such as fluorescent molecules or radionuclides, were coupled with antibody macromolecules (THIO-MAB, huA33) modified with TCO in order to study the in vivo pretargeting strategy (Figure A,B), ,− while the modification of small molecules with TCO was applied through the incorporation of 18 F-labeled Tz into the small molecule-based radioactive product by Tz/TCO-based pretargeting for detecting hypoxia level (Figure C) . Moreover, Lu et al developed a metabolic pretargeting strategy by conjugating azido sugars with 64 Cu-labeled DBCO tracer using SPAAC reaction for cytotoxic T lymphocytes (CTLs) imaging, whereas a dual-receptor enhanced pretargeting (DRPT) strategy was first reported by the use of IEDDA reaction . The authors investigated the in vivo performance of DRPT targeting EGFR and integrin α v β 3 and then suggested that this DRPT strategy is suitable to radiolabel peptides and small molecules or internalize mAbs to provide higher tumor uptake of radionuclides and relatively increased tumor specificity (Figure D).…”

“…61 Moreover, Lu et al developed a metabolic pretargeting strategy by conjugating azido sugars with 64 Culabeled DBCO tracer using SPAAC reaction for cytotoxic T lymphocytes (CTLs) imaging, 145 whereas a dual-receptor enhanced pretargeting (DRPT) strategy was first reported by the use of IEDDA reaction. 146 The authors investigated the in vivo performance of DRPT targeting EGFR and integrin α v β 3 and then suggested that this DRPT strategy is suitable to radiolabel peptides and small molecules or internalize mAbs to provide higher tumor uptake of radionuclides and relatively increased tumor specificity (Figure 8D).…”