ADVS

Vollständiger Abstract

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The expansion of personalized medicine is encouraging the development of platforms capable of supporting individualized imaging and therapeutic strategies. The combination of antibodies, with their intrinsic selectivity, and a modular molecular probe provides a strong foundation for such approaches. In this context, a versatile platform enabling positron emission tomography (PET) imaging followed by copper-free click-based functionalization is developed. A DFO-Lysine-DBCO probe is synthesized and site-specifically coupled to trastuzumab, allowing the introduction of diverse payloads, including β- or α-emitter chelators, a fluorophore, and a cytotoxic agent. Within this toolbox, the DFO/DOTAGA bischelate is selected for detailed evaluation. Radiolabeling confirms the selectivity of DFO and DOTAGA for 89Zr and 177Lu, respectively. PET imaging in mice bearing HCC1954 xenografts (HER2-overexpressing, trastuzumab-resistant) using [89Zr]Zr-ss-Tzb-DFO-DOTAGA and [89Zr]Zr-ss-Tzb-DFO-Lu(III)DOTAGA, in which DOTAGA is pre-loaded with cold lutetium, enables clear tumor visualization and indicates that second-chelator occupancy does not alter biodistribution. Despite unexpectedly lower internalization and tumor uptake, [177Lu]Lu-ss-Tzb-DFO-DOTAGA demonstrates significant antitumor activity with good tolerability in a preliminary therapeutic study. This modular platform, enabling site-specific conjugation, provides a broadly adaptable route to generate multifunctional antibody constructs, offering a versatile foundation for integrating imaging, therapy, and payload customization within a single molecular scaffold.

Abstract: PubMed · Datensatz