Imaging using radiolabelled targeted proteins: radioimmunodetection and beyond

Abstract

The use of radiolabelled antibodies was proposed in 1970s for staging of malignant tumours. Intensive research established chemistry for radiolabelling of proteins and understanding of factors determining biodistribution and targeting properties. The use of radioimmunodetection for staging of cancer was not established as common practice due to approval and widespread use of [¹⁸F]-FDG, which provided a more general diagnostic use than antibodies or their fragments. Expanded application of antibody-based therapeutics renewed the interest in radiolabelled antibodies. RadioimmunoPET emerged as a powerful tool for evaluation of pharmacokinetics of and target engagement by biotherapeutics. In addition to monoclonal antibodies, new radiolabelled engineered proteins have recently appeared, offering high-contrast imaging of expression of therapeutic molecular targets in tumours shortly after injection. This creates preconditions for noninvasive determination of a target expression level and stratification of patients for targeted therapies. Radiolabelled proteins hold great promise to play an important role in development and implementation of personalised targeted treatment of malignant tumours. This article provides an overview of biodistribution and tumour-seeking features of major classes of targeting proteins currently utilized for molecular imaging. Such information might be useful for researchers entering the field of the protein-based radionuclide molecular imaging.

Keywords: antibodies; antibody fragments; imaging; radionuclide; scaffold proteins.

Fig. 1

Relative size of proteins applied for radioimmunodetection and molecular imaging. Images are taken from Protein Data Bank ( https://www.rcsb.org/)

Fig. 2

Targeting of HER2-expressing tumours in mice using positron-emitting imaging agents. a. Uptake of the antibody [⁸⁹Zr]Zr-DFO*-trastuzumab in tumour, blood, kidneys and major metastatic sites. b. Uptake of small targeting probes in tumour, blood, kidneys and major metastatic sites. Data are from (Vugts et al. 2017). c Tumor-to-tissue ratios for an antibody [⁸⁹Zr]Zr-DFO*-trastuzumab 144 h after injection (Vugts et al. 2017), [⁶⁸Ga]Ga-ABY-025 affibody molecule 3 h after injection (Kramer-Marek et al. 2011), ADAPT [⁶⁸Ga]Ga-ADAPT6 3 h after injection (Lindbo et al. 2018a, 2018b) and [⁶⁸Ga]Ga-sdAb 2Rs15d 1.5 h after injection (Massa et al. 2016).

Fig. 3

Small-animal PET images of uptake in NCI-N87 xenografts relative to other tissues of [¹²⁴I]I-PIB-ZHER2:342 (a–c) and [¹²⁴I]I-PIB-trastuzumab (d–f) in representative mice sacrificed at 6 (a and d), 24 (B and E), and 72 h (c and f) after intravenous injection of Affibody molecule (1.2 MBq) or of mAb (0.8 MBq). The image is reproduced from (Orlova et al. 2009)

Fig. 4

Imaging of EGFR-expression in A431 xenografted mice using antibodies and affibody molecules. Imaging using A. [⁸⁶Y]Y-CHX-A”-DTPA-panitumumab at different time points (Nayak et al. 2010). B. [⁶⁸Ga]Ga-DOTA-ZEGFR:2377 3 h after injection ( Garousi et al. 2017b); C. [⁵⁷Co]Co- DOTA-ZEGFR:2377 3 h after injection; D. [⁵⁷Co]Co- DOTA-ZEGFR:2377 24 h after injection ( Garousi et al. 2017b); E. [⁶⁸Ga]Ga-DFO-ZEGFR:2377 3 h after injection (Oroujeni et al. 2018a, 2018b)

Fig. 5

SPECT/CT imaging (4 h after injection) of CAIX-expression in SK-RC-52 xenografted mice using [¹¹¹In]In-DOTA-ZCAIX:2 and [¹¹¹In]In-DTPA-G250(Fab’)₂. Images are presented as maximum intensity projection (MIP). Images are reproduced from (Garousi et al. 2019)