Preclinical Evaluation of a New Format of 68Ga- and 111In-Labeled Affibody Molecule ZIGF-1R:4551 for the Visualization of IGF-1R Expression in Malignant Tumors Using PET and SPECT

Abstract

The Insulin-like growth factor-1 receptor (IGF-1R) is a molecular target for several monoclonal antibodies undergoing clinical evaluation as anticancer therapeutics. The non-invasive detection of IGF-1R expression in tumors might enable stratification of patients for specific treatment and improve the outcome of both clinical trials and routine treatment. The affibody molecule ZIGF-1R:4551 binds specifically to IGF-1R with subnanomolar affinity. The goal of this study was to evaluate the 68Ga and 111In-labeled affibody construct NODAGA-(HE)3-ZIGF-1R:4551 for the imaging of IGF-1R expression, using PET and SPECT. The labeling was efficient and provided stable coupling of both radionuclides. The two imaging probes, [68Ga]Ga-NODAGA-(HE)3-ZIGF-1R:4551 and [111In]In-NODAGA-(HE)3-ZIGF-1R:4551, demonstrated specific binding to IGF-1R-expressing human cancer cell lines in vitro and to IGF-1R-expressing xenografts in mice. Preclinical PET and SPECT/CT imaging demonstrated visualization of IGF-1R-expressing xenografts already one hour after injection. The tumor-to-blood ratios at 3 h after injection were 7.8 ± 0.2 and 8.0 ± 0.6 for [68Ga]Ga-NODAGA-(HE)3-ZIGF-1R:4551 and [111In]In-NODAGA-(HE)3-ZIGF-1R:4551, respectively. In conclusion, a molecular design of the ZIGF-1R:4551 affibody molecule, including placement of a (HE)3-tag on the N-terminus and site-specific coupling of a NODAGA chelator on the C-terminus, provides a tracer with improved imaging properties for visualization of IGF-1R in malignant tumors, using PET and SPECT.

Direct Intra-Patient Comparison of Scaffold Protein-Based Tracers, [99mTc]Tc-ADAPT6 and [99mTc]Tc-(HE)3-G3, for Imaging of HER2-Positive Breast Cancer

“…The preclinical development of scaffold protein-based targeting agents is rapidly expanding. Probes, which are based on DARPin, affibody and anticalin scaffolds, have been proposed for the radionuclide imaging of cancer-associated targets such as epithelial cell adhesion molecule (EpCAM) [ 33 ], check point protein B7-H3 [ 34 ], programmed death ligand 1 (PD-L1) [ 35 ], prostate-specific membrane antigen (PSMA) [ 36 ], insulin-like growth factor-1 receptor (IGF-1R) [ 37 ] and HER2 [ 38 ] during the last two years. Still, clinical data are available mainly for HER2-targeting affibody molecules [ 26 , 28 , 29 , 39 , 40 , 41 ].…”

Biomarkers as Biomedical Bioindicators: Approaches and Techniques for the Detection, Analysis, and Validation of Novel Biomarkers of Diseases

“…Drug candidates, e.g., monoclonal antibodies, showing direct interactions with IGF-1R include dalotuzumab, figitumumab, ganitumab, and cixutumumab, etc. Therefore, the non-invasive analyses of IGF-1R targeting antibodies in various cancer types would enable the classification of patients for personalized treatment options and could lead to improved outcomes both in the case of clinical studies as well as other routine treatment schedules [ 119 ].…”

Comparison of approaches for increasing affinity of affibody molecules for imaging of B7-H3: dimerization and affinity maturation

“…These are essential advantages of Affibody molecules compared with monoclonal antibodies. Affibody molecules have been successfully evaluated as promising targeting agents for both preclinical (Orlova et al 2006 ; Strand et al 2014 ; Rosestedt et al 2015 ; Garousi et al 2016 ; Andersson et al 2016 ; Oroujeni et al 2018 , 2021 ; Liu et al 2022 ) and clinical (Sörensen et al 2014 , 2016 ; Alhuseinalkhudhur et al 2023 ; Bragina et al 2023 ) imaging of different molecular targets. Safety of this drug class has furthermore been demonstrated clinically with up to three years chronic patient dosing, suggesting viability for repeated administrations (Klint et al 2023 ).…”