In Vivo Preclinical Assessment of the VEGF Targeting Potential of the Newly Synthesized [52Mn]Mn-DOTAGA-Bevacizumab Using Experimental Cervix Carcinoma Mouse Model

Abstract

Among humanized monoclonal antibodies, bevacizumab specifically binds to vascular endothelial growth factor A (VEGF-A). VEGF-A is an overexpressed biomarker in cervix carcinoma and is involved in the development and maintenance of tumor-associated neo-angiogenesis. The non-invasive positron emission tomography using radiolabeled target-specific antibodies (immuno-PET) provides the longitudinal and quantitative assessment of tumor target expression. Due to antibodies having a long-circulating time, radioactive metal ions (e.g., 52Mn) with longer half-lives are the best candidates for isotope conjugation. The aim of our preclinical study was to assess the biodistribution and tumor-targeting potential of 52Mn-labeled DOTAGA-bevacizumab. The VEGF-A targeting potential of the new immuno-PET ligand was assessed by using the VEGF-A expressing KB-3-1 (human cervix carcinoma) tumor-bearing CB17 SCID mouse model and in vivo PET/MRI imaging. Due to the high and specific accumulation found in the subcutaneously located experimental cervix carcinoma tumors, [52Mn]Mn-DOTAGA-bevacizumab is a promising PET probe for the detection of VEGF-A positive gynecological tumors, for patient selection, and monitoring the efficacy of therapies targeting angiogenesis.

Advances in macrocyclic chelators for positron emission tomography imaging

“…More recently, Csikos et al successfully synthesized a 52 Mn-DOTAGA-bevacizumab PET probe with high RCY and suitable stability properties for in vivo PET/MR imaging in a VEGF-A expressing KB-3-1 cervix carcinoma tumor-bearing mouse. 178 The quantitative PET images showed that the KB-3-1 tumors were recognizable from 4 h after injection, and the accumulation of radiopharmaceuticals increased with time and started to plateau 2-3 days (Figure 10B). Although it gradually declined over time, tumor-to-organ ratios remained high until the end of the study, and traditional Mn 2+ target organs such as the thyroid, liver, pancreas, and kidney had little tracer uptake.…”

“…White arrows: subcutaneously growing KB-3-1 cervix tumors. 178 Reproduced with permission. 161 Copyright 2019, Royal Society of Chemistry.…”

“…175,176 DOTA have been successfully employed as chelators for Mn 2+ radioisotopes and showed high in vitro and in vivo inertness. 177,178 Graves et al originally published the in vivo assessment of 52 Mn-labeled mAb in 2015. 177 PET imaging in mice bearing 4T1 xenograft tumors showed peak tumor uptake of 18.7 ± 2.7%ID/g at 24 h p.i., with a delayed blood clearance over time and a relatively significant bone and spleen uptake (>10%ID/g, 120 h p.i.).…”

“…Representative decay‐corrected coronal PET/MRI images were obtained from 4 h to 10 days post injection of 52 Mn‐DOTAGA‐bevacizumab. White arrows: subcutaneously growing KB‐3‐1 cervix tumors 178 . Reproduced with permission 161 .…”

“…Copyright 2019, Royal Society of Chemistry. Reproduced under the terms of the CC‐BY license 178 . Copyright 2023, Csaba Csikos.…”