Abstract
PurposeTEM-1 (tumor endothelial marker-1) is a single-pass transmembrane cell surface glycoprotein expressed at high levels by tumor vasculature and malignant cells. We aimed to perform a preclinical investigation of a novel anti-TEM-1 scFv-Fc fusion antibody, 1C1m-Fc, which was radiolabeled with 177Lu for use in soft tissue sarcomas models.Methods1C1m-Fc was first conjugated to p-SCN-Bn-DOTA using different excess molar ratios and labeled with 177Lu. To determine radiolabeled antibody immunoreactivity, Lindmo assays were performed.The in vivo behavior of [177Lu]Lu-1C1m-Fc was characterized in mice bearing TEM-1 positive (SK-N-AS) and negative (HT-1080) tumors by biodistribution and single-photon emission SPECT/CT imaging studies. Estimated organ absorbed doses were obtained based on biodistribution results.ResultsThe DOTA conjugation and the labeling with 177Lu were successful with a radiochemical purity of up to 95%. Immunoreactivity after radiolabeling was 86% ± 4%. Biodistribution showed a specific uptake in TEM-1 positive tumor versus liver as critical non-specific healthy organ, and this specificity is correlated to the number of chelates per antibody. A 1.9-fold higher signal at 72 h was observed in SPECT/CT imaging in TEM-1 positive tumors versus control tumors.ConclusionTEM-1 is a promising target that could allow a theranostic approach to soft-tissue sarcoma, and 1C1m-Fc appears to be a suitable targeting candidate. In this study, we observed the influence of the ratio DOTA/antibody on the biodistribution. The next step will be to investigate the best conjugation to achieve an optimal tumor-to-organ radioactivity ratio and to perform therapy in murine xenograft models as a prelude to future translation in patients.
Highlights
The tumor endothelial marker 1 (TEM-1) known as endosialin or CD248 is a type I single-pass transmembrane cell surface glycoprotein of 757 amino acids (80.9 kD) belonging to the C-lectin receptor superfamily
1C1m-Fc and its conjugates were analyzed by highpressure liquid chromatography (HPLC) (Fig. 2)
For group 1 with KiovigTM saturation, uptake in TEM-1 negative tumor was significantly lower than TEM-1 positive tumor with uptake clearing over time from 8.4 ± 0.97% injected activity (IA)/g at 24 h (p = 0.0006) and 4.4 ± 1.9% IA/g on day 6 (p = 0.02)
Summary
The tumor endothelial marker 1 (TEM-1) known as endosialin or CD248 is a type I single-pass transmembrane cell surface glycoprotein of 757 amino acids (80.9 kD) belonging to the C-lectin receptor superfamily. TEM-1 is expressed on mesenchymal lineage cells including pericytes and fibroblasts during tissue development, tumor neovascularization, and inflammation [4, 5]. TEM-1 expression has been localized to tumor vasculature, mainly in pericytes and stromal fibroblasts and in some cases to malignant cells [6, 7]. TEM-1 is implicated in tumor cell adhesion and migration, development, neoangiogenesis, and tumor progression [8, 9]. It has been associated with tumor aggressiveness and poor patient prognosis [10, 11]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call