177Lu radiolabeling and preclinical theranostic study of 1C1m-Fc: an anti-TEM- 1 scFv-Fc fusion protein in soft tissue sarcoma

J. Delage (1, 2) , A. Faivre-Chauvet (3) , J K Fierle (1, 2) , S Gnesin (1, 2) , N Schaefer (1, 2) , G Coukos (1, 2) , S M Dunn (1, 2) , D Viertl (1, 2) , J O Prior (1, 2)

1 UNIL - Université de Lausanne = University of Lausanne
2 CHUV - Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
3 CRCINA-ÉQUIPE 13 - Nuclear Oncology

Purpose: TEM-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 177 Lu for use in soft tissue sarcomas models. Methods: 1C1m-Fc was first conjugated to p-SCN-Bn-DOTA using different excess molar ratios and labeled with 177 Lu. 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. Results: The DOTA conjugation and the labeling with 177 Lu 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. Conclusion: TEM-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.

Mots clés: TEM-1; CD-248; Soft-tissue sarcoma; Theranostic; 1C1m-Fc; DOTA conjugation

Domaines: Cancer

J. Delage, A. Faivre-Chauvet, J K Fierle, S Gnesin, N Schaefer, et al.. 177Lu radiolabeling and preclinical theranostic study of 1C1m-Fc: an anti-TEM- 1 scFv-Fc fusion protein in soft tissue sarcoma. EJNMMI Research, 2020, 10 (1), pp.98. ⟨10.1186/s13550-020-00685-3⟩. ⟨inserm-02923381⟩