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Biodistribution and pharmacokinetic evaluation of different mAb formats, targeting endothelin A receptor-positive glioblastoma stem cells using in vivo immunoPET imaging
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International audience. Aim/Introduction: Glioblastoma (GBM) is the most common histological type of brain tumor and its incidence has been steadily increasing since 1990. They contain cells with different levels of differentiation and highly tumorigenic GBM stem cells. The latter, which are poorly sensitive to current anti-mitotic treatments, are probably one of the causes of the resurgence of this cancer in patients. To improve survival rates and quality of life, the detection of GBM stem cells becomes a major issue. Endothelin-1 receptors (ETA and ETB) are known to be deregulated and overexpressed in several tumors and particularly in GBM (1,2). In order to develop novel diagnostic strategies against glioblastoma, we have developed a radioligand based on antibody anti-ETA (rendomab A63) (3) coupled with 89Zr isotope (t1/2=3.3 days). We previously described the capacity of fluorescent RA63 to target ETA in a preclinical model (4). To diagnose endothelin A receptor-positive glioblastoma stem cells, we investigated the biodistribution and pharmacokinetic of two chimeric RA63 formats by immunoPET imaging (the full-length mAb xiRA63 and the Fab xiRA63) in a preclinical orthotopic xenograft mouse model with an ETA+ GBM stem cell line, Gli7, established from a patient’s biopsies (5). Materials and Methods: In vitro production and functionality assessment of xiRA63 and Fab xiRA63 were carried out using Expi-CHO cells. We radiolabeled them with 89Zr through DFO chelator randomly conjugated. Both radioligands were i.v. injected on a nude mouse model implanted orthotopically with Gli7 cells and imaged overtime. Results: We described the generation of the two fully functional recombinant chimeric mAb formats: xiRA63 and its Fab. We were able to assess the passage of the blood-brain tumor barrier (BBTB) and their capacity to bind the ETA receptor by the biodistribution and PK studies in a preclinical GBM mouse model by immunoPET imaging.Conclusion: The antibody xiRA63 demonstrates better BBTB translocation into the brain compared to its Fab fragment as well as the binding ability to the ETA positive GBM stem cells. References: 1. Egidy, G. et al. Lab. Investig. J. Tech. Methods Pathol. 80, 1681-1689 (2000). 2. Rosanò, L., Spinella, F. & Bagnato, A. Nat. Rev. Cancer 13, 637-651 (2013). 3. Boquet, D., French patent 07/02/2018 2018FR-0051026, WO2019/155151. 4. Herbet, A. et al. Physiol. Res. 67, 257-264 (2018). 5. Guichet, P.-O. et al. Glia (2012) doi:10.1002/glia.22429.
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