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Radiolabelling and preclinical characterisation of [89Zr]Zr-Df-ATG-101 bispecific to PD-L1/4–1BB.

Authors :
Cao, Zhipeng
Wichmann, Christian Werner
Burvenich, Ingrid Julienne Georgette
Osellame, Laura Danielle
Guo, Nancy
Rigopoulos, Angela
O'Keefe, Graeme Joseph
Scott, Fiona Elizabeth
Lorensuhewa, Nirmal
Lynch, Kevin Patrick
Scott, Andrew Mark
Source :
European Journal of Nuclear Medicine & Molecular Imaging; Sep2024, Vol. 51 Issue 11, p3202-3214, 13p
Publication Year :
2024

Abstract

Purpose: ATG-101, a bispecific antibody that simultaneously targets the immune checkpoint PD-L1 and the costimulatory receptor 4-1BB, activates exhausted T cells upon PD-L1 crosslinking. Previous studies demonstrated promising anti-tumour efficacy of ATG-101 in preclinical models. Here, we labelled ATG-101 with <superscript>89</superscript>Zr to confirm its tumour targeting effect and tissue biodistribution in a preclinical model. We also evaluated the use of immuno-PET to study tumour uptake of ATG-101 in vivo. Methods: ATG-101, anti-PD-L1, and an isotype control were conjugated with p-SCN-Deferoxamine (Df). The Df-conjugated antibodies were radiolabelled with <superscript>89</superscript>Zr, and their radiochemical purity, immunoreactivity, and serum stability were assessed. We conducted PET/MRI and biodistribution studies on [<superscript>89</superscript>Zr]Zr-Df-ATG-101 in BALB/c nude mice bearing PD-L1-expressing MDA-MB-231 breast cancer xenografts for up to 10 days after intravenous administration of [<superscript>89</superscript>Zr]Zr-labelled antibodies. The specificity of [<superscript>89</superscript>Zr]Zr-Df-ATG-101 was evaluated through a competition study with unlabelled ATG-101 and anti-PD-L1 antibodies. Results: The Df-conjugation and [<superscript>89</superscript>Zr]Zr -radiolabelling did not affect the target binding of ATG-101. Biodistribution and imaging studies demonstrated biological similarity of [<superscript>89</superscript>Zr]Zr-Df-ATG-101 and [<superscript>89</superscript>Zr]Zr-Df-anti-PD-L1. Tumour uptake of [<superscript>89</superscript>Zr]Zr-Df-ATG-101 was clearly visualised using small-animal PET imaging up to 7 days post-injection. Competition studies confirmed the specificity of PD-L1 targeting in vivo. Conclusion: [<superscript>89</superscript>Zr]Zr-Df-ATG-101 in vivo distribution is dependent on PD-L1 expression in the MDA-MB-231 xenograft model. Immuno-PET with [<superscript>89</superscript>Zr]Zr-Df-ATG-101 provides real-time information about ATG-101 distribution and tumour uptake in vivo. Our data support the use of [<superscript>89</superscript>Zr]Zr-Df-ATG-101 to assess tumour and tissue uptake of ATG-101. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
16197070
Volume :
51
Issue :
11
Database :
Complementary Index
Journal :
European Journal of Nuclear Medicine & Molecular Imaging
Publication Type :
Academic Journal
Accession number :
179394604
Full Text :
https://doi.org/10.1007/s00259-024-06742-6