Journal
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
Volume 48, Issue 10, Pages 3075-3088Publisher
SPRINGER
DOI: 10.1007/s00259-021-05251-0
Keywords
PD-L1; TGF-β Bintrafusp alfa; Zirconium-89; Immunotherapy
Funding
- EMD Serono/Merck KGaA
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This study aimed to optimize the Zr-89-radiolabelling of bintrafusp alfa investigational drug product and controls and characterize the radioconjugates in vitro and in vivo. Results showed nanomolar affinities for PD-L1 with Zr-89-Df-bintrafusp alfa and Zr-89-avelumab, demonstrating their biologic similarity in a murine breast cancer model. The in vivo distribution pattern of bintrafusp alfa is driven by its PD-L1 binding arm, as shown in biodistribution and imaging studies.
Purpose tau his study aimed to optimize the Zr-89-radiolabelling of bintrafusp alfa investigational drug product and controls, and perform the in vitro and in vivo characterization of Zr-89-Df-bintrafusp alfa and Zr-89-Df-control radioconjugates. Methods Bintrafusp alfa (anti-PD-L1 human IgG1 antibody fused to TGF-beta receptor II (TGF-beta RII), avelumab (anti-PD-L1 human IgG1 control antibody), isotype control (mutated inactive anti-PD-L1 IgG1 control antibody), and trap control (mutated inactive anti-PD-L1 human IgG1 fused to active TGF-beta RII) were chelated with p-isothiocyanatobenzyl-desferrioxamine (Df). After radiolabelling with zirconium-89 (Zr-89), radioconjugates were assessed for radiochemical purity, immunoreactivity, antigen binding affinity, and serum stability in vitro. In vivo biodistribution and imaging studies were performed with PET/CT to identify and quantitate Zr-89-Df-bintrafusp alfa tumour uptake in a PD-L1/TGF-beta-positive murine breast cancer model (EMT-6). Specificity of Zr-89-Df-bintrafusp alfa was assessed via a combined biodistribution and imaging experiment in the presence of competing cold bintrafusp alfa (1 mg/kg). Results Nanomolar affinities for PD-L1 were achieved with Zr-89-Df-bintrafusp alfa and Zr-89-avelumab. Biodistribution and imaging studies in PD-L1- and TGF-beta-positive EMT-6 tumour-bearing BALB/c mice demonstrated the biologic similarity of Zr-89-Df-bintrafusp alfa and Zr-89-avelumab indicating the in vivo distribution pattern of bintrafusp alfa is driven by its PD-L1 binding arm. Competition study with 1 mg of unlabelled bintrafusp alfa or avelumab co-administered with trace dose of Zr-89-labelled bintrafusp alfa demonstrated the impact of dose and specificity of PD-L1 targeting in vivo. Conclusion Molecular imaging of Zr-89-Df-bintrafusp alfa biodistribution was achievable and allows non-invasive quantitation of tumour uptake of Zr-89-Df-bintrafusp alfa, suitable for use in bioimaging clinical trials in cancer patients.
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