Radiolabelling and preclinical characterization of <sup>89</sup>Zr-Df-radiolabelled bispecific anti-PD-L1/TGF-βRII fusion protein bintrafusp alfa.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33608805.
- Also identified by DOI 10.1007/s00259-021-05251-0.
- No licence information is recorded for this record.
- Because redistribution is not established, this page shows the abstract only. Follow the links below for the full text.
Abstract
Τhis study aimed to optimize the <sup>89</sup>Zr-radiolabelling of bintrafusp alfa investigational drug product and controls, and perform the in vitro and in vivo characterization of <sup>89</sup>Zr-Df-bintrafusp alfa and <sup>89</sup>Zr-Df-control radioconjugates. Bintrafusp alfa (anti-PD-L1 human IgG1 antibody fused to TGF-β receptor II (TGF-βRII), 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-βRII) were chelated with p-isothiocyanatobenzyl-desferrioxamine (Df). After radiolabelling with zirconium-89 (<sup>89</sup>Zr), 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 <sup>89</sup>Zr-Df-bintrafusp alfa tumour uptake in a PD-L1/TGF-β-positive murine breast cancer model (EMT-6). Specificity of <sup>89</sup>Zr-Df-bintrafusp alfa was assessed via a combined biodistribution and imaging experiment in the presence of competing cold bintrafusp alfa (1 mg/kg). Nanomolar affinities for PD-L1 were achieved with <sup>89</sup>Zr-Df-bintrafusp alfa and <sup>89</sup>Zr-avelumab. Biodistribution and imaging studies in PD-L1- and TGF-β-positive EMT-6 tumour-bearing BALB/c mice demonstrated the biologic similarity of <sup>89</sup>Zr-Df-bintrafusp alfa and <sup>89</sup>Zr-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 <sup>89</sup>Zr-labelled bintrafusp alfa demonstrated the impact of dose and specificity of PD-L1 targeting in vivo. Molecular imaging of <sup>89</sup>Zr-Df-bintrafusp alfa biodistribution was achievable and allows non-invasive quantitation of tumour uptake of <sup>89</sup>Zr-Df-bintrafusp alfa, suitable for use in bioimaging clinical trials in cancer patients.
Medical subject headings
- B7-H1 Antigen
- Positron Emission Tomography Computed Tomography