Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/25908
Title: Radiolabelling and preclinical characterization of 89Zr-Df-radiolabelled bispecific anti-PD-L1/TGF-βRII fusion protein bintrafusp alfa.
Austin Authors: Burvenich, Ingrid J G;Goh, Yit Wooi;Guo, Nancy;Gan, Hui K ;Rigopoulos, Angela;Cao, Diana;Liu, Zhanqi;Ackermann, Uwe ;Wichmann, Christian Werner;McDonald, Alexander Franklin;Huynh, Nhi;O'Keefe, Graeme Joseph;Gong, Sylvia Jie;Scott, Fiona Elizabeth;Li, Linghui;Geng, Wanping;Zutshi, Anup;Lan, Yan;Scott, Andrew M 
Affiliation: EMD Serono Research & Development Institute, Inc., a business of Merck KGaA, Darmstadt, Germany, Billerica, MA, USA
Olivia Newton-John Cancer Research Institute
School of Cancer Medicine, La Trobe University, Melbourne, Australia
Molecular Imaging and Therapy
Department of Medicine, University of Melbourne, Melbourne, Australia
School of Engineering and Mathematical Sciences, La Trobe University, Melbourne, Australia
Issue Date: 19-Feb-2021
metadata.dc.date: 2021-02-19
Publication information: European Journal of Nuclear Medicine and Molecular Imaging 2021; online first: 19 February
Abstract: Τhis study aimed to optimize the 89Zr-radiolabelling of bintrafusp alfa investigational drug product and controls, and perform the in vitro and in vivo characterization of 89Zr-Df-bintrafusp alfa and 89Zr-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 (89Zr), 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 89Zr-Df-bintrafusp alfa tumour uptake in a PD-L1/TGF-β-positive murine breast cancer model (EMT-6). Specificity of 89Zr-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 89Zr-Df-bintrafusp alfa and 89Zr-avelumab. Biodistribution and imaging studies in PD-L1- and TGF-β-positive EMT-6 tumour-bearing BALB/c mice demonstrated the biologic similarity of 89Zr-Df-bintrafusp alfa and 89Zr-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 89Zr-labelled bintrafusp alfa demonstrated the impact of dose and specificity of PD-L1 targeting in vivo. Molecular imaging of 89Zr-Df-bintrafusp alfa biodistribution was achievable and allows non-invasive quantitation of tumour uptake of 89Zr-Df-bintrafusp alfa, suitable for use in bioimaging clinical trials in cancer patients.
URI: https://ahro.austin.org.au/austinjspui/handle/1/25908
DOI: 10.1007/s00259-021-05251-0
ORCID: 0000-0001-8384-2403
0000-0001-7319-8546
0000-0001-9259-2258
0000-0001-5341-8804
0000-0001-5261-8118
0000-0002-6656-295X
PubMed URL: 33608805
Type: Journal Article
Subjects: Bintrafusp alfa
Immunotherapy
PD-L1
TGF-β
Zirconium-89
Appears in Collections:Journal articles

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