Denis R Beckford-Vera1, Alba Gonzalez-Junca2, Jessica S Janneck3, Tony L Huynh3, Joseph E Blecha3, Youngho Seo3, Xiaojuan Li3, Henry F VanBrocklin3, Benjamin L Franc3. 1. Department of Radiology and Molecular Imaging, University of California San Francisco, 185 Berry St., Suite 350, San Francisco, CA, 94107, USA. denis.beckfordvera@ucsf.edu. 2. Department of Radiation Oncology, University of California San Francisco, 2340 Sutter St., San Francisco, CA, 94115, USA. 3. Department of Radiology and Molecular Imaging, University of California San Francisco, 185 Berry St., Suite 350, San Francisco, CA, 94107, USA.
Abstract
PURPOSE: Tumor necrosis factor alpha (TNFα) drives inflammation and bone degradation in patients with rheumatoid arthritis (RA). Some RA patients experience a rapid clinical response to TNFα inhibitors such as certolizumab pegol (CZP) while other patients show limited to no response. Current methods for imaging RA have limited sensitivity and do not assist in the selection of patients most likely to respond to immune-mediated therapy. Herein, we developed a novel positron emission tomography (PET) radiotracer for immuno-PET imaging of TNFα in transgenic human TNFα-expressing mice. PROCEDURES: CZP was modified with p-isothiocyanatobenzyl-deferoxamine (DFO) and radiolabeled with Zr-89. The biological activity of [89Zr]DFO-CZP was evaluated by HPLC and binding assay using human recombinant TNFα (hTNFα). The feasibility of specific immuno-PET imaging of human TNFα was assessed in a transgenic mouse model of RA that expresses human TNFα. This model resembles the progression of RA in humans by maintaining lower levels of circulating hTNFα and exhibits chronic arthritis in the forepaw and hind paw joints. The dosimetry of [89Zr]DFO-CZP in humans was estimated using microPET/CT imaging in Sprague Dawley rats. RESULTS: [89Zr]DFO-CZP was isolated with radiolabeling yields of 85 ± 6 % (n = 5) and specific activities ranging from 74 to 185 MBq/mg (n = 5). Following size exclusion purification, the radiochemical purity of [89Zr]DFO-CZP was greater than 97 %. [89Zr]DFO-CZP retained high immunoreactivity with more than 95 % of the radioactivity shifted into higher molecular weight complexes. Images showed increasing uptake of the tracer in forepaw and hind paw joints with disease progression. No uptake was observed in the model previously administered with an excess amount of unmodified CZP and in normal control mice, demonstrating in vivo specific uptake of [89Zr]DFO-CZP. CONCLUSION: The feasibility of immuno-PET imaging of human TNFα with [89Zr]DFO-CZP has been demonstrated in a preclinical model of RA.
PURPOSE:Tumor necrosis factor alpha (TNFα) drives inflammation and bone degradation in patients with rheumatoid arthritis (RA). Some RA patients experience a rapid clinical response to TNFα inhibitors such as certolizumab pegol (CZP) while other patients show limited to no response. Current methods for imaging RA have limited sensitivity and do not assist in the selection of patients most likely to respond to immune-mediated therapy. Herein, we developed a novel positron emission tomography (PET) radiotracer for immuno-PET imaging of TNFα in transgenic human TNFα-expressing mice. PROCEDURES: CZP was modified with p-isothiocyanatobenzyl-deferoxamine (DFO) and radiolabeled with Zr-89. The biological activity of [89Zr]DFO-CZP was evaluated by HPLC and binding assay using human recombinant TNFα (hTNFα). The feasibility of specific immuno-PET imaging of human TNFα was assessed in a transgenic mouse model of RA that expresses human TNFα. This model resembles the progression of RA in humans by maintaining lower levels of circulating hTNFα and exhibits chronic arthritis in the forepaw and hind paw joints. The dosimetry of [89Zr]DFO-CZP in humans was estimated using microPET/CT imaging in Sprague Dawley rats. RESULTS: [89Zr]DFO-CZP was isolated with radiolabeling yields of 85 ± 6 % (n = 5) and specific activities ranging from 74 to 185 MBq/mg (n = 5). Following size exclusion purification, the radiochemical purity of [89Zr]DFO-CZP was greater than 97 %. [89Zr]DFO-CZP retained high immunoreactivity with more than 95 % of the radioactivity shifted into higher molecular weight complexes. Images showed increasing uptake of the tracer in forepaw and hind paw joints with disease progression. No uptake was observed in the model previously administered with an excess amount of unmodified CZP and in normal control mice, demonstrating in vivo specific uptake of [89Zr]DFO-CZP. CONCLUSION: The feasibility of immuno-PET imaging of human TNFα with [89Zr]DFO-CZP has been demonstrated in a preclinical model of RA.
Authors: Fatemeh Khodadust; Aiarpi Ezdoglian; Maarten M Steinz; Judy R van Beijnum; Gerben J C Zwezerijnen; Gerrit Jansen; Sander W Tas; Conny J van der Laken Journal: Int J Mol Sci Date: 2022-06-25 Impact factor: 6.208
Authors: Alba Gonzalez-Junca; Oliver Reiners; Luis D Borrero-Garcia; Denis Beckford-Vera; Ann A Lazar; William Chou; Steve Braunstein; Henry VanBrocklin; Benjamin L Franc; Mary Helen Barcellos-Hoff Journal: Int J Radiat Oncol Biol Phys Date: 2020-09-29 Impact factor: 7.038
Authors: Sinan Wang; Jun Li; Jun Hua; Yang Su; Denis R Beckford-Vera; Walter Zhao; Mayuri Jayaraman; Tony L Huynh; Ning Zhao; Yung-Hua Wang; Yangjie Huang; Fujun Qin; Sui Shen; Daniel Gioeli; Robert Dreicer; Renuka Sriram; Emily A Egusa; Jonathan Chou; Felix Y Feng; Rahul Aggarwal; Michael J Evans; Youngho Seo; Bin Liu; Robert R Flavell; Jiang He Journal: Clin Cancer Res Date: 2020-12-08 Impact factor: 13.801
Authors: Denis R Beckford-Vera; Robert R Flavell; Youngho Seo; Enrique Martinez-Ortiz; Maya Aslam; Cassandra Thanh; Emily Fehrman; Marion Pardons; Shreya Kumar; Amelia N Deitchman; Vahid Ravanfar; Brailee Schulte; I-Wei Katherine Wu; Tony Pan; Jacqueline D Reeves; Christopher C Nixon; Nikita S Iyer; Leonel Torres; Sadie E Munter; Tony Hyunh; Christos J Petropoulos; Rebecca Hoh; Benjamin L Franc; Lucio Gama; Richard A Koup; John R Mascola; Nicolas Chomont; Steven G Deeks; Henry F VanBrocklin; Timothy J Henrich Journal: Nat Commun Date: 2022-03-09 Impact factor: 17.694