Automated radiosynthesis of [89Zr]Zr-DFOSq-Durvalumab for imaging of PD-L1 expressing tumours in vivo

Wichmann, Christian; Poniger, Stan; Guo, Nancy; Roselt, Peter; Rudd, Stacey E.; Donnelly, Paul S.; Blyth, Benjamin; Zuylekom, Jessica Van; Rigopoulos, Angela; Burvenich, Ingrid; Morandeau, Laurence; Mohamed, Shifaza; Nowak, Anna K.; Hegi‐Johnson, Fiona; MacManus, Michael; Scott, Andrew

doi:10.1016/j.nucmedbio.2023.108351

Cited by 8 publications

(12 citation statements)

References 27 publications

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“…The radiolabeling of DFOSq–mAb conjugates has been optimized to give radiochemical yields of 95.6% ± 0.7% after only 15 min at 1 μg/MBq. The labeling has also been further developed into an automated radiosynthesis which allows for consistent, reproducible synthesis across multiple sites, with the conjugate demonstrating excellent stability over 7 days …”

Section: Radiolabeling Antibodies With Zirconium-89mentioning

confidence: 99%

“…(c) PET/CT maximum intensity projection images of PD-L1 positive HCC827 xenograft mice 24, 48, and 144 h post administration of [ 89 Zr]ZrDFOSq–durvalumab (T = tumor). Reproduced with permission from Wichmann et al Copyright 2023 the authors. .…”

Section: Translation To Imaging In Humansmentioning

confidence: 99%

“…The DFOSq–durvalumab conjugate is easily radiolabeled with [ 89 Zr]Zr IV (Figure b), and the process has now been fully automated to give radiochemical yields of up to 75% with a radiochemical purity >99%, providing a radiochemistry protocol that can be independently repeated . [ 89 Zr]ZrDFOSq–durvalumab was evaluated in preclinical mouse model PET imaging and demonstrated excellent uptake and retention of the tracer in PDL1-positive xenografts with low background signal and encouraged translation to studies in humans (Figure c).…”

Section: Translation To Imaging In Humansmentioning

confidence: 99%

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Diagnostic Positron Emission Tomography Imaging with Zirconium-89 Desferrioxamine B Squaramide: From Bench to Bedside

Rudd,

Noor,

Morgan

et al. 2024

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS: Molecular imaging with antibodies radiolabeled with positron-emitting radionuclides combines the affinity and selectivity of antibodies with the sensitivity of Positron Emission Tomography (PET).PET imaging allows the visualization and quantification of the biodistribution of the injected radiolabeled antibody, which can be used to characterize specific biological interactions in individual patients. This characterization can provide information about the engagement of the antibody with a molecular target such as receptors present in elevated levels in tumors as well as providing insight into the distribution and clearance of the antibody. Potential applications of clinical PET with radiolabeled antibodies include identifying patients for targeted therapies, characterization of heterogeneous disease, and monitoring treatment response.Antibodies often take several days to clear from the blood pool and localize in tumors, so PET imaging with radiolabeled antibodies requires the use of a radionuclide with a similar radioactive half-life. Zirconium-89 is a positron-emitting radionuclide that has a radioactive half-life of 78 h and relatively low positron emission energy that is well suited to radiolabeling antibodies. It is essential that the zirconium-89 radionuclide be attached to the antibody through chemistry that provides an agent that is stable in vivo with respect to the dissociation of the radionuclide without compromising the biological activity of the antibody. This Account focuses on our research using a simple derivative of the bacterial siderophore desferrioxamine (DFO) with a squaramide ester functional group, DFO-squaramide (DFOSq), to link the chelator to antibodies. In our work, we produce conjugates with an average ∼4 chelators per antibody, and this does not compromise the binding of the antibody to the target. The resulting antibody conjugates of DFOSq are stable and can be easily radiolabeled with zirconium-89 in high radiochemical yields and purity. Automated methods for the radiolabeling of DFOSq−antibody conjugates have been developed to support multicenter clinical trials. Evaluation of several DFOSq conjugates with antibodies and low molecular weight targeting agents in tumor mouse models gave PET images with high tumor uptake and low background. The promising preclinical results supported the translation of this chemistry to human clinical trials using two different radiolabeled antibodies. The potential clinical impact of these ongoing clinical trials is discussed. The use of DFOSq to radiolabel relatively low molecular weight targeting molecules, peptides, and peptide mimetics is also presented. Low molecular weight molecules typically clear the blood pool and accumulate in target tissue more rapidly than antibodies, so they are usually radiolabeled with positron-emitting radionuclides with shorter radioactive half-lives such as fluorine-18 (t 1/2 ∼ 110 min) or gallium-68 (t 1/2 ∼ 68 min). Radiolabeling peptides and peptide mimetics with z...

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Section: Radiolabeling Antibodies With Zirconium-89mentioning

confidence: 99%

Section: Translation To Imaging In Humansmentioning

confidence: 99%

Section: Translation To Imaging In Humansmentioning

confidence: 99%

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Diagnostic Positron Emission Tomography Imaging with Zirconium-89 Desferrioxamine B Squaramide: From Bench to Bedside

Rudd,

Noor,

Morgan

et al. 2024

Acc. Chem. Res.

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“…The most commonly applied 89 Zr purification procedure is based on the methodology reported initially by Verel et al and involves dissolving the target in concentrated HCl, and loading it onto hydroxamate resin, trapping the 89 Zr onto the resin, washing the hydroxamate resin with 2 M HCl and water to eliminate the residual yttrium, and eluting the 89 Zr from the hydroxamate resin with 1 M oxalic acid solution (Verel et al 2003 ; Queern et al 2017 ). Lower concentrations of oxalic acid (down to 0.05 M) or other reagents like sodium citrate have been reported for elution, potentially improving subsequent radiolabeling applications (Wichmann et al 2023 ; Larenkov et al 2019 ). This process effectively removes elemental impurities, including trace radionuclidic impurities that may have been formed from the irradation of target components (Gaja et al 2020 ).…”

Section: Production Of Zirconium-89mentioning

confidence: 99%

Good practices for 89Zr radiopharmaceutical production and quality control

Wuensche,

Lyashchenko,

van Dongen

et al. 2024

EJNMMI radiopharm. chem.

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Background During the previous two decades, PET imaging of biopharmaceuticals radiolabeled with zirconium-89 has become a consistent tool in preclinical and clinical drug development and patient selection, primarily due to its advantageous physical properties that allow straightforward radiolabeling of antibodies (89Zr-immuno-PET). The extended half-life of 78.4 h permits flexibility with respect to the logistics of tracer production, transportation, and imaging and allows imaging at later points in time. Additionally, its relatively low positron energy contributes to high-sensitivity, high-resolution PET imaging. Considering the growing interest in radiolabeling antibodies, antibody derivatives, and other compound classes with 89Zr in both clinical and pre-clinical settings, there is an urgent need to acquire valuable recommendations and guidelines towards standardization of labeling procedures. Main body This review provides an overview of the key aspects of 89Zr-radiochemistry and radiopharmaceuticals. Production of 89Zr, conjugation with the mostly used chelators and radiolabeling strategies, and quality control of the radiolabeled products are described in detail, together with discussions about alternative options and critical steps, as well as recommendations for troubleshooting. Moreover, some historical background on 89Zr-immuno-PET, coordination chemistry of 89Zr, and future perspectives are provided. This review aims to serve as a quick-start guide for scientists new to the field of 89Zr-immuno-PET and to suggest approaches for harmonization and standardization of current procedures. Conclusion The favorable PET imaging characteristics of 89Zr, its excellent availability due to relatively simple production and purification processes, and the development of suitable bifunctional chelators have led to the widespread use of 89Zr. The combination of antibodies and 89Zr, known as 89Zr-immuno-PET, has become a cornerstone in drug development and patient selection in recent years. Despite the advanced state of 89Zr-immuno-PET, new developments in chelator conjugation and radiolabeling procedures, application in novel compound classes, and improved PET scanner technology and quantification methods continue to reshape its landscape towards improving clinical outcomes.

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“…A growing variety of commercially available radiosynthesis systems offer automated radiolabeling, purification, and formulation of radiopharmaceuticals. These systems, also known as modules, provide users with a high degree of flexibility with respect to the chemistry and processes they can perform, allowing users to manufacture a wide range of products 1–4 . While processes involving F‐18 and C‐11 typically make use of many of these features, such as semi‐preparative HPLC purification of the intermediate or final compound, radiopharmaceuticals labeled with a radiometal often do not 1,5 .…”

Section: Introductionmentioning

confidence: 99%

Automated radiolabeling and handling of ¹⁷⁷Lu‐ and ²²⁵Ac‐PSMA‐617 using a robotic pipettor

Ahn,

Belanger

2024

Labelled Comp Radiopharmac

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While automated modules for F‐18 and C‐11 radiosyntheses are standardized with features such as multiple reactors, vacuum connection and semi‐preparative HPLC, labeling and processing of compounds with radiometals such as Zr‐89, Lu‐177 and Ac‐225 often do not require complex manipulations and are frequently performed manually by a radiochemist. These procedures typically involve transferring solutions to and from vials using pipettes followed by heating of the reaction mixture, and do not require all the features found in most commercial automated synthesis units marketed as F‐18 or C‐11 modules. Here we present an efficient automated method for performing radiosyntheses involving radiometals by adapting a commercially available robotic pipettor originally developed for high‐throughput processing of biological samples. While a robotic pipettor is less costly than a radiosynthesis module, it holds many similar advantages over manual radiosynthesis such as minimization of operator error, lower operator exposure rates, and abbreviated synthesis times, among others. To demonstrate the feasibility of using the OpenTrons OT‐2 robotic pipettor to perform automated radiosyntheses, we radiolabeled and formulated 177Lu‐PSMA‐617 and 225Ac‐PSMA‐617 on the system. The OT‐2 was then used to help streamline the quality control process for both products, further minimizing manual handling by and exposure to the radiochemist.

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Automated radiosynthesis of [89Zr]Zr-DFOSq-Durvalumab for imaging of PD-L1 expressing tumours in vivo

Cited by 8 publications

References 27 publications

Diagnostic Positron Emission Tomography Imaging with Zirconium-89 Desferrioxamine B Squaramide: From Bench to Bedside

Diagnostic Positron Emission Tomography Imaging with Zirconium-89 Desferrioxamine B Squaramide: From Bench to Bedside

Good practices for 89Zr radiopharmaceutical production and quality control

Automated radiolabeling and handling of ¹⁷⁷Lu‐ and ²²⁵Ac‐PSMA‐617 using a robotic pipettor

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Automated radiosynthesis of [89Zr]Zr-DFOSq-Durvalumab for imaging of PD-L1 expressing tumours in vivo

Cited by 8 publications

References 27 publications

Diagnostic Positron Emission Tomography Imaging with Zirconium-89 Desferrioxamine B Squaramide: From Bench to Bedside

Diagnostic Positron Emission Tomography Imaging with Zirconium-89 Desferrioxamine B Squaramide: From Bench to Bedside

Good practices for 89Zr radiopharmaceutical production and quality control

Automated radiolabeling and handling of 177Lu‐ and 225Ac‐PSMA‐617 using a robotic pipettor

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Product

Resources

About

Automated radiolabeling and handling of ¹⁷⁷Lu‐ and ²²⁵Ac‐PSMA‐617 using a robotic pipettor