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Direct radiolabeling of nivolumab with Ga-68: A novel PET tracer to detect PD-1 expressing tumors

Silvia Migliari

Nuclear Medicine and Molecular Imaging Department, University Hospital of Parma, via Gramsci 14, 43126 Parma, Italy

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Antonino Sammartano

Nuclear Medicine and Molecular Imaging Department, University Hospital of Parma, via Gramsci 14, 43126 Parma, Italy

Benedetta Pellegrino

Medical Oncology Unit, University Hospital of Parma, via Gramsci 14, 43126 Parma, Italy

Davide Cavazzini

Department of Chemical and Life Sciences, University of Parma, Parco Area delle Scienze, 11/a - 43124 Parma, Italy

Simone Ottonello

Department of Chemical and Life Sciences, University of Parma, Parco Area delle Scienze, 11/a - 43124 Parma, Italy

Gabriele Missale

Laboratory of Viral Immunopathology, University Hospital of Parma, via Gramsci 14, 43126 Parma, Italy

Antonino Musolino

Medical Oncology Unit, University Hospital of Parma, via Gramsci 14, 43126 Parma, Italy

Livia Ruffini

Nuclear Medicine and Molecular Imaging Department, University Hospital of Parma, via Gramsci 14, 43126 Parma, Italy

DOI: 10.15761/MCA.1000116

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In recent years, the blockade of immune checkpoint molecules with monoclonal antibodies, like those targeting the PD-1/PD-L1 pathway, has enabled the development of breakthrough therapies in oncology, leading to delayed tumor growth and increased survival.

Non-invasive methods permitting whole-body detection of PD-1 and PD-L1 at high sensitivity and resolution could thus be highly useful in-patient selection and monitoring of PD-1/PD-L1 expression during disease progression and treatment, therefore different approaches have been developed in order to label tumor-specific monoclonal antibodies (Mo)Abs with PET and SPECT radioisotopes.

Aim of this study was to develop an immunoPET tracer for imaging PD-1 using Nivolumab (BMS-936558, ONO-4538, or MDX1106, trade name Opdivo®; Bristol-Myers Squibb, Princeton, NJ, USA), the first-in-human immunoglobulin G4 (IgG4) PD-1 immune checkpoint inhibitor antibody, and the PET radioisotope Gallium-68.

Direct labeling approach procedure involves the use of a solution to buffer the acidity of the eluate 68GaCl3 of a commercially avaible TiO2-based 68Ge/68Ga generator (Eckert & Ziegler, E&Z, Berlin, Germany) in order to prepare the carboxylic and aminic groups of Nivolumab that can be conveniently used as coordinating sites to bind Gallium-68.

The 68Ge/68Ga generator was eluted with 10 ml 0.1 M HCl following the manufacture's protocol.

A solution of ultrapure Na2021 Copyright OAT. All rights reserv99%, metal basis) was added to this 0.1M HCl solution of [68Ga]Ga-Chloride bringing the pH to 4.5-5. The resulting [68Ga]Ga-acetate solution (ca. 50-100 MBq) was added to Nivolumab (10 mg/ml) protein solution.

The [68Ga]Ga-Nivolumab solution was incubated in a heat block at 45°C for 40 minutes. The resulting [68Ga]Ga-Nivolumab was isolated by centrifugation and the radiolabeling yield has been calculated.

The radiochemical purity of [68Ga]Ga-Nivolumab was determined using instant thin layer chromatography (TLC): TLC-SG strips are used as stationary phase and ammonium acetate (sol aq. 10%) : MeOH (1:1) as mobile phase to separate free Gallium-68, which remains at the bottom, while the radiolabelled (Mo)Abs moved to the top.

The promising labeling results show an efficient and rapid direct procedure to label (Mo)Abs with Gallim-68 reducing reaction steps and antibody preparation and allowing the future formulation of freeze-dried kit to obtain a PET imaging of PD-1 expressing tumors.

Article Type

Short Communication

Publication history

Received date: October 04, 2017
Accepted date: October 19, 2017
Published date: October 23, 2017

Copyright

© 2017 Migliari S. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Migliari S, Sammartano A, Pellegrino B, Cavazzini D, Ottonello S, et al. (2017) Direct radiolabeling of Nivolumab with Ga-68: A novel PET tracer to detect PD-1 expressing tumors. Med Clin Arch 1: DOI: 10.15761/MCA.1000116

Corresponding author

Silvia Migliari

Nuclear Medicine and Molecular Imaging Department, University Hospital of Parma, via Gramsci 14, 43126 Parma, Italy

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

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