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      Application of Immuno-PET in Antibody–Drug Conjugate Development

      , PhD 1 , , PhD 1
      Molecular Imaging
      SAGE Publications
      immuno-PET, antibody–drug conjugates, cancer, molecular imaging, companion diagnostics

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          Targeted therapies hold great promise for cancer treatment and may exhibit even greater efficacy when combined with patient selection tools. The clinical impact of identifying likely responders includes reducing the number of unnecessary and ineffective therapies as well as more accurately determining drug effects. Positron emission tomography (PET) imaging using zirconium-89 radiolabeled monoclonal antibodies (mAbs), also referred to as zirconium-89 ( 89Zr)-immuno-PET, provides a potential biomarker to measure target expression and verify optimal delivery of targeted agents to tumors. Antibody–drug conjugates (ADCs) combine the high affinity and specificity of mAbs with the potency of cytotoxic drugs to target tumor-expressing antigen and destroy cancer cells. Thus, 89Zr-immuno-PET of whole-body biodistribution, pharmacokinetics, and tumor targeting of antibodies and ADCs to predict toxicity and efficacy could help guide individualized treatment. Here, we review how 89Zr-immuno-PET is being used as a companion diagnostic with the development of ADCs. Furthermore, we discuss how 89Zr-immuno-PET may be utilized in future clinical trials as an adjunct tool with novel ADCs to select cancer patients who have the greatest potential to benefit from treatment and improve ADC dosing regimens.

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          Most cited references43

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          Conjugation and radiolabeling of monoclonal antibodies with zirconium-89 for PET imaging using the bifunctional chelate p-isothiocyanatobenzyl-desferrioxamine.

          The positron emitter zirconium-89 ((89)Zr) has very attractive properties for positron emission tomography (PET) imaging of intact monoclonal antibodies (mAbs) using immuno-PET. This protocol describes the step-by-step procedure for the facile radiolabeling of mAbs or other proteins with (89)Zr using p-isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS). First, Df-Bz-NCS is coupled to the lysine-NH(2) groups of a mAb at pH 9.0 (pre-modification), followed by purification using gel filtration. Next, the pre-modified mAb is labeled at room temperature by the addition of [(89)Zr]Zr-oxalic acid solution followed by purification using gel filtration. The entire process of pre-modification, radiolabeling and purification steps will take about 2.5 h.
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            Molecular imaging as a tool to investigate heterogeneity of advanced HER2-positive breast cancer and to predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial.

            Only human epidermal growth factor receptor (HER)2 status determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) has been validated to predict efficacy of HER2-targeting antibody-drug-conjugate trastuzumab emtansine (T-DM1). We propose molecular imaging to explore intra-/interpatient heterogeneity in HER2 mapping of metastatic disease and to identify patients unlikely to benefit from T-DM1.
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              PET imaging with ⁸⁹Zr: from radiochemistry to the clinic.

              The advent of antibody-based cancer therapeutics has led to the concomitant rise in the development of companion diagnostics for these therapies, particularly nuclear imaging agents. A number of radioisotopes have been employed for antibody-based PET and SPECT imaging, notably ⁶⁴Cu, ¹²⁴I, ¹¹¹In, and (99m)Tc; in recent years, however, the field has increasingly focused on ⁸⁹Zr, a radiometal with near ideal physical and chemical properties for immunoPET imaging. In the review at hand, we seek to provide a comprehensive portrait of the current state of ⁸⁹Zr radiochemical and imaging research, including work into the production and purification of the isotope, the synthesis of new chelators, the development of new bioconjugation strategies, the creation of novel ⁸⁹Zr-based agents for preclinical imaging studies, and the translation of ⁸⁹Zr-labeled radiopharmaceuticals to the clinic. Particular attention will also be dedicated to emerging trends in the field, ⁸⁹Zr-based imaging applications using vectors other than antibodies, the comparative advantages and limitations of ⁸⁹Zr-based imaging compared to that with other isotopes, and areas that would benefit from more extensive investigation. At bottom, it is hoped that this review will provide both the experienced investigator and new scientist with a full and critical overview of this exciting and fast-developing field.

                Author and article information

                Mol Imaging
                Mol Imaging
                Molecular Imaging
                SAGE Publications (Sage CA: Los Angeles, CA )
                29 October 2018
                Jan-Dec 2018
                : 17
                : 1536012118801223
                [1 ]Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
                Author notes
                [*]Kendra S. Carmon and Ali Azhdarinia, Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, 1825 Pressler Street, SRB, Houston, TX77030, USA. Emails: kendra.s.carmon@ 123456uth.tmc.edu ; ali.azhdarinia@ 123456uth.tmc.edu
                © The Author(s) 2018

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                : 10 May 2018
                : 01 August 2018
                : 01 August 2018
                Funded by: John S. Dunn Foundation, FundRef https://doi.org/10.13039/100006988;
                Award ID: L-AU-0002-19940421
                Review Article
                Custom metadata
                January-December 2018

                immuno-pet,antibody–drug conjugates,cancer,molecular imaging,companion diagnostics


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