Immuno-PET: Design options and clinical proof-of-concept

Radioimmunoconjugates have been used for over 30 years in nuclear medicine applications. In the last few years, advances in cancer biology knowledge have led to the identification of new molecular targets specific to certain patient subgroups. The use of these targets in targeted therapies approaches has allowed the developments of specifically tailored therapeutics for patients. As consequence of the PET-imaging progresses, nuclear medicine has developed powerful imaging tools, based on monoclonal antibodies, to in vivo characterization of these tumor biomarkers. This imaging modality known as immuno-positron emission tomography (immuno-PET) is currently in fastest-growing and its medical value lies in its ability to give a non-invasive method to assess the in vivo target expression and distribution and provide key-information on the tumor targeting. Currently, immuno-PET presents promising probes for different nuclear medicine topics as staging/stratification tool, theranostic approaches or predictive/prognostic biomarkers. To develop a radiopharmaceutical drug that can be used in immuno-PET approach, it is necessary to find the best compromise between the isotope choice and the immunologic structure (full monoclonal antibody or derivatives). Through some clinical applications, this paper review aims to discuss the most important aspects of the isotope choice and the usable proteic structure that can be used to meet the clinical needs.

[1]  S. Larson,et al.  Pretargeting: A Path Forward for Radioimmunotherapy , 2022, The Journal of Nuclear Medicine.

[2]  C. Pirich,et al.  ImmunoPET: Antibody-Based PET Imaging in Solid Tumors , 2022, Frontiers in Medicine.

[3]  Kwang Il Kim,et al.  Therapeutic Response Monitoring with 89Zr-DFO-Pertuzumab in HER2-Positive and Trastuzumab-Resistant Breast Cancer Models , 2022, Pharmaceutics.

[4]  A. Redfern,et al.  89Zirconium-labelled girentuximab (89Zr-TLX250) PET in Urothelial Cancer Patients (ZiPUP): protocol for a phase I trial of a novel staging modality for urothelial carcinoma , 2022, BMJ Open.

[5]  Jinha M. Park,et al.  Use of 64Cu-DOTA-Trastuzumab PET to Predict Response and Outcome of Patients Receiving Trastuzumab Emtansine for Metastatic Breast Cancer: A Pilot Study , 2021, The Journal of Nuclear Medicine.

[6]  I. C. Kok,et al.  89Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer. , 2021, Annals of oncology : official journal of the European Society for Medical Oncology.

[7]  A. Wu,et al.  ImmunoPET: harnessing antibodies for imaging immune cells , 2021, Molecular Imaging and Biology.

[8]  R. Boellaard,et al.  Potential and pitfalls of 89Zr-immuno-PET to assess target status: 89Zr-trastuzumab as an example , 2021, EJNMMI Research.

[9]  J. Wolchok,et al.  CD8-Targeted PET Imaging of Tumor-Infiltrating T Cells in Patients with Cancer: A Phase I First-in-Humans Study of 89Zr-Df-IAB22M2C, a Radiolabeled Anti-CD8 Minibody , 2021, The Journal of Nuclear Medicine.

[10]  T. Uehara,et al.  Copper-64-Labeled Antibody Fragments for Immuno-PET/Radioimmunotherapy with Low Renal Radioactivity Levels and Amplified Tumor-Kidney Ratios , 2021, ACS omega.

[11]  R. Boellaard,et al.  PD-L1 PET/CT Imaging with Radiolabeled Durvalumab in Patients with Advanced-Stage Non–Small Cell Lung Cancer , 2021, The Journal of Nuclear Medicine.

[12]  B. Zeglis,et al.  Inverse electron demand Diels–Alder click chemistry for pretargeted PET imaging and radioimmunotherapy , 2021, Nature Protocols.

[13]  N. Devoogdt,et al.  Site-Specific Radiolabeling of a Human PD-L1 Nanobody via Maleimide–Cysteine Chemistry , 2021, Pharmaceuticals.

[14]  P. Hofman,et al.  Nanobodies for Medical Imaging: About Ready for Prime Time? , 2021, Biomolecules.

[15]  E. Oosterwijk,et al.  Phase I study to assess safety, biodistribution and radiation dosimetry for 89Zr-girentuximab in patients with renal cell carcinoma , 2021, European Journal of Nuclear Medicine and Molecular Imaging.

[16]  P. Jonasson,et al.  Preclinical Evaluation of 99mTc-ZHER2:41071, a Second-Generation Affibody-Based HER2-Visualizing Imaging Probe with a Low Renal Uptake , 2021, International journal of molecular sciences.

[17]  V. Rohmer,et al.  Anti-CEA Pretargeted Immuno-PET Shows Higher Sensitivity Than DOPA PET/CT in Detecting Relapsing Metastatic Medullary Thyroid Carcinoma: Post Hoc Analysis of the iPET-MTC Study , 2021, The Journal of Nuclear Medicine.

[18]  Byung Il Kim,et al.  A preliminary clinical trial to evaluate 64Cu-NOTA-Trastuzumab as a positron emission tomography imaging agent in patients with breast cancer , 2020, EJNMMI Research.

[19]  F. Mottaghy,et al.  HER2-directed antibodies, affibodies and nanobodies as drug-delivery vehicles in breast cancer with a specific focus on radioimmunotherapy and radioimmunoimaging , 2020, European Journal of Nuclear Medicine and Molecular Imaging.

[20]  Yakun Wan,et al.  Nuclear imaging-guided PD-L1 blockade therapy increases effectiveness of cancer immunotherapy , 2020, Journal for ImmunoTherapy of Cancer.

[21]  Jason S. Lewis,et al.  Harnessing 64Cu/67Cu for a theranostic approach to pretargeted radioimmunotherapy , 2020, Proceedings of the National Academy of Sciences.

[22]  A. Krishnan,et al.  Identifying CD38+ cells in patients with multiple myeloma: first-in-human imaging using copper-64-labeled daratumumab. , 2020, Blood advances.

[23]  C. Bailly,et al.  Promising clinical performance of pretargeted immuno-PET with anti-CEA bispecific antibody and gallium-68-labelled IMP-288 peptide for imaging colorectal cancer metastases: a pilot study , 2020, European Journal of Nuclear Medicine and Molecular Imaging.

[24]  Zachary T. Rosenkrans,et al.  Noninvasive Evaluation of CD20 Expression Using 64Cu-Labeled F(ab′)2 Fragments of Obinutuzumab in Lymphoma , 2020, The Journal of Nuclear Medicine.

[25]  H. Ploegh,et al.  Nanobodies as non-invasive imaging tools , 2020, Immuno-oncology technology.

[26]  L. Shen,et al.  Impact of 68Ga-NOTA-MAL-MZHER2 PET imaging in advanced gastric cancer patients and therapeutic response monitoring , 2020, European Journal of Nuclear Medicine and Molecular Imaging.

[27]  R. Fields,et al.  Preclinical Evaluation of an Engineered Single-Chain Fragment Variable-Fragment Crystallizable Targeting Human CD44 , 2020, The Journal of Nuclear Medicine.

[28]  R. Fields,et al.  Preclinical Evaluation of an Engineered scFv-Fc Targeting Human CD44. , 2020, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[29]  Gary A Ulaner,et al.  CD38-targeted Immuno-PET of Multiple Myeloma: From Xenograft Models to First-in-Human Imaging. , 2020, Radiology.

[30]  Zheyan Liu,et al.  A pooled analysis of the prognostic value of PD-L1 in melanoma: evidence from 1062 patients , 2020, Cancer Cell International.

[31]  Zachary T. Rosenkrans,et al.  ImmunoPET: Concept, Design, and Applications. , 2020, Chemical reviews.

[32]  M. Campone,et al.  Initial Clinical Results of a Novel Immuno-PET Theranostic Probe in Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer , 2020, The Journal of Nuclear Medicine.

[33]  W. Oyen,et al.  Lesion detection by [89Zr]Zr-DFO-girentuximab and [18F]FDG-PET/CT in patients with newly diagnosed metastatic renal cell carcinoma , 2019, European Journal of Nuclear Medicine and Molecular Imaging.

[34]  J. Humm,et al.  Copper-64 trastuzumab PET imaging: a reproducibility study. , 2019, The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of....

[35]  H. Waldmann Human Monoclonal Antibodies: The Benefits of Humanization. , 2018, Methods in molecular biology.

[36]  Ronald Boellaard,et al.  89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer , 2018, Nature Medicine.

[37]  Laurent S Dumas,et al.  Radiometal-labeled anti-VCAM-1 nanobodies as molecular tracers for atherosclerosis – impact of radiochemistry on pharmacokinetics , 2018, Biological chemistry.

[38]  S. Sleijfer,et al.  89Zr-trastuzumab PET supports clinical decision making in breast cancer patients, when HER2 status cannot be determined by standard work up , 2018, European Journal of Nuclear Medicine and Molecular Imaging.

[39]  E. D. de Vries,et al.  Molecular Imaging of Radiolabeled Bispecific T-Cell Engager 89Zr-AMG211 Targeting CEA-Positive Tumors , 2018, Clinical Cancer Research.

[40]  J. Steinbach,et al.  Recent progress using the Staudinger ligation for radiolabeling applications. , 2018, Journal of labelled compounds & radiopharmaceuticals.

[41]  R. Bose,et al.  Evaluation of [89Zr]trastuzumab-PET/CT in differentiating HER2-positive from HER2-negative breast cancer , 2018, Breast Cancer Research and Treatment.

[42]  S. Larson,et al.  Pharmacokinetics, Biodistribution, and Radiation Dosimetry for 89Zr-Trastuzumab in Patients with Esophagogastric Cancer , 2018, The Journal of Nuclear Medicine.

[43]  Jinha M. Park,et al.  Tumor Uptake of 64Cu-DOTA-Trastuzumab in Patients with Metastatic Breast Cancer , 2018, The Journal of Nuclear Medicine.

[44]  Serge K. Lyashchenko,et al.  89Zr-Trastuzumab PET/CT for Detection of Human Epidermal Growth Factor Receptor 2–Positive Metastases in Patients With Human Epidermal Growth Factor Receptor 2–Negative Primary Breast Cancer , 2017, Clinical nuclear medicine.

[45]  M. Brechbiel,et al.  Bifunctional aryliodonium salts for highly efficient radioiodination and astatination of antibodies. , 2017, Bioorganic & medicinal chemistry.

[46]  Katsunori Tanaka,et al.  A One-Pot Three-Component Double-Click Method for Synthesis of [67Cu]-Labeled Biomolecular Radiotherapeutics , 2017, Scientific Reports.

[47]  S. Gambhir,et al.  Development of Novel ImmunoPET Tracers to Image Human PD-1 Checkpoint Expression on Tumor-Infiltrating Lymphocytes in a Humanized Mouse Model , 2017, Molecular Imaging and Biology.

[48]  G. Riggins,et al.  Prevention of tumor seeding during needle biopsy by chemotherapeutic-releasing gelatin sticks , 2017, Oncotarget.

[49]  P. Lambin,et al.  PET imaging of zirconium-89 labelled cetuximab: A phase I trial in patients with head and neck and lung cancer. , 2017, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[50]  D. de Jong,et al.  Performance of 89Zr-Labeled-Rituximab-PET as an Imaging Biomarker to Assess CD20 Targeting: A Pilot Study in Patients with Relapsed/Refractory Diffuse Large B Cell Lymphoma , 2017, PloS one.

[51]  R. Reilly,et al.  Development and preclinical studies of 64Cu-NOTA-pertuzumab F(ab′)2 for imaging changes in tumor HER2 expression associated with response to trastuzumab by PET/CT , 2017, mAbs.

[52]  P. Lambin,et al.  Quantitative assessment of Zirconium-89 labeled cetuximab using PET/CT imaging in patients with advanced head and neck cancer: a theragnostic approach , 2016, Oncotarget.

[53]  V. Rohmer,et al.  Immuno-PET Using Anticarcinoembryonic Antigen Bispecific Antibody and 68Ga-Labeled Peptide in Metastatic Medullary Thyroid Carcinoma: Clinical Optimization of the Pretargeting Parameters in a First-in-Human Trial , 2016, The Journal of Nuclear Medicine.

[54]  Sarah A. Frye,et al.  [89Zr]Trastuzumab: Evaluation of Radiation Dosimetry, Safety, and Optimal Imaging Parameters in Women with HER2-Positive Breast Cancer , 2016, Molecular Imaging and Biology.

[55]  Emily B. Ehlerding,et al.  Preclinical Pharmacokinetics and Biodistribution Studies of 89Zr-Labeled Pembrolizumab , 2017, The Journal of Nuclear Medicine.

[56]  H. Struijker‐Boudier,et al.  On the Origin of Urinary Renin: A Translational Approach. , 2016, Hypertension.

[57]  W. Oyen,et al.  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. , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[58]  S. Larson,et al.  Targeting of radiolabeled J591 antibody to PSMA-expressing tumors: optimization of imaging and therapy based on non-linear compartmental modeling , 2016, EJNMMI Research.

[59]  C. Vanhove,et al.  Phase I Study of 68Ga-HER2-Nanobody for PET/CT Assessment of HER2 Expression in Breast Carcinoma , 2016, The Journal of Nuclear Medicine.

[60]  Jason S. Lewis,et al.  18F-Based Pretargeted PET Imaging Based on Bioorthogonal Diels–Alder Click Chemistry , 2015, Bioconjugate chemistry.

[61]  Zhongyu Yuan,et al.  High PD-L1 expression was associated with poor prognosis in 870 Chinese patients with breast cancer , 2015, Oncotarget.

[62]  R. Boellaard,et al.  89Zr-cetuximab PET imaging in patients with advanced colorectal cancer , 2015, Oncotarget.

[63]  Danny F. Martinez,et al.  A Phase I/II Study for Analytic Validation of 89Zr-J591 ImmunoPET as a Molecular Imaging Agent for Metastatic Prostate Cancer , 2015, Clinical Cancer Research.

[64]  G. V. van Dongen,et al.  Tumour targeting and radiation dose of radioimmunotherapy with 90Y-rituximab in CD20+ B-cell lymphoma as predicted by 89Zr-rituximab immuno-PET: impact of preloading with unlabelled rituximab , 2015, European Journal of Nuclear Medicine and Molecular Imaging.

[65]  Sharon S. Hori,et al.  Development and Validation of an Immuno-PET Tracer as a Companion Diagnostic Agent for Antibody-Drug Conjugate Therapy to Target the CA6 Epitope. , 2015, Radiology.

[66]  C. Bodet-Milin,et al.  Tumor Immunotargeting Using Innovative Radionuclides , 2015, International journal of molecular sciences.

[67]  K. Togashi,et al.  Gallium-68-Labeled Anti-HER2 Single-Chain Fv Fragment: Development and In Vivo Monitoring of HER2 Expression , 2015, Molecular Imaging and Biology.

[68]  R. Boellaard,et al.  Pilot study of 89Zr-bevacizumab positron emission tomography in patients with advanced non-small cell lung cancer , 2014, EJNMMI Research.

[69]  W. Oyen,et al.  PET/CT with 89Zr-trastuzumab and 18F-FDG to individualize treatment with trastuzumab emtansine (T-DM1) in metastatic HER2-positive breast cancer (mBC). , 2014 .

[70]  Serge K. Lyashchenko,et al.  A prospective pilot study of (89)Zr-J591/prostate specific membrane antigen positron emission tomography in men with localized prostate cancer undergoing radical prostatectomy. , 2014, The Journal of urology.

[71]  R. Tavaré,et al.  Quantitative ImmunoPET of Prostate Cancer Xenografts with 89Zr- and 124I-Labeled Anti-PSCA A11 Minibody , 2014, The Journal of Nuclear Medicine.

[72]  Chris Orvig,et al.  Matching chelators to radiometals for radiopharmaceuticals. , 2014, Chemical Society reviews.

[73]  J. Bading,et al.  Functional Imaging of Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer Using 64Cu-DOTA-Trastuzumab PET , 2014, The Journal of Nuclear Medicine.

[74]  L. Khawli,et al.  Enhanced tumor retention of a radiohalogen label for site-specific modification of antibodies. , 2013, Journal of medicinal chemistry.

[75]  M. Brechbiel,et al.  Mapping biological behaviors by application of longer-lived positron emitting radionuclides. , 2013, Advanced drug delivery reviews.

[76]  Marleen Keyaerts,et al.  Synthesis, Preclinical Validation, Dosimetry, and Toxicity of 68Ga-NOTA-Anti-HER2 Nanobodies for iPET Imaging of HER2 Receptor Expression in Cancer , 2013, The Journal of Nuclear Medicine.

[77]  M. Lubberink,et al.  Biodistribution, radiation dosimetry and scouting of 90Y-ibritumomab tiuxetan therapy in patients with relapsed B-cell non-Hodgkin’s lymphoma using 89Zr-ibritumomab tiuxetan and PET , 2012, European Journal of Nuclear Medicine and Molecular Imaging.

[78]  T. Nayak,et al.  86Y based PET radiopharmaceuticals: radiochemistry and biological applications. , 2011, Medicinal chemistry (Shariqah (United Arab Emirates)).

[79]  R. Reilly,et al.  A comparison of 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT , 2011, EJNMMI research.

[80]  G. V. van Dongen,et al.  (89)Zr-labeled compounds for PET imaging guided personalized therapy. , 2011, Drug discovery today. Technologies.

[81]  A. Martineau,et al.  A method for accurate modelling of the crystal response function at a crystal sub-level applied to PET reconstruction , 2011, Physics in medicine and biology.

[82]  P. L. Jager,et al.  Biodistribution of 89Zr‐trastuzumab and PET Imaging of HER2‐Positive Lesions in Patients With Metastatic Breast Cancer , 2010, Clinical pharmacology and therapeutics.

[83]  J. Barbet,et al.  Feasibility of the radioastatination of a monoclonal antibody with astatine-211 purified by wet extraction. , 2008, Journal of labelled compounds & radiopharmaceuticals.

[84]  Shuang Liu Bifunctional coupling agents for radiolabeling of biomolecules and target-specific delivery of metallic radionuclides. , 2008, Advanced drug delivery reviews.

[85]  Tom K Lewellen,et al.  Recent developments in PET detector technology , 2008, Physics in medicine and biology.

[86]  A. Ullrich,et al.  Paul Ehrlich's magic bullet concept: 100 years of progress , 2008, Nature Reviews Cancer.

[87]  M. Brechbiel,et al.  Development of radioimmunotherapeutic and diagnostic antibodies: an inside-out view. , 2007, Nuclear medicine and biology.

[88]  J. Humm,et al.  Preoperative characterisation of clear-cell renal carcinoma using iodine-124-labelled antibody chimeric G250 (124I-cG250) and PET in patients with renal masses: a phase I trial. , 2007, The Lancet. Oncology.

[89]  W. Moses Recent Advances and Future Advances in Time-of-Flight PET. , 2006, Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment.

[90]  R. Boellaard,et al.  89Zr immuno-PET: comprehensive procedures for the production of 89Zr-labeled monoclonal antibodies. , 2003, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[91]  Jamal Zweit,et al.  Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody: implications for trial design of antiangiogenic antibodies. , 2002, Journal of the National Cancer Institute.

[92]  J. Finley,et al.  The Spectrum of Immunohistochemical Reactivity of Monoclonal Antibody DS6 in Nongynecologic Neoplasms , 2002, Applied immunohistochemistry & molecular morphology : AIMM.

[93]  T. Waldmann,et al.  Preparation and in vivo evaluation of linkers for 211At labeling of humanized anti-Tac. , 2001, Nuclear medicine and biology.

[94]  J. Humm,et al.  PET Imaging of 86Y-Labeled Anti-Lewis Y Monoclonal Antibodies in a Nude Mouse Model: Comparison Between 86Y and 111In Radiolabels , 2001 .

[95]  C. Baird,et al.  The pilot study. , 2000, Orthopedic nursing.

[96]  A. Lefvert,et al.  The clinical significance of HAMA in patients treated with mouse monoclonal antibodies , 1992, Cell Biophysics.

[97]  J. McGahan,et al.  Treatment of a Patient with b Cell Lymphoma by 1-131 Lym-1 Monoclonal Antibodies , 1987, The International journal of biological markers.

[98]  J. Bender,et al.  Phase I Trial , 1983 .

[99]  R. Reba,et al.  Radiolabeling of antibodies. , 1980, Cancer research.

[100]  M. Herlyn,et al.  Colorectal carcinoma-specific antigen: detection by means of monoclonal antibodies. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[101]  J R van Nagell,et al.  Use of radiolabeled antibodies to carcinoembryonic antigen for the detection and localization of diverse cancers by external photoscanning. , 1978, The New England journal of medicine.

[102]  G. Köhler,et al.  Immunoglobulin production by lymphocyte hybridomas , 1978, European journal of immunology.

[103]  C. Milstein,et al.  Continuous cultures of fused cells secreting antibody of predefined specificity , 1975, Nature.

[104]  W. Hunter,et al.  The labelling of proteins to high specific radioactivities by conjugation to a 125I-containing acylating agent. , 1973, The Biochemical journal.

[105]  Goldenberg,et al.  Immuno-PET using anti-CEA bispecific antibody and 68 Ga-labeled peptide in metastatic medullary thyroid carcinoma: clinical optimization of the pretargeting parameters in a First-in Human trial. , 2016 .

[106]  S. Batra,et al.  Antibody labeling with radioiodine and radiometals. , 2014, Methods in molecular biology.

[107]  Lynn C Francesconi,et al.  PET imaging with ⁸⁹Zr: from radiochemistry to the clinic. , 2013, Nuclear medicine and biology.

[108]  J. Humm,et al.  PET imaging of (86)Y-labeled anti-Lewis Y monoclonal antibodies in a nude mouse model: comparison between (86)Y and (111)In radiolabels. , 2001, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[109]  D. Wilbur,et al.  Radiohalogenation of proteins: an overview of radionuclides, labeling methods, and reagents for conjugate labeling. , 1992, Bioconjugate chemistry.