Table of Contents
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PREFACE
List of Contributors
Molecular Imaging in the Development of Antibody-Drug Conjugates
Abstract
INTRODUCTION
ANTIBODY-DRUG CONJUGATES AS A CANCER THERAPEUTIC
Design and Structure
Mechanism of Action
Clinical Development and Design
Target Antigen Selection
Antibody Selection
Drug Payload
Antibody-Drug Conjugation
ROLE OF MOLECULAR IMAGING IN ADC DEVELOPMENT
Pre-clinical Studies of Molecular Imaging of ADCs
Molecular Imaging in Clinical Development of ADCs
ErbB2/HER2
EGFR
TAG-72
CONCLUSION AND FUTURE DIRECTIONS
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Preclinical Applications with Phage Display-derived Peptides
Abstract
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
References
Perspectives in 11C and 18F Radiochemistry
Abstract
INTRODUCTION
11C - EXPANDING THE TOOLBOX
18F - TOWARDS ENHANCED BIOORTHOGONALITY
OUTLOOK
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Introduction to Radionanotargeting in the 1990's: Dosimetry and Optimization of Antisense Oligonucleotide Radiotherapy in Vivo
Abstract
Introduction
Dose Calculation: From Macro to Micro
Discussion
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
References
Role of SPECT/CT Imaging with Gamma-emitted Radionuclides in Personalized Treatment of Cancer Patients
Abstract
INTRODUCTION
Radioiodine SPECT/CT 131I diagnosis and treatment of thyroid cancer
SPECT/CT Imaging of Retrosternal Goiter and Thyroid Nodularity
SPECT/CT Imaging оf Parathyroid Adenomas
SPECT/CT Imaging of Neuroendocrine Tumors
SPECT/CT Imaging with 123I /131I-MIBG
SPECT/CT Imaging of Prostate Cancer
SPECT/CT Imaging of Sentinel Lymph Nodes
SPECT/CT Imaging in Bone Scintigraphy
SPECT/CT Tumor Imaging with 99mTc-Sestamibi/99mTc-Tetrofosmin
REFERENCES
Radionanotargeting and Precision Radiotherapy Planning in Patients with Breast Cancer
Abstract
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
References
The Diagnostic Potential of Radiolabelled Neurotensin in PET Imaging of Patients with Pancreatic Cancer: Results from In Vivo, Animal And Human Studies
Abstract
Neurotensin and Neurotensin Receptors in Pancreatic Ductal Adenocarcinoma
Diagnostics of Pancreatic Ductal Adenocarcinoma with Radiolabelled Neurotensin Analogues: Preclinical Data
Diagnostics of Pancreatic Ductal Adenocarcinoma with Radiolabelled Neurotensin Analogues: Clinical Data
Conclusion
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
References
Dr. Saul Hertz (1905–1950) Discovers the Medical Uses of Radioactive Iodine: The First Targeted Cancer Therapy
Abstract
A Pivotal Question
Laboratory Studies
The First Therapeutic Use of RAI
RAI: The First and Gold Standard of Targeted Cancer Therapy
Legacy
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Dosimetric Approach to Radioactive Iodine Therapy of Differentiated Thyroid Cancer
Abstract
INTRODUCTION
My Friendship with Prof. Kalevi Kairemo
Background of Dosimetric Approach to RAI treatment of DTC
SUBJECTS AND METHODS
Patients
Determination of Therapy Response
Measurement of MPD by Counting Blood Radioactivity
Measurement of MPD by Metaphase Chromosomal Analysis of Peripheral Blood Lymphocytes
RAI Whole-body Scan (WBS)
Statistical Analysis
RESULTS
Determination of MPD
Treatment Response and Side Effects of RAI Treatment
DISCUSSION
CONCLUDING REMARKS
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Extent of Surgery and Following Treatment Depending on The Risk Evaluation of Thyroid Cancer
Abstract
Meeting in Lappeenranta
Strange Attitude
Primary Diagnostics of Cancer
Extent of Surgery in Thyroid Cancer Patients
Using Methods of Nuclear Medicine
CONCLUSIONS
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
References
The Rise of Biopharmaceuticals and Immuno-PET: Where Pharmacy and Radiopharmacy Meet
Abstract
The Emerging Role of Biopharmaceuticals
The Early Days of Imaging Biopharmaceuticals
Intermezzo Dedicated to My Friend Prof. Dr. Kalevi Kairemo
The Introduction of 89Zr-immuno-PET
Technical Maturation of89Zr-immuno-PET
89Zr-Tracer Quantification
89Zr-immuno-PET in Drug Development
CONCLUSIONS
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
In the Wake of European Winds and Head and Neck Radioisotope Imaging
Abstract
INTRODUCTION I - Friendship
INTRODUCTION II - Research
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Radionuclide Management of Prostate Cancer: Molecular Targeting of Tumour; Strategic Targeting of Patients
Abstract
INTRODUCTION
Current Oncology Practice in Prostate Cancer
Radionuclide PSMA PET Diagnosis in Prostate Cancer
Radionuclide PSMA Therapy of Prostate Cancer
CONCLUDING REMARKS
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Ga-PSMA PET/CT for Patients with Prostate Cancer with PSA Relapse
Abstract
Introduction
Results
Discussion
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
References
Imaging Bladder Cancer
Abstract
INTRODUCTION
Cystoscopy
Advances in Cystoscopy
Fluorescence Cystoscopy or Blue Light Cystoscopy
Optical Coherence Tomography
Storz Professional Image Enhancement System
Narrow-Band Imaging
Other Cystoscopic Techniques
Ultrasound
Computed Tomography
CT for Initial Diagnosis of BCa
CT for BCa Staging
CT for BCa Restaging
Magnetic Resonance Imaging
Morphologic MRI
Diffusion Weighted MRI
Dynamic Contrast-enhanced MRI
Lymphotrophic Nanoparticle Enhanced MRI
Multi-parametric MRI (mp-MRI)
Vesical Imaging-reporting and Data System
Positron Emission Tomography
PET/CT
18F-FDG-PET/CT
18F-FDG-PET/CT for Staging of BCa
18F-FDG-PET/CT for the Response of Neoadjuvant Chemotherapy and Restaging
18F-Sodium Fluoride-PET/CT for Detection of Bone Metastasis
11C-choline/ 11C-acetate-PET/CT
Copper-64-TP3805-PET/CT
PET/MRI
18F-FDG-PET/MRI
11C-acetate-PET/MRI
CONCLUDING REMARKS
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGMENTS
REFERENCES
Radiomolecular Therapy of Neuroendocrine Character, Positive for sst2 Receptor Hepatocellular Malignancies
Abstract
INTRODUCTION
MATERIALS AND METHODS
Patients
Equipment and Procedure
Dosimetry Assessment
Post-treatment and Follow-up Studies
Statistical Analysis
RESULTS
CONCLUSIONS
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGMENTS
REFERENCES
Theranostics in Japan
Abstract
INTRODUCTION
131I-MIBG for malignant pheochromocytoma /paraganglioma
131I-MIBG for high-risk neuroblastoma
211At[NaAt]
meta-211At-astato-benzylguanidine (211At-MABG)
Other 211at Radiocompounds
225Ac-fibroblast activation protein inhibitor (FAPI)
64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM)
P-cadherin-targeted Radioimmunotherapy
68Ga/18F/177Lu-PSMA PET
Endnote
Appreciation
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
References
Theragnostics in Austria
Abstract
Introduction
Thera(g)nostics
Siderophores for Molecular Imaging and Therapy
Cholecystokinin Receptor Thera(g)nostics
Angiogenesis Imaging – Non-invasive Determination of the Integrin αvβ3-Expression
Non-invasive Determination of the Functional Liver Reserve
MITIGATE, NeoFIND, & NeoRAY Clinical Studies
Prostate Cancer Thera(g)nostics
Somatostatin Receptor Thera(g)nostics
Neurotensin Receptor Imaging
Conclusion
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
References
Precision Oncology Through Radiating Bullets: What All We Have Conquered and What All We Have To
Abstract
INTRODUCTION
NUCLEAR MEDICINE JOURNEY OF INDIA
JOURNEY OF THERAGNOSTICS IN INDIA
AVAILABILITY OF THERAGNOSTIC RADIOISOTOPES AND RADIOPHARMACEUTICALS
WHERE ARE WE TODAY IN THERAGNOSTICS
CONSTRAINTS & EXPECTED SOLUTIONS
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Current Status of PSMA Targeted Alpha Therapy in Prostate Cancer Patients
Abstract
Introduction
Clinical Experience in 225Ac-PSMA
225Ac-PSMA TAT Toxicity Profile
Clinical Experience with 213Bismuth-PSMA TAT
CONCLUSION AND FUTURE RECOMMENDATIONS
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Nanotheranostics: A Dream Coming True
Abstract
Prospects of Multimodal Imaging in Medicine
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
“Fit for Purpose” 64Cu Labeled Liposome Formulations Specialized for Enriched Targeting to 1) Bone Marrow Spleen; 2) lymph Nodes; or 3) Tumor
Abstract
Introduction
Methods
Results and Discussion
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Theranostics at the Crossroads of Precision Health and Precision Medicine
Abstract
Precision Health
Precision Medicine
Theranostics
Conclusion
References
Oncolytic Immunotherapy: From Spontaneous Regression to Development of Armed Gene Modified Viruses
Abstract
Introduction
Inducing Spontaneous Regression
Using Bacteria Against Cancer
Use of Wild Type Viruses in Tumor Therapy
The War Against Cancer
Cancer Immunotherapy
Naturally Occurring Oncolytic Viruses
Recombinant Oncolytic Viruses
Armed Oncolytic Viruses
Oncolysis Causes Antitumor Immunity
Dendritic Cell Therapy
Adoptive T-cell Therapy
Gene Modified T-cell Therapy
Tumors that Disappear without Being Detected
Checkpoint Inhibitors
An Unexpected Twist: The Gut Microbiome
Nature’s Own Anti-cancer Device?
Conclusion
CONSENT FOR PUBLICATION
Conflict of interest
Acknowledgements
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Boron Neutron Capture Therapy and Targeted Alpha Therapy for Intractable Cancers Combined with Positron Emission Tomography/Computed Tomography
Abstract
INTRODUCTION
Boron Neutron Capture Therapy (BNCT)
18F-FBPA PET in Normal Humans
Clinical Trial of the BNCT
Targeted α Therapy with Astatine 211 (211At)
211At Production and Purification
211At-NaAt for Thyroid Cancer
Tumor Growth Suppression Effect of 211At-NaAt
211At-labeled Phenylalanine (211At-Phe)
Tumor Growth Suppression Effect of 211At-Phe
211 At-astatino α-methyl Tyrosine (211At-AAMT)
Tumor Growth Suppression Effect of 211At-AAMT
CONCLUDING REMARKS
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Targeting Imaging Brain Lesions with PET/CT: F18-CH and F-18-FLT
Abstract
F-18-CH: a Less Investigated Radiopharmaceutical in Brain Tumors
FLT: Targeting Proliferation in Brain Tumors; Where We Stand
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
FDG Uptake by Brown Adipose Tissue in Paediatric and Adolescent Hodgkin Lymphoma, Visualised on PET/CT Performed at Diagnosis
Abstract
Introduction
Material and Methods
Patients
FDG PET/CT Practice
FDG PET/CT Reading
Statistics
Results
Discussion
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
References
[99mTc]Tc – MIBI as Oncologic Radiotracer
Abstract
99m-Tc-MIBI – PHYSIOLOGIC DISTRIBUTION
99mTc-MIBI IN MULTIPLE MYELOMA (MM)
99m-Tc-MIBI IN BRAIN TUMORS
SCINTIMAMMOGRAPHY
LUNG CANCER
99m-Tc MIBI IN THYROID NODULES
OTHER MALIGNANCIES
Conclusion
References
The Actual Role of Nuclear Molecular Imaging in the Follow-up of Chemotherapy-Induced Cardiac Dysfunction
Abstract
INTRODUCTION
Clinical Features of Cardiotoxicity
Common Chemotherapeutics with Cardiotoxicity and Their Mode of Action
Cardiotoxicity Diagnosis and Monitoring Techniques
Endomyocardial Biopsy
Biomarkers
Cardiovascular Imaging
Echocardiography
Cardiac Magnetic Resonance Imaging (CMR)
Nuclear Imaging Techniques
Cardiac Function Monitoring
Nuclear Imaging in Chemotherapy-Induced Cardiac Damage
In-111 Monoclonal Antimyosin Scintigraphy
Tc-99m Annexin V Scintigraphy
I-123 MIBG Scintigraphy
Tc-99m-MIBI Scintigraphy
I-123-BMIPP Scintigraphy
PET/MR Studies
In Summary
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
References
Quantitation of Myocardial Perfusion using 15O-Water PET: From a Research Tool to Clinical Routine
Abstract
Early years of 15oxygen PET imaging
Early Cardiac 15O-water PET Studies in Turku PET Centre
Towards Routine Clinical use for The Diagnosis of CAD
The Outcome and Quantitative Myocardial Perfusion
From Research Tool to Clinical Routine
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
Bone Targeted Radionuclide Therapy in Russia From Beta- to Alpha- Emitters
Abstract
INTRODUCTION
SHORT HISTORY OF THE BONE-SEEKING RADIOPHARMACEUTICALS USE IN RUSSIA
Strontium-89 Chloride
153 Sm Oxabifor/153 Sm EDMP
Re-188 Based RPhs
Radium Chloride [223Ra] (Xofigo®)
CLINICAL CASE
SURVIVAL OF PATIENTS RECEIVING BONE-TARGETED THERAPY
CONCLUSION
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENT
References
Role of Beta-Emitter Sm-153 in Combined and Complex Therapy of Skeletal Metastases
Abstract
Introduction
Material and methods
Results
Conclusions
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
References
Molecular Radiobiology and Radionuclides Therapy Concepts
Abstract
INTRODUCTION
Basic Concepts of Radiation Biology
Direct Interaction
Indirect Interaction
Bystander Effect
Concepts of Radionuclides Therapy (RNT)
Radionuclides Therapy Emitter Types
Beta Emitter
Alpha Emitter
Conclusion
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
REFERENCES
War and Peace Inside - imaging Immune Attack in Blood Vessels
Abstract
Introduction
Immune Escape by Microbes and Tumor Cells
Complement and its Regulators
Dysfunction of Complement
Maintaining Tolerance to Self
Radioscintigraphy Showed that Factor H Binding in Vivo Depends on Prior Deposition of C3b
Immune Escape by the Intravascular Parasite Schistosoma Mansoni
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
Acknowledgments
References
Observations on Russia’s COVID-19 Politics
Abstract
Conclusions
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
References
Radiomics Analysis of 177Lu-PSMA I&T Radioligand Therapy Dosimetry in a Castration Resistant Metastatic Prostate Cancer Patient
Abstract
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
References
Dancing in the Rain. Cancer as a Personal Experience
Abstract
INTRODUCTION
My Own Cancer Experience
Getting To Know That You Have Cancer
Having Cancer and Fighting It
When To Give Up the Fight
Dying in Cancer
Planning For Your Death
Survival as a Phenomenon
CONCLUSION
REFERENCES
The Flat Earth: Working with Patients and Patient Advocates in our Connected World
Abstract
CONSENT FOR PUBLICATION
CONFLICT OF INTEREST
ACKNOWLEDGEMENTS
References
The Evolution of Radionanotargeting towards Clinical Precision Oncology: A Festschrift in Honor of Kalevi Kairemo
Edited by:
Antti Jekunen
Professor in Clinical Oncology,
Turku University, Finland
Chief Physician,
Vaasa Oncology Clinic, Finland
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FOREWORD
The last decade has seen the emergence of radionanotargeting as a practice changing therapeutic approach in the clinic, particularly in the field of oncology. This has extended from regulatory approvals for radiolabeled peptide therapy in somatostatin-expressing tumors [1], to impressive results with radiolabeled peptides and antibodies against prostate-specific membrane antigen (PSMA) in prostate cancer patients [2], and exciting results for a broad array of radiolabeled engineered protein and peptide-based therapeutics and nanoparticles extending from preclinical studies into human trials [3-5]. The breadth of clinical activity across countries and in different clinical areas clearly demonstrates the momentum for the field.
The ability of molecular imaging with radiotracers to identify targets suitable for therapy in individual patients was established decades ago with 131I as an exemplar of precision oncology, and which now extends to an impressive array of cellular, microenvironment and immune targets which can be used for therapeutic approaches [3, 4]. The principles of therapeutic drug development utilizing an initial imaging based approach, which eliminates the potential for error of biopsy results for assessment of genomic or protein expression profiles in tumors, has been built on painstaking validation and pioneering work over many years [5-7]. The development of novel targeting and radiochemistry approaches, protein design, preclinical validation, and extension into carefully conducted human trials, has provided the basis for the current approach to treating patients utilizing targeting molecules and an image-guided, or "theranostics" approach.
In addition to the developments in targeting techniques, imaging and therapeutic radionuclide approaches, the technology developed in this field has also led to new ways to improve drug development. Through sophisticated radioimaging studies, new drugs can be assessed for biodistribution, pharmacokinetics and pharmacodynamics, which can dramatically impact patient and dose selection, and clinical development programs [6, 7]. This approach is being increasingly used by pharmaceutical companies and biotech as they develop new therapeutics.
"The Evolution of Radionanotargeting towards Clinical Precision Oncology" provides an overview of key advances in the field of radionanotargeting, and the directions in which this area of medicine will have an impact on patient care. Our colleague, Prof Kalevi Kairemo, has been a pioneer in this field through his research and clinical translation of novel radiolabeled therapeutics. This has required his pursuing a ground-breaking multidisciplinary approach to science, development of significant expertise across the fields of chemistry, biology, engineering, physics and clinical medicine, and the ability to assemble teams for a common scientific purpose. We have enjoyed the collaboration, scientific endeavour, and friendship of Kalevi for almost 30 years, beginning with our time spent working together at Memorial Sloan-Kettering Cancer Centre, and we can attest to his insight, determination, and commitment to the field and patient care throughout this time (Fig. 1). This Festschrift book provides a wonderful outline of the field and his achievements over many years.
Fig. (1))
International Symposium on Radiopharmaceutical Therapy (WARMTH), Helsinki City Hall, November 2018: Homer Macapinlac, Steven Larson, Kalevi Kairemo, Andrew Scott.
REFERENCES
[1]Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med 2017; 376(2): 125-35.[http://dx.doi.org/10.1056/NEJMoa1607427] [PMID: 28076709][2]Hofman MS, Emmett L, Sandhu S, et al. TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group[177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet 2021; 397(10276): 797-804.[http://dx.doi.org/10.1016/S0140-6736(21)00237-3] [PMID: 33581798][3]Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer 2012; 12(4): 278-87.[http://dx.doi.org/10.1038/nrc3236] [PMID: 22437872][4]Kratochwil C, Flechsig P, Lindner T, et al.68Ga-FAPI PET/CT: Tracer Uptake in 28 Different Kinds of Cancer. J Nucl Med 2019; 60(6): 801-5.[http://dx.doi.org/10.2967/jnumed.119.227967] [PMID: 30954939][5]Larson SM, Carrasquillo JA, Cheung NK, Press OW. Radioimmunotherapy of human tumours. Nat Rev Cancer 2015; 15(6): 347-60.[http://dx.doi.org/10.1038/nrc3925] [PMID: 25998714][6]Ciprotti M, Tebbutt NC, Lee FT, et al. Phase i imaging and pharmacodynamic trial of CS-1008 in patients with metastatic colorectal cancer. J Clin Oncol 2015; 33(24): 2609-16.[http://dx.doi.org/10.1200/JCO.2014.60.4256] [PMID: 26124477][7]Pillarsetty N, Jhaveri K, Taldone T, et al. Paradigms for precision medicine in epichaperome cancer therapy. Cancer Cell 2019; 36(5): 559-573.e7.[http://dx.doi.org/10.1016/j.ccell.2019.09.007] [PMID: 31668946]
Andrew M. Scott
Department of Molecular Imaging and Therapy
Austin Health, and University of Melbourne
Melbourne
Australia
Olivia Newton-John Cancer Research Institute
School of Cancer Medicine
La Trobe University, Melbourne
Australia Homer A. Macapinlac
Department of Nuclear Medicine
MD Anderson Cancer Center
Houston, Texas
USA & Steven M. Larson
Molecular Imaging and Therapy Service
Memorial Sloan-Kettering Cancer Centre
New York, NY
USA
PREFACE
This is a remarkable book honoring Professor Kalevi Kairemo’s work, and it is fitting that the table of contents for the book were finalized by the World Theragnostics Day on 31.3.2021, which is precisely 80 years after the first radioiodine treatment was performed by Saul Hertz on 31.3.1941. The idea for the topic/title of this book came from discussions about the partially unrecognized role of radioisotopes in the development of targeted drug development. In fact, the radionuclide approach is nearly always included in the first tools used in research when in vitro findings are transferred to the in vivo level. Usually, new cellular elements are needed for applications to determine their location in vivo in preclinical animal models and, ultimately, in humans. In these applications, radioactive isotopes have had a major role. Protein targeting was the first step towards more specific targeting, starting from the concept of receptors in the cell membrane with specific binding and functional capacity. The use of antibody-augmented targeting increased further, and evolution continued towards increasingly small cell structures. Nanotargeting has been derived even against DNA and RNA and thus shows extreme specificity. Gene therapy and antisense radionucleotide therapies are examples of the highest specificity possible against cell structures. Radionuclides and their molecular constructs have the potential to be developed into therapies involving in vivo imaging of targets followed by the application of active agents with higher radioactive doses. Radioactivity makes visualization possible and may augment therapeutic effects. Thus, radionanotargeting has a large application base and is developing towards theragnostics. All this research is based on multiomics, which involves multiple elements: genomics, transcriptomics, proteomics, metabolomics, microbiomics, epigenomics, exposome, imaging, and precision medicine. Multiomics is an approach that is also featured on the cover of this book.
This book contains a unique collection of articles that will deepen the understanding of targeting with radioactive isotopes. Radioactivity with low trace doses can enable one to visualize targets, providing the possibility of simulating events before using higher doses with stronger effects. This is a perfect situation for cancer therapy. Radiotargeting has evolved from targeting proteins through other cellular macromolecules, e.g., DNA, towards specific gene targeting with antisense techniques. Hopefully, we will see gene silencing therapeutics in clinical oncology in the near future. This development has already been fascinating, and radiotargeting has had a major role in it.
This book starts with a foreword to this research field by Andrew M. Scott, Homer A. Macapinlac and Steven M. Larson. Radionanotargeting and theragnostics are subjects for the next segment in the form of four chapters. Imaging is dealt with in three chapters before the therapy segment, which includes sections for thyroid cancer, head and neck cancer, genitourinary cancers and neuroendocrine neoplasms. The segment on theragnostics is covered in four chapters. In addition, nanoparticles and precision oncology have their own segments. The supporting sciences segment consists of four sections: metabolic imaging, cardiovascular radionuclide imaging, combined and bone therapies. Radiobiology is covered
in one chapter before three chapters dedicated to a patient experience segment. The final segment consists of Professor Kairemo’s own memoir “Seven decades in health care” and memoirs from colleagues.” Finally, there is a personal introduction to Kalevi Kairemo with a photographic cavalcade of his participation in WARMTH. I am sure that this complex issue will be covered comprehensively and will open up new avenues for future innovations.
Antti Jekunen, MD, Ph.D,
Professor in Clinical Oncology, Turku University, Finland
Chief Physician, Vaasa Oncology Clinic, Finland
List of Contributors
Balogova SonaMédecine Nucléaire, Hôpital Tenon, AP-HP Sorbonne Université, Paris, France
Department of Nuclear Medicine, Comenius University, Faculty of Medicine; St.Elisabeth Cancer Institute, Bratislava, Slovak RepublicBom Hee-Seung HenryProfessor, Chonnam National University Hwasun Hospital, Jeonnam, South KoreaChoudhury Partha S.Director-Nuclear Medicine, Rajiv Gandhi Cancer Center & Research Institute, Delhi, IndiaCottereau Anne-SégolèneMédecine Nucléaire, Hôpital Tenon, AP-HP Sorbonne Université, Paris, FranceDierckx Rudi A. J. ODepartment of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University of Groningen, University Medical Center Groningen, The Netherlandsvan Dongen GuusVUMC Imaging Center Amsterdam, Radiology & Nuclear Medicine, Amsterdam, The NetherlandsElliyanti AisyahMedical Physics Department of Faculty of Medicine Universitas Andalas, Kampus Limau Manis, Padang, West Sumatra, Indonesia
Nuclear Medicine Installation of the Radiology Department of Dr.M.Djamil Hospital, Padang, IndonesiaElsinga Philip H.Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University of Groningen, University Medical Center Groningen, Groningen, The NetherlandsErselcan TanerMugla Sitki Kocman University Faculty of Medicine, Mugla, Turkiye
Department of Nuclear Medicine, Mugla, TurkiyeFeringa Ben L.Nobel Laureate Chemistry 2016, Stratingh Institute for Chemistry, University of Groningen, Groningen, The NetherlandsGan Hui K.Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia
Department of Medical Oncology, Austin Health, Melbourne, Australia
School of Cancer Medicine, La Trobe University, Melbourne, AustraliaGupta ManojNuclear Medicine, Rajiv Gandhi Cancer Center & Research Institute, Delhi, IndiaHafeez UmbreenTumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia
Department of Medical Oncology, Austin Health, Melbourne, Australia
School of Cancer Medicine, La Trobe University, Melbourne, AustraliaHatazawa JunDepartment of Quantum Cancer Therapy, Research Center for Nuclear Physics, Osaka University, Osaka, Japan
Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, Osaka, Japan
Department of Nuclear Medicine in Osaka University Hospital, Osaka, JapanHelbert HugoDepartment of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
Stratingh Institute for Chemistry, University of Groningen, Groningen, The NetherlandsHemminki AkseliProfessor of Oncology, Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
Helsinki University Hospital Comprehensive Cancer Center, Helsinki, FinlandHertz BarbaraDr. Saul Hertz Archives, Greenwich, CT, USAHodolic MarinaNuclear Medicine Research Department, IASON, Graz, Austria
Department of Nuclear Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czech RepublicHopsu ErkkiChief Physician, ENT - Department, Kymenlaakso Central Hospital, Kotka, Finlandvon Eyben Finn EdlerCenter of Tobacco Control Research, Odense, DenmarkJadvar HosseinAssociate Professor of Radiology, Urology, and Biomedical Engineering (Tenure), Division of Nuclear Medicine and Molecular Imaging Center, Keck School of Medicine & Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USAJekunen AnttiProfessor in Clinical Oncology, Turku University, Finland
Chief Physician, Vaasa Oncology Clinic, FinlandJorgov LindaMédecine Nucléaire, Hôpital Tenon, AP-HP Sorbonne Université, Paris, France
Department of Nuclear Medicine, Semmelweis University, Budapest, HungaryKairemo KaleviDepartment of Molecular Radiotherapy, Docrates Cancer Center, Helsinki, Finland
Department of Nuclear Medicine, The University of TexasMD Anderson Cancer Center, Houston, Texas, USAKanaev SergeyDepartment of Radiotherapy and Nuclear Medicine, N.N. Petrov Institute of Oncology, St Petersburg, RussiaKangaspuro MarkkuProfessor, Director, Aleksanteri Institute, Finnish Centre for Russian and East European Studies, University of Helsinki, Helsinki, FinlandKelk EveChief Physician in Nuclear Medicine, Clinic of Diagnostics Nuclear Medicine Centre, East Tallinn Central Hospital, EstoniaKinuya SeigoProfessor, Department of Nuclear Medicine, Kanazawa University, Takaramachi, Kanazawa, JapanKnuuti JuhaniTurku PET Centre, University of Turku and Turku University Hospital, Turku, FinlandKochetova T.Yu.A. Tsyb Medical Radiological Research Centre - branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Obninsk, RussiaKoivunen ErkkiProfessor, Molecular and Integrative Biosciences, University of Helsinki, Helsinki, FinlandKrivorotko PetrSurgery Department, N.N. Petrov Institute Oncology, St Petersburg, RussiaKrylov V.V.A. Tsyb Medical Radiological Research Centre - branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Obninsk, RussiaKrzhivitskiy PavelHead of Nuclear Med. Department, Department of Radiotherapy and Nuclear Medicine, N.N. Petrov Institute of Oncology, St Petersburg, RussiaKumari ManishaDepartment of Radiology, Radiation oncology and Urology, Kimmel Cancer Center, Thomas Jefferson University, 359 JAH, 1020 Locust Street, PhiladelphiaLarson Steven M.Donna and Benjamin M. Rosen Chair, Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Laboratory Head, Molecular Pharmacology Program, Sloan Kettering Institute, New York, NY, USALee Sang-GyuLarson Lab, Molecular Pharmacology Program, Sloan Kettering Institutes, Memorial Sloan Kettering Cancer Center, New York, NY, USALee Sze-TingTumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia
Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia
School of Cancer Medicine, La Trobe University, Melbourne, Australia
Department of Medicine, University of Melbourne, Melbourne, AustraliaLengana ThaboDepartment of Nuclear Medicine, University of Pretoria & Steve Biko Academic Hospital, Pretoria, South AfricaLimouris Georgios S.Professor in Nuclear Medicine, National and Kapodistrian University, Athens-Hellas, GreeceLuurtsema GertDepartment of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University of Groningen, University Medical Center Groningen, Groningen, The NetherlandsMacapinlac Homer A.Chair & Professor, Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USAMailman JoshPatient Advocate, NET, San Francisco, CA, USAMeri SeppoDepartment of Bacteriology & Immunology, Haartman Institute, University of Helsinki, Helsinki, FinlandMititelu RalucaDept of Nuclear Medicine, Bucharest, Central Universitary Emergency Military Hospital "Dr Carol Davila", Romanian Society of Nuclear Medicine, RomaniaMontravers FrançoiseMédecine Nucléaire, Hôpital Tenon, AP-HP Sorbonne Université, Paris, FranceNikaki AlexandraDepartment of Clinical Physiology and Isotope, Kanta-Häme Central Hospital, Hämeenlinna, Finland
Nuclear Medicine Department, University Hospital of Larissa, Larissa, Thessaly, Greece
PET/CT Department, Hygeia Hospital, Athens, GreeceNovikov SergeyDepartment of Radiotherapy and Nuclear Medicine, N.N. Petrov Institute of Oncology, St Petersburg, RussiaParakh SagunTumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia
Department of Medical Oncology, Austin Health, Melbourne, Australia
School of Cancer Medicine, La Trobe University, Melbourne, AustraliaPenate Medina OulaDepartment of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein, Kiel University, Kiel, Germany
MOIN CC - Institut für Experimentelle Tumorforschung, Kiel, GermanyPenate Medina TuulaDepartment of Radiology and Neuroradiology, University Medical Center Schleswig-Holstein, Kiel University, Kiel, Germany
MOIN CC - Institut für Experimentelle Tumorforschung, Kiel, GermanyPillarsetty KishoreLarson Lab, Molecular Pharmacology Program, Sloan Kettering Institutes, Memorial Sloan Kettering Cancer Center, New York, NY, USARasulova NigoraDepartment of Nuclear Medicine, Republic Specialized Center of Surgery, Tashkent, Uzbekistan
Department of Nuclear Medicine, Farwaniya Hospital, KuwaitRoos Jeja-PekkaFaculty of Common Matters, University of Helsinki, Helsinki, FinlandSantos Joao M.Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, Helsinki, FinlandSathekge Mike M.Department of Nuclear Medicine, University of Pretoria & Steve Biko Academic Hospital, Pretoria, South Africa
Nuclear Medicine Research Infrastructure (NuMeRI), Steve Biko Academic Hospital, Pretoria, South AfricaScott Andrew M.Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia
Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia
School of Cancer Medicine, La Trobe University, Melbourne, Australia
Department of Medicine, University of Melbourne, Melbourne, AustraliaSeleva N.G.A. Tsyb Medical Radiological Research Centre - branch of the National Medical Research, Radiological Centre of the Ministry of Health of the Russian Federation, Obninsk, RussiaSenko ClareTumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia
Department of Molecular Imaging and Therapy, Austin Health, Melbourne, AustraliaSergieva SonyaDepartment of Nuclear Medicine, Sofia Cancer Center, Sofia, BulgariaSleptsov Ilya V.North-West Centre of Endocrinology & Endocrine Surgery, St.Petersburg, RussiaSzymanski WiktorStratingh Institute for Chemistry, University of Groningen, Groningen, The Netherlands
Department of Radiology, Medical Imaging Center, University of Groningen, University Medical Center Groningen, Groningen, The NetherlandsTalbot Jean-NoëlMédecine Nucléaire, Hôpital Tenon, AP-HP Sorbonne Université, Paris, FranceTenhunen MikkoHead of Radiotherapy Department, Helsinki University, Helsinki, FinlandThakur MathewDepartment of Radiology, Radiation oncology and Urology, Kimmel Cancer Center, Thomas Jefferson University, 359 JAH, 1020 Locust Street, PhiladelphiaTripathi SushilDepartment of Radiology, Radiation oncology and Urology, Kimmel Cancer Center, Thomas Jefferson University, 359 JAH, 1020 Locust Street, PhiladelphiaTurner J HarveyThe University of Western Australia, Fremantle, AustraliaVirgolini IreneDepartment of Nuclear Medicine, Medical University of Innsbruck, Austria
Molecular Imaging in the Development of Antibody-Drug Conjugates
Clare Senko1,2,Sze-Ting Lee1,2,4,5,*,Hui K. Gan1,3,4,Umbreen Hafeez1,3,4,Sagun Parakh1,3,4,Andrew M. Scott1,2,4,5
1 Tumor Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, VIC 3084, Australia
2 Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC 3084, Australia
3 Department of Medical Oncology, Austin Health, Melbourne, VIC 3084, Australia
4 School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
5 Department of Medicine, University of Melbourne, Melbourne, VIC 3084, Australia
Abstract
Antibody-drug conjugates (ADCs) are novel drugs that deliver a potent cytotoxic payload to the tumor site, by exploiting the specificity of a monoclonal antibody (mAb) to tumor antigens expressed on cancer cells. ADCs allow the delivery of drugs to tumor cells or microenvironment while minimizing toxicity to normal tissue. More than 80 ADCs worldwide are currently under clinical development, of which nine have already received FDA approval. Molecular imaging can play a vital role in evaluating the biodistribution and pharmacokinetics of ADCs for optimal patient selection and early clinical trial development. This chapter provides an overview of ADC structure and design, outlines approved ADCs, discusses the role of molecular imaging in drug development, and highlights clinical and pre-clinical experience with radiolabelled ADCs [1].
Keywords: Antibody, Antibody-drug conjugate, Diabody, Drug development, Molecular imaging, Target antigens.
*Corresponding author Sze-Ting Lee: Department of Medicine, University of Melbourne, Melbourne, VIC 3084, Australia. E-mail:
[email protected]INTRODUCTION
Antibody-drug conjugates (ADCs) are targeted agents that deliver toxic payloads at the tumor site by linking a monoclonal antibody with specificity for a tumor antigen to a cytotoxic drug or toxin via a linker. This mechanism improves the efficacy of drug treatment whilst reducing systemic exposure and toxicity [1].
There are currently more than 80 ADCs worldwide under clinical development, with nine having received regulatory approval by FDA for use in the USA and eight approved by the European Medicines Agency (EMA) [1-4].
Successful development of an ADC requires an intricate understanding of ADC in-vivo properties, drug delivery parameters, target expression, and the mechanism of therapeutic action that can be validated in pre-clinical models and extended into clinical trials. Molecular imaging has successfully been utilized in ADC development to study the biodistribution and pharmacodynamics of ADCs, detect heterogeneity between lesions, determine tumor target expression, predict response to the ADC, inform patient selection and assist in decisions in drug development in early phase clinical trials [1, 5].
Fig. (1))
Structure of antibody-drug conjugate [adapted from 1].
ANTIBODY-DRUG CONJUGATES AS A CANCER THERAPEUTIC
Design and Structure
ADCs comprise a tumor antigen-specific monoclonal antibody (mAb) or related engineered construct conjugated via a stable chemical linker to a potent cytotoxin. Guided by the specificity and high affinity of antibodies for antigens on tumor cells, these three components can deliver normally intolerable drugs or payloads directly and specifically to cancer cells [1] (Fig. 1).
Mechanism of Action
Once the ADC is bound to its target antigen, the ADC-antigen complex is internalized into the cell via pinocytosis clathrin- or caveolae-mediated endocytosis [1, 6]. Internalisation of the ADC results in trafficking through an early endosome, formed by inward budding of the cell membrane, which matures into a late endosome prior to fusing with lysosomes. The cleavage mechanisms usually occur in early or late endosomes for ADCs with cleavable linkers. In contrast, a more complex proteolytic cleavage is required by cathepsin B and plasmin in the lysosomes for ADCs with non-cleavable linkers. Once inside the lysosome, the ADC is degraded, and free drug payload is released into the cell cytoplasm, leading to cell death [1, 7]. The mechanism of cell death is dependent on the type of cytotoxic payload, for example, by microtubule disruption or DNA targeting. ADCs are typically administered intravenously due to poor oral availability [1, 6].
Clinical Development and Design
Target Antigen Selection
Appropriate selection of a target antigen is a critical step for the success of an antibody-drug conjugate. An appropriate target antigen should have the following features: 1) antigen abundance on the tumor cell or microenvironment target surface to be available for binding by circulating ADC, 2) preferential expression on tumor cells with a minimal expression on healthy tissue to minimize off-target toxicity, 3) minimal secretion in the circulation to avoid sequestration in the blood compartment of the ADC, thus limiting available ADC for tumor targeting, 4) ability to internalize efficiently upon ADC binding, and 5) appropriate intracellular trafficking and degradation to allow the cytotoxic payload to be released [1, 8-12]. More than 50 known antigens have been used as targets in ADCs in both pre-clinical and clinical development [1] (Table 1).
Table 1ADC target agents in development and current practice (adapted from 1).TargetsIndicationCD25, CD33, CD123 (IL-3Rα), FLT3Acute myeloid leukemiaCD38, CD46 (MCP), CD56, CD74, CD138, CD269 (BCMA), endothelin B receptorMultiple myelomaAxl, alpha v beta6, CD25, CD56, CD71 (transferrin R), CD228 (P79, SEMF), CD326, CRIPTO, EGFR, ErbB3 (HER3), FAP, Globo H, GD2, IGF-1R, integrin β-6, mesothelin, PTK7 (CCK4), ROR2, SLC34A2 (Napi2b), SLC39A6 (LIV1A ZIP6)Lung cancerCD25, CD30, CD197 (CCR7)Hodgkin’s lymphomaCD19, CD20, CD22, CD25, CD30, CD37, CD70, CD71 (transferrin R), CD72, CD79, CD180, CD205 (Ly75), ROR1Non-Hodgkin’s lymphomaCD71 (transferrin R), CD197 (CCR7), EGFR, SLC39A6 (LIV1A ZIP6)Head and neck cancerEGFR, EphA3, EphA2, CD25Gliomas grade III and IVCD25, CD197 (CCR7), CD228 (P79, SEMF), FLOR1 (FRα), Globo H, GRP20, GCC, SLC39A6 (LIV1A ZIP6)Gastric cancerCD74, CD174, CD166, CD227 (MUC-1), CD32 (Epcam), CEACAM5, CRIPTO, FAP, ED-B, ErbB3 (HER3)Colorectal cancerCD25, CD205 (Ly75)Bladder cancerCD25, CD174, CD197 (CCR7), CD205 (Ly75), CD228 (P79, SEMF), c-MET, CRIPTO, ErbB2 (HER2), ErbB3 (HER3), FLOR1 (FRα), Globo H, GPNMB, IGF-1R, integrin β-6, PTK7 (CCK4), nectin-4 (PVRL4), ROR2, SLC39A6 (LIV1A ZIP6)Breast cancerCD276 (B7-H3), c-METLiver cancerCD276 (B7-H3), GD2, GPNMB, ED-B, PMEL 17, endothelin B receptorMelanomaMesothelin, CD228 (P79, SEMF)MesotheliomaCA125 (MUC16), CD142 (TF), CD205 (Ly75), FLOR1 (FRα), GloboH, mesothelin, PTK7 (CCK4)Ovarian cancerCD25, CD71 (transferrin R), CD74, CD227 (MUC1), CD228 (P79, SEMF), GRP20, GCC, IGF-1R, integrin β-6, nectin-4 (PVRL4), SLC34A2 (Napi2b), SLC44A4, alpha v beta6, mesothelinPancreatic cancerCD46 (MCP), PSMA, STEAP-1, SLC44A4, TENB2Prostate cancerAGS-16, EGFR, c-MET, CAIX, CD70, FLOR1 (FRα)Renal cell cancer
Antibody Selection
Appropriate antibody or recombinant construct selection is paramount, as the antibody utilised in an ADC can have a significant impact on efficacy, therapeutic index, pharmacokinetic and pharmacodynamic profiles [1]. The ideal monoclonal antibody for ADC should be target-specific with high binding affinity, low immunogenicity, minimal normal tissue cross-reactivity, efficient internalization, and suitable pharmacokinetics [1, 13, 14].
Early ADCs used murine antibodies, which had reduced efficacy and increased toxicity due to high immunogenicity [1, 15, 16]. The next-generation ADCs use chimeric, humanized, or fully human antibodies to overcome this problem. Of the five main classes of antibodies in humans (IgA, IgD, IgE, IgG, and IgM), the IgG1 subtype is used most frequently. The IgG antibody has two heavy chains, two light chains, two antigen-binding fragments (Fabs), and a constant fragment (Fc). The Fabs mediate antigen recognition, and the Fc mediates binding of the antibody with effector cells of the immune system [1] (Fig. 1). The IgG antibody has the most favorable characteristics for therapeutics regarding serum stability and strong binding affinity for the Fc receptor. The benefit of using a fully humanized antibody is to prevent the development of an immune response against these antigens [1, 17].
Drug Payload
Early ADCs had relatively low efficacy due to the use of readily available conventional cytotoxics (e.g. doxorubicin, methotrexate), with issues of relatively low potency, lack of selectivity, and poor accumulation in target cells. Desirable characteristics for ADC payloads include high potency, plasma stability, small molecular weight, low immunogenicity, and a long-half-life, with chemistry that does not disrupt the internalization properties of the parental mAb [1]. Subsequently, more potent payloads have been utilized, most commonly targeting either DNA or tubulins, with IC50 values in the subnanomolar range [1, 18]. DNA targeting payloads include calicheamicins, duocarmycins, pyrrolobenzodiazepines (PBDs), SN-38 and DXd, which cause DNA damage resulting in cell death. The anti-tubulin agents include auristatins and maytansinoids, which disrupt microtubules and induce cell cycle arrest in the G2/M phase [1, 19].
Linkers play a crucial role in the pharmacokinetic and pharmacodynamic properties of ADC, as they link the antibody to the cytotoxic payload, and therefore consideration must be paid to various factors such as mode and site of conjugation and linker chemistry. Linkers must be readily cleaved when internalised for payload release, however, the ADC must maintain stability in the blood circulation in order to reach the cancer cell intact [1]. They are broadly classified as cleavable or non-cleavable linkers, with cleavable linkers being further subdivided into acid, protease, or glutathione sensitive depending on the physiological conditions in the cell for linker cleavage. Non-cleavable linkers have greater stability in the bloodstream, longer half-lives, and reduced off-target toxicity due to the formation of non-reducible bonds with the amino acid residues of the mAb [1, 20]. Although there have been 7 ADCs approved in the last three years (Table 2), there are more than 80 ADCs in development worldwide [1, 21, 22].
Antibody-Drug Conjugation
Conventional drug conjugation usually occurs on the mAb backbone via either alkylation or acylation of lysine sidechains or reduction of disulfide bonds that can liberate cysteine residues to be attached to linkers. The drug to antibody ratio (DAR) may vary between 0-8, with higher DAR producing more potent ADCs, but at the risk of destabilisation, aggregation increased off-target toxicity, and enhanced drug clearance from systemic circulation. Site-specific conjugation (SCC) is garnering interest, with the ability to produce more homogenous ADCs through the insertion of unnatural amino acids in the antibody sequence, engineered cysteine residues, or enzymatic conjugation through glycotransferases and transglutaminases [1].
Table 2Antibody-drug conjugates approved for clinical use (adapted from 1).ADCTarget AntigenPayloadApproved Indication(s)Year of FDA ApprovalYear of EMA ApprovalInotuzumab ozogamicin (Besponsa)CD22Calicheamicin derivativeB cell precursor, ALL20172017Gemtuzumab ozogamicin (Mylotarg)CD33Calicheamicin derivativeCD33-positive AML2000 (withdrawn 2010); reapproved 20172018Trastuzumab emtansine (T-DM1, Kadcyla)ErbB2DM1ErbB2-positive metastatic breast cancer20132013Brentuximab vedotin (SGN-35, Adcetris)CD30MMAEHodgkin’s lymphoma, ALCL, PTCL, mycosis fungoides20112012Polatuzumab vedotin (Polivy)CD79MMAEDLBCL20192020Enfortumab bedotin (ASG-22ME, Padcev)Nectin-4MMAEAdvanced urothelial cancer20192020Belantamab mafodotin (GSK2857916, Blenrep)BCMAMMAFRelapsed/refractory multiple myeloma20202020Trastuzumab deruxtecan (DS-8201a, Enhertu)ErbB2DXd (DK-8951 derivative)Metastatic ErbB2-positive breast cancer20192021Sacituzumab govitecan (IMMU-132, Trodelvy)TROP2SN-38Triple-negative breast cancer2020Not approved
ROLE OF MOLECULAR IMAGING IN ADC DEVELOPMENT
SPECT- and PET-based approaches have demonstrated the role of molecular imaging in ADC development. Molecular imaging allows the development of imaging probes that can identify normal tissue distribution and pharmacokinetics in real-time, including identification of target expression and confirmation of in vivo target delivery. This information is vital to understanding the in vivo behavior of ADCs to ensure optimal ADC dose, allow valid assessment of the therapeutic effects of ADCs, and inform patient selection for clinical trials [1].
Pre-clinical Studies of Molecular Imaging of ADCs
The development of molecular imaging probes for ADCs for cancer therapy involves radiochemistry development of suitable radiolabeled ADCs which retain target binding affinity and specificity and demonstrate suitable in-vivo stability and imaging properties [23-25]. The radioisotopes that have been utilized range from SPECT isotopes (e.g111In, 123I) to PET isotopes (e.g.124I, 89Zr), and are selected based on suitable half-life for the in-vivo biodistribution of the candidate ADC. The techniques for radiolabeling, and chelate selection have been extensively reviewed [23-25], and have similar approaches to that utilized for non-drug conjugated antibodies and engineered proteins, but with the additional requirement of confirmation of drug/payload retention of activity following radiolabeling.
A broad range of targets and models have been explored and reported for molecular imaging of ADC biodistribution and tumor uptake in-vivo. These include ADCs against CD30 in lymphoma and lung cancer [26, 27], TENB2 and STEAP1 in prostate cancer [28], mesothelin in pancreatic and ovarian cancer [29], LGR5 in colorectal cancer [30], Ley in solid tumors [31], ErbB family targets in a range of cancer types [6, 32] and TAG-72 [33]. These have provided the platform for extending molecular imaging of targets and construct biodistribution into clinical trials and assisting with the development of ADC-based approaches in patients with hematologic malignancies and advanced or metastatic solid tumors.
Molecular Imaging in Clinical Development of ADCs
The phase 1 dose-escalation study of CMD-193 was a pioneering study that provided the first demonstration of a radiolabeled ADC (111In-CMD-193) informing the development of ADCs in solid tumor patients. CMD-193 is composed of G193 (a humanized anti-Lewisy monoclonal antibody-based on Hu3S193) conjugated to cytotoxic calicheamicin via an acid-labile AcBut linker. Patients in this study received a single infusion of 111In-CMD-193, followed by unlabeled CMD-193 infusions every three weeks for the duration of the study. Biodistribution analysis, performed by whole-body gamma camera scans for the week following 111In-CMD-193 infusion, revealed a rapid clearance of 111In-CMD-193 from blood followed by a marked increase in hepatic uptake, without significant tumor uptake [1, 31] (Fig. 2). The clinical development of CMD-193 was discontinued based on this study, however, this clinical trial highlighted the role of molecular imaging in understanding pharmacodynamics and biodistribution in early phase clinical drug development [1].
Fig. (2))Representative biodistribution pattern of 111In-CMD-193. Anterior whole-body gamma camera images in patient 106 (1.0mg/m2 dose cohort) following infusion are showing for day 1 (A), day 3 (B), and day 8 (C). Following infusion of 111In-CMD-193, there was initial blood pooling, followed by markedly increased hepatic uptake by day 2 that persisted to day 8. No tumor uptake was apparent in the whole-body gamma camera images (arrow) or SPECT (D). Corresponding CT scan shows the large hepatic metastasis (E) and evident in (F), coregistered SPECT/CT scan. Reprinted from the phase I biodistribution and pharmacokinetic study of Lewis Y-targeting immunoconjugate CMD-193 in patients with advanced epithelial cancers [31].
ErbB2/HER2
The ZEPHIR study was the first study to measure ErbB2 expression and predict response to trastuzumab emtansine (T-DM1) using the molecular imaging probe 89Zr-Trastuzumab. Patients with ErbB2-positive advanced breast cancer underwent ErbB2-PET (89Zr-trastuzumab PET/CT) and FDG-PET/CT followed by one cycle of T-DM1, a further FDG-PET/CT (after cycle 1), then standard CT scans after cycle 3 of therapy for response assessment. Combining ErbB2-PET/CT and FDG-PET/CT accurately predicted morphological response in these patients (negative and positive predictive value of 100%) and distinguished patients with a median time to treatment failure (TTF) of only 2.8 months (n=12, 95% CI 1.4-7.6) from those with a TTF of 15 months (n=25, 95% CI 9.7-not calculable). This study highlighted the role of molecular imaging as an additional diagnostic tool for ADC therapy in selecting patients who may or may not benefit from treatment [6].
EGFR
The EGFR gene is a validated target in oncology, with monoclonal antibodies against EGFR approved and used to treat head and neck, colon, and lung cancer patients. ABT-806 is a humanized recombinant IgG1 antibody that is specific for a unique, conformationally exposed epitope of EGFR, which is available for binding only under conditions where there is dysregulated EGFR activation due to EGFR amplification, presence of specific mutations such as EGFRVIII, or presence of autocrine loops [32]. Indium-111 radiolabeled ABT-806 (ABT-806i) is a novel radiopharmaceutical that was developed for real-time scintigraphic imaging of biodistribution of ABT-806. A phase 1 first-in-human trial of ABT-806i explored the ability to image the conformational epitope of EGFR bound by ABT-806, the impact of ABT-806 therapy on ABT-806i uptake, and the relationship of ABT-806i uptake to tumor EGFR by IHC [34]. Eligible patients had advanced tumors likely to express EGFR and measurable disease by RECIST 1.1. The first cohort of 6 patients was administered bolus ABT-806i (to determine baseline drug distribution) followed by SPECT and whole-body planar scans. The second cohort of 12 patients was imaged similarly, followed by three doses of unlabeled ABT-806, then another dose of ABT-806i (in week 6) to determine the effects of unlabeled antibody on receptor occupancy. For both cohorts, those with the stable or responding disease were enrolled into an extension study where unlabeled ABT-806 was administered every 2 weeks until progressive disease, withdrawal of consent or intolerable toxicity [33].
In this study, ABT-806i uptake was observed in tumors of all patients, and was best seen after day 3 with increasing intensity up to day 8. Importantly, specific uptake in many tumor types was evident, and high selective uptake in glioblastoma (GBM) was identified (Fig. 3). The data from this study led to the exploration of ADC forms of ABT-806 in multiple tumor types, including Phase II/III trials of ABT-414 in GBM patients [35-37]. Real-time imaging of EGFR conformational expression in tumors provided important additional information regarding antigen expression compared to standard approaches using archival tissue. The advent of next-generation ADCs based on ABT-806 has been directly facilitated by the use of molecular imaging to confirm target expression and suitable cancer types for clinical development.
Fig. (3))ABT-806i biodistribution and SPECT/CT images of a patient with squamous cell carcinoma of the head and neck.(A) Whole-body planar image of 111In-ABT-806i biodistribution at day 8 in patient 8. The arrow shows localization in the tumor area in the right neck. (B) Week 1 SPECT image of 111In-ABT-806i uptake in right parapharyngeal lesion and right cervical node (arrows), which appear smaller than week 1 images. (D) CT at baseline showing tumor in the right parapharyngeal region and right cervical node (arrows), which also showed 111In-ABT-806i uptake. (E) CT at week 16 restaging, showing reduction in size of right parapharyngeal lesion and right cervical node (arrows), assessed as RECIST partial response. Reproduced with permission from the Journal of Nuclear Medicine [34].
TAG-72
Multimeric antibody fragments (i.e., diabodies, triabodies, minibodies) are characterized by increased in-vivo tissue penetration, high avidity, and faster blood clearance and are an alternative to intact antibodies. A first-in-human clinical trial of a monospecific, bivalent diabody (PEG-AVP0458) specific for tumor-associated glycoprotein 72 (TAG-72) recruited a total of 6 patients with TAG-72 positive prostate or ovarian cancer to assess the safety of a single dose of 124I-labeled PEG-AVP0458, as well as the biodistribution, tumor uptake, pharmacokinetics, and immunogenicity [33]. 124I was utilized due to the slow internalization rate of TAG-72, and prior studies of antibodies to TAG-72 (CC49) where radioiodine was used for radiolabeling and excellent biodistribution imaging was obtained [38]. 124I-labeled PEG-AVP0458 achieved rapid, high uptake in tumor without significant normal tissue or kidney retention, and no adverse effects related to the study drug were observed. Both biodistribution and dosimetry analysis confirmed no specific normal tissue uptake, no saturable normal tissue compartment, and high tumor uptake in liver metastases and tumor-involved lymph nodes. This human validation of a pegylated dimer providing excellent targeting of TAG-72 has been followed by experimental model data with an ADC based on PEG-AVP0458 that supports the development of a PEG-AVP0458 (or PEG-avibody construct) as a payload delivery platform and for theranostic use in cancer patients [39].
CONCLUSION AND FUTURE DIRECTIONS
Advances in molecular imaging have led to the ability to facilitate a quantitative assessment of ADC target expression and drug delivery to tumor, with great potential to contribute to early clinical development. The ongoing use of molecular imaging to guide clinical decision-making requires standardization of protocols and optimisation of approaches to provide more accurate and reproducible data, in order to demonstrate that initiating or ceasing treatment based on molecular imaging results in improved patient outcomes [1]. Molecular imaging will continue to play a key role in the pre-clinical and clinical development of ADCs in the future.
CONSENT FOR PUBLICATION
Not Applicable.
CONFLICT OF INTEREST
The author confirms that this chapter contents have no conflict of interest.
ACKNOWLEDGEMENTS
Declared none.
REFERENCES
[1]Hafeez U, Parakh S, Gan HK, Scott AM. Antibody-drug conjugates for cancer therapy. Molecules 2020; 25(20): 4764.[http://dx.doi.org/10.3390/molecules25204764] [PMID: 33081383][2]Sievers EL, Senter PD. Antibody-drug conjugates in cancer therapy. Annu Rev Med 2013; 64: 15-29.[http://dx.doi.org/10.1146/annurev-med-050311-201823] [PMID: 23043493][3]Sharma V. CPHI Annual Report 2018.[4]Chau CH, Steeg PS, Figg WD. Antibody-drug conjugates for cancer. Lancet 2019; 394(10200): 793-804.[http://dx.doi.org/10.1016/S0140-6736(19)31774-X] [PMID: 31478503][5]Dammes N, Peer D. Monoclonal antibody-based molecular imaging strategies and theranostic opportunities. Theranostics 2020; 10(2): 938-55.[http://dx.doi.org/10.7150/thno.37443] [PMID: 31903161][6]Gebhart G, Lamberts LE, Wimana Z, 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. Ann Oncol 2016; 27(4): 619-24.[http://dx.doi.org/10.1093/annonc/mdv577] [PMID: 26598545][7]Conner SD, Schmid SL. Regulated portals of entry into the cell. Nature 2003; 422(6927): 37-44.[http://dx.doi.org/10.1038/nature01451] [PMID: 12621426][8]Kalim M, Chen J, Wang S, et al. Intracellular trafficking of new anticancer therapeutics: antibody-drug conjugates. Drug Des Devel Ther 2017; 11: 2265-76.[http://dx.doi.org/10.2147/DDDT.S135571] [PMID: 28814834][9]Smith LM, Nesterova A, Alley SC, Torgov MY, Carter PJ. Potent cytotoxicity of an auristatin-containing antibody-drug conjugate targeting melanoma cells expressing melanotransferrin/p97. Mol Cancer Ther 2006; 5(6): 1474-82.[http://dx.doi.org/10.1158/1535-7163.MCT-06-0026] [PMID: 16818506][10]Ingle GS, Chan P, Elliott JM, et al. High CD21 expression inhibits internalization of anti-CD19 antibodies and cytotoxicity of an anti-CD19-drug conjugate. Br J Haematol 2008; 140(1): 46-58.[PMID: 17991300][11]Perez HL, Cardarelli PM, Deshpande S, et al. Antibody-drug conjugates: current status and future directions. Drug Discov Today 2014; 19(7): 869-81.[http://dx.doi.org/10.1016/j.drudis.2013.11.004] [PMID: 24239727][12]Ritchie M, Tchistiakova L, Scott N. Implications of receptor-mediated endocytosis and intracellular trafficking dynamics in the development of antibody drug conjugates. MAbs 2013; 5(1): 13-21.[http://dx.doi.org/10.4161/mabs.22854] [PMID: 23221464][13]Hughes B. Antibody-drug conjugates for cancer: poised to deliver? Nat Rev Drug Discov 2010; 9(9): 665-7.[http://dx.doi.org/10.1038/nrd3270] [PMID: 20811367][14]Khongorzul P, Ling CJ, Khan FU, Ihsan AU, Zhang J. Antibody-Drug Conjugates: A Comprehensive Review. Mol Cancer Res 2020; 18(1): 3-19.[http://dx.doi.org/10.1158/1541-7786.MCR-19-0582] [PMID: 31659006][15]Wang YJ, Li YY, Liu XY, Lu XL, Cao X, Jiao BH. Marine Antibody-Drug Conjugates: Design Strategies and Research Progress. Mar Drugs 2017; 15(1): 18.[http://dx.doi.org/10.3390/md15010018] [PMID: 28098746][16]Yasunaga M, Manabe S, Tsuji A. Development of Antibody-Drug Conjugates Using DDS and Molecular Imaging. Bioengineering 2017; 1(4): 78.[http://dx.doi.org/10.3390/bioengineering4030078][17]Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol 2014; 5: 520-0.[http://dx.doi.org/10.3389/fimmu.2014.00520] [PMID: 25368619][18]Senter PD. Potent antibody drug conjugates for cancer therapy. Curr Opin Chem Biol 2009; 13(3): 235-44.[http://dx.doi.org/10.1016/j.cbpa.2009.03.023] [PMID: 19414278][19]Trendowski M. Recent Advances in the Development of Antineoplastic Agents Derived from Natural Products. Drugs 2015; 75(17): 1993-2016.[http://dx.doi.org/10.1007/s40265-015-0489-4] [PMID: 26501980][20]Moore KN, Martin LP, O’Malley DM, et al. A review of mirvetuximab soravtansine in the treatment of platinum-resistant ovarian cancer. Future Oncol 2018; 14(2): 123-36.[http://dx.doi.org/10.2217/fon-2017-0379] [PMID: 29098867][21]Junutula JR, Raab H, Clark S, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol 2008; 26(8): 925-32.[http://dx.doi.org/10.1038/nbt.1480] [PMID: 18641636][22]Gauzy-Lazo L, Sassoon I, Brun MP. Advances in Antibody-Drug Conjugate Design: Current Clinical Landscape and Future Innovations. SLAS Discov 2020; 25(8): 843-68.[http://dx.doi.org/10.1177/2472555220912955] [PMID: 32192384][23]Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer 2012; 12(4): 278-87.[http://dx.doi.org/10.1038/nrc3236] [PMID: 22437872][24]Carmon KS, Azhdarinia A. Application of Immuno-PET in Antibody-Drug Conjugate Development. Mol Imaging 2018; 17: 1536012118801223.[http://dx.doi.org/10.1177/1536012118801223] [PMID: 30370812][25]van Dongen GAMS, Beaino W, Windhorst AD. The navigating and de-risking role of (89)Zr-immuno-PET in the development of biopharmaceuticals. J Nucl Med 2020; 4: junmed.119239558..[26]Kang L, Jiang D, Ehlerding EB, et al. Noninvasive Trafficking of Brentuximab Vedotin and PET Imaging of CD30 in Lung Cancer Murine Models. Mol Pharm 2018; 15(4): 1627-34.[http://dx.doi.org/10.1021/acs.molpharmaceut.7b01168] [PMID: 29537283][27]Gong J, Guo F, Cheng W, Fan H, Miao Q, Yang J. Preliminary biological evaluation of 123I-labelled anti-CD30-LDM in CD30-positive lymphomas murine models. Artif Cells Nanomed Biotechnol 2020; 48(1): 408-14.[http://dx.doi.org/10.1080/21691401.2019.1709857] [PMID: 31913714][28]Williams SP, Ogasawara A, Tinianow JN, et al. ImmunoPET helps predicting the efficacy of antibody-drug conjugates targeting TENB2 and STEAP1. Oncotarget 2016; 7(18): 25103-12.[http://dx.doi.org/10.18632/oncotarget.8390] [PMID: 27029064][29]Lamberts LE, Menke-van der Houven van Oordt CW, ter Weele EJ, et al. ImmunoPET with Anti-Mesothelin Antibody in Patients with Pancreatic and Ovarian Cancer before Anti-Mesothelin Antibody-Drug Conjugate Treatment. Clin Cancer Res 2016; 22(7): 1642-52.[http://dx.doi.org/10.1158/1078-0432.CCR-15-1272] [PMID: 26589435][30]Azhdarinia A, Voss J, Ghosh SC, et al. Evaluation of Anti-LGR5 Antibodies by ImmunoPET for Imaging Colorectal Tumors and Development of Antibody-Drug Conjugates. Mol Pharm 2018; 15(6): 2448-54.[http://dx.doi.org/10.1021/acs.molpharmaceut.8b00275] [PMID: 29718672][31]Herbertson RA, Tebbutt NC, Lee FT, et al. Phase I biodistribution and pharmacokinetic study of Lewis Y-targeting immunoconjugate CMD-193 in patients with advanced epithelial cancers. Clin Cancer Res 2009; 15(21): 6709-15.[http://dx.doi.org/10.1158/1078-0432.CCR-09-0536] [PMID: 19825951][32]Gan H, Burgess AW, Clayton AHA, Scott AM. Targeting of a conformationally exposed, tumor-specific epitope of EGFR as a strategy for cancer therapy. Cancer Res 2012; 72(12): 2924-30.[http://dx.doi.org/10.1158/0008-5472.CAN-11-3898] [PMID: 22659454][33]Scott AM, Akhurst T, Lee FT, et al. First clinical study of a pegylated diabody 124I-labeled PEG-AVP0458 in patients with tumor-associated glycoprotein 72 positive cancers. Theranostics 2020; 10(25): 11404-15.[http://dx.doi.org/10.7150/thno.49422] [PMID: 33052222][34]Gan HK, Burge M, Solomon B, et al. A Phase 1 and Biodistribution Study of ABT-806i, an 111In-Radiolabeled Conjugate of the Tumor-Specific Anti-EGFR Antibody ABT-806. J Nucl Med 2021; 62(6): 787-94.[http://dx.doi.org/10.2967/jnumed.120.253146] [PMID: 33509972][35]van den Bent M, Gan HK, Lassman AB, et al. Efficacy of depatuxizumab mafodotin (ABT-414) monotherapy in patients with EGFR-amplified, recurrent glioblastoma: results from a multi-center, international study. Cancer Chemother Pharmacol 2017; 80(6): 1209-17.[http://dx.doi.org/10.1007/s00280-017-3451-1] [PMID: 29075855][36]Gan HK, Reardon DA, Lassman AB, et al. Safety, pharmacokinetics, and antitumor response of depatuxizumab mafodotin as monotherapy or in combination with temozolomide in patients with glioblastoma. Neuro-oncol 2018; 20(6): 838-47.[http://dx.doi.org/10.1093/neuonc/nox202] [PMID: 29077941][37]Lassman AB, van den Bent MJ, Gan HK, et al. Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR-amplified, recurrent glioblastoma: results from an international phase I multicenter trial. Neuro-oncol 2019; 21(1): 106-14.[http://dx.doi.org/10.1093/neuonc/noy091] [PMID: 29982805][38]Divgi CR, Scott AM, Dantis L, et al. Phase I radioimmunotherapy trial with iodine-131-CC49 in metastatic colon carcinoma. J Nucl Med 1995; 36(4): 586-92.[PMID: 7699446][39]Rossin R, Versteegen RM, Wu J, et al. Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice. Nat Commun 2018; 9(1): 1484.[http://dx.doi.org/10.1038/s41467-018-03880-y] [PMID: 29728559]
