workshop - belgian molecular imaging community · biotechnological engineering, antibodies are...
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Workshop Immuno-Imaging and Molecular Therapy
April 1st - 5th 2019
Auditorium TI. K Vrije Universiteit Brussel (VUB)Faculty of Medicine & PharmacyBuilding KLaarbeeklaan 1031090 BrusselsBelgiumBelgium
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Workshop description: Due to their low immunogenicity, high affinity/specificity and flexibility towards biotechnological engineering, antibodies are interesting vehicles for molecular diagnosis, imaging and therapy. The workshop ‘Immuno-imaging and molecular therapy’ aims to bring together national and international experts in the fields of antibody-engineering, clinical and preclinical nuclear imaging, tracer design, image acquisition and reconstruction, (radio)chemistry, targeted radionuclide therapy, optical imaging, immunogenicity and intellectual property. Altogether, a full overview of the research topic ‘immunotheranostics’ will be provided through the organization of lectures, discussion groups and hands-on sessions. In particular, a special focus will be put on nanobodies as an example of engineered antibody vehicle for noninvasive imaging and targeted therapy. The organising committee particularly welcomes the PhD students from the PET3D ITN network (www.PET3D.eu) as participants. For whom ? This workshop is targeted towards anybody interested in the broad topic of 'immune-theranostics'. Basic knowledge of radiation, biotechnology, biochemistry, medicine and engineering is required. Masters in Biology, Biomedical Sciences, Biotechnology, (Bio)Chemistry, Medicine or Pharmacy, PhD students, technologists and postdoctoral fellows working or interested in this field of research are encouraged to participate. Venue: The workshop will be held at the Health Campus of the Free University Brussels (Vrije Universiteit Brussel), Laarbeeklaan 103, B-1090 Brussels, Belgium. The lectures will be held in the auditorium of the dental clinic, building K ground floor. Lunches, refreshments, discussions, practical sessions and the central meeting point will be the seminar room of the ICMI laboratory, also located in building K ground floor.
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Workshop schedule: Monday April 1st to Friday April 5th 2019, each day from 9AM to 5PM, unless otherwise specified. Thursday April 4th is a public event, also open to researchers not following the workshop and/or not part of the PET3D program. PET3D participants will follow an alternative track on Friday April 5th. Accommodation: The workshop participants themselves are responsible for their own accommodation. Workshop attendants need to take care of their own daily breakfast and dinner, unless noted otherwise. Registration deadline and fee: March 8th, 2019 €300 for 5-day program* Registration includes attendance of the workshop, lunches, refreshments and participation to the social event. The participation to the social event is optional for VUB students, but will cost €25 per person. *VUB and PET3D students have to register but their fee is waived. Contact and registration: Carlien Geldof Email: [email protected] Phone: +32(0)2 477 4924
Organisation Commitee: Director: Prof. Dr. Nick Devoogdt Administration: Carlien Geldof
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Program: Monday April 1st, Auditorium Dental Institute (TI) 08u30-09u30 Arrival, coffee and registration 09u30-10u00 Prof Nick Devoogdt (VUB)
Welcome, round table introduction 10u00-11u15 Prof Nick Devoogdt (VUB)
Do's and dont's in immunotracer design
11u15-11u30 Bio-break 11u30-12u30 Prof Christian Van Hove (UGent)
Overview of imaging modalities, part I
12u30-13u30 Sandwich lunch + poster mounting 13u30-14u30 Prof Christian Van Hove (UGent)
Overview of imaging modalities, part II 14u30-15u30 Prof Marleen Keyaerts (VUB/UZ Brussel) Introduction to clinical nuclear medicine 15u30-15u45 Bio-break 15u45-17u00 Dr Géraldine Gebhart & Dr Zéna Wimana (Bordet Institute Brussels) Clinical immuno-PET
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Tuesday April 2nd, Auditorium Dental Institute (TI)
09u00-10u15 Prof Serge Muyldermans (VUB) Nanobody discovery and biotechnological applications 10u15-10u30 Bio-break 10u30-11u45 Prof Nick Devoogdt (VUB) Imaging with nanobodies in preclinical models 11u45-14u15 Sandwich lunch + poster session 1 14u15-15u30 Prof Catarina Xavier (VUB) Radiochemistry of nanobodies 15u30-15u45 Bio-break 15u45-17u00 Prof Marleen Keyaerts (VUB/UZ Brussel) Clinical translation of nanobody-tracers 17u00-... Social event (Brussels sightseeing & dinner)
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Wednesday April 3rd, Auditorium Dental Institute (TI) 09u00-10u15 Dr Chloé Ackaert (ImmunXperts inc.) Immunogenicity of proteins and nanobodies 10u15-10u45 Bio-break 10u45-12u00 Prof Sophie Hernot (VUB) Fluorescence and cardiovascular applications of nanobodies 12u00-14u15 Sandwich lunch + poster session 2 14u15-15u30 Dr Ahmet Krasniqi (VUB) Targeted radionuclide therapy, focus on nanobodies 15u30-15u45 Bio-break 15u45-17u00 Prof Geert Raes (VUB/VIB) Intellectual property of biologics 17u00-17u15 Group picture
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Thursday April 4th: Open symposium "Integrating PET imaging in drug development: a market model for PET imaging", Auditorium Dental Institute (TI)
09u00-10u00
10u00-10u15
10u15-11u15
11u15-11u30
11u30-12u30
12u30-13u30
13u30-14u30
14u30-14u45
14u45-15u45
15u45-16u00
16u00-17u00
Prof Alison Murray (University Aberdeen, Scotland) FDG PET in clinical practice and clinical trials of Alzheimer’s Disease and Frontotemporal dementias
Bio-break
Prof Mats Bergstrom (Key Opinion Leader, consultant) Imaging and the three Pillars in Drug Development – Options, Pitfalls and Collaboration models
Bio-break
Dr Magnus Schou (AstraZeneca ) The use of PET imaging to drive drug discovery and development
Sandwich lunch
Prof Guus van Dongen (VU Amsterdam) PET Imaging in Drug Design and Development: costs, benefits and value
Bio-break
Prof Neil Vasdev (University of Toronto & Centre for Addiction and Mental Health (CAMH) Academic-Industrial Partnerships for PET Radiochemistry and Imaging in Drug Development
Bio-break
Prof Jason Lewis (Memorial Sloan Kettering Cancer Center, New York, USA) Molecular Imaging: Creating Windows into Cancer
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Friday April 5th
VUB Masterclass & External Participants (not for PET3D participants): Hands-on sessions at the ICMI lab 09u00-12u00 Hands-on session 1 (to be chosen from one of the topics) 12u00-13u00 Sandwich lunch 13u00-16u00 Hands-on session 2 (to be chosen from one of the topics) 16u00-17u00 Round-table discussion and meeting adjourn
Hands-on sessions: - Nanobody lead selection analysis (Prof. Dr. Nick Devoogdt) - Visit to the nuclear medicine department and cyclotron unit of the UZ Brussel hospital
(Prof. Dr. Marleen Keyaerts & Prof. Dr. Vicky Caveliers) - Biodistribution analysis in mice (Prof. Dr. Sophie Hernot) - Nanobody radiochemistry techniques (Prof. Dr. Catarina Xavier)
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Information about the lecturers:
Nick Devoogdt Professor Vrije Universiteit Brussel (VUB) Research cluster Imaging and Physical Sciences (BEFY) In vivo Cellular and Molecular Imaging laboratory
Email: [email protected] Phone: +32 2 477 4991
Nick Devoogdt was trained as a Master in Molecular Biology at the Free University of Brussels (Vrije Universiteit Brussel, VUB), where he obtained his degree with high distinction in 1997. He obtained an FWO scholarship and in 2004 obtained a PhD in Applied Biological Sciences under the promotorship of Prof De Baetselier, working on cancer genetics, cellular biology and immunity. Again he acquired a FWO grant to continue his postdoctoral research for the periode 2004-2007. In 2004-2005 he was a visiting scientist at the National Cancer Institute in Bethesda USA, studying ovarian cancer genetics and biomarkers, after which he returned to VUB in Belgium for additional training as a postdoctoral scientist: in 2005-2006 in the field of cellular immunology and cancer genetics, in 2007 in antibody-engineering and from 2008 onwards in molecular imaging. In 2013 he became assistant professor in the small animal imaging lab ICMI and in 2016 tenure-track full professor. In 2014 he also co-founded the spinoff company Camel-IDS where he is still active as coordinator of the discovery pipeline.
His research aims to develop novel applications in molecular and nuclear imaging and targeted therapies. His current focus is on the nanobody-technology as targeting vehicles. More in particular, his research is focused on the generation of new probes for their application (nuclear or other types of imaging an therapy) in small animal models of disease, and in a second phase on testing in patients. Hence, his preclinical and translational research is supportive and closely connected with clinically-oriented research teams within the faculty of medicine and the university hospital.
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Christian Vanhove Associate professor Ghent University Medical Imaging and Signal Processing Head of preclinical core imaging facility UGent (INFINITY) Email: [email protected] Phone: +32 9 332 4115
Christian Vanhove graduated as a Biomedical and Clinical Engineer from Brussels University in 1990. From 1991 until 1996, he worked as a Medical Physicist at the Nuclear Medicine department of the Sint-Elisabeth hospital in Zottegem, where he was doing research and developments for the industry in a clinical environment. Research and developments were focused on all aspects of medical image processing, including image reconstruction, image registration and image quantification. In 1996, he moved to the Nuclear Medicine department of the Brussels University Hospital. As a Medical Physicist Expert he continued his research in the field of medical image processing and obtained his PhD in Medical Science in 2004. During his PhD, a new algorithm for the automatic segmentation and quantification of gated blood pool SPECT images, in both humans and small animals, was developed and validated. In 2005, he was one of the initiators of the small animal imaging lab of Brussels University and worked as a postdoctoral researcher at this preclinical imaging facility. During this period his research was focused on quantitative pinhole SPECT. Since February 2011, he joined the Medical Imaging and Signal Processing (MEDISIP) research group of the Faculty of Engineering of Ghent University, where he is responsible for the INnovative Flemish IN-vivo Imaging TechnologY (INFINITY) lab. This lab focuses on multimodal in-vivo imaging strategies and serves as a core facility for preclinical imaging within Ghent University. The major research domains of INFINITY are the evaluation of pathophysiology in neurological diseases, cancer and inflammation. Christian Vanhove is associate professor and lecturer in molecular imaging.
Marleen Keyaerts Assistant professor Vrije Universiteit Brussel – In vivo cellular and molecular imaging laboratory Head of clinics UZ Brussel – Department of nuclear medicine Email: [email protected] Phone: +32 2 477 50 20
Marleen studied medicine at the Vrije Universiteit Brussel and performed her master thesis at the nuclear medicine department of the UZ Brussel on the biodistribution of a new radiopharmaceutical in healthy subjects. She immediately started her PhD at the ICMI lab after graduation, which was completed in 2011. In her PhD project, Marleen investigated bioluminescence imaging for the assessment of tumor burden. When she moved back to the clinic to complete her clinical training in nuclear medicine, a first nanobody lead compound was ready for first in human testing. Marleen was strongly involved in this phase I clinical trial using anti-HER2 Nanobody PET/CT imaging in breast carcinoma patients and she is currently primary investigator in the phase II trial.
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Geraldine Gebhart MD, PhD, Physician in Nuclear Medicine, Jules Bordet Institute, Brussels Email: [email protected]
Geraldine studied medicine at the « Université Libre de Bruxelles », including one year in Berlin as part of the Erasmus program. In 2009, with a good background of internal medicine, she started to work in Nuclear Medicine under the supervision of Prof. Patrick Flamen. She discovered with great enthusiasm, molecular imaging, which is today an emerging field in oncology. Her PhD project focused on the contribution of molecular imaging to early evaluation of response to anti-HER2 agents in Breast Cancer. In brief, she contributed to different projects including - the evaluation of the FDG-PET/CT scans performed in the biological window of the NEOALTTO trial, which has compared, in HER2 positive breast cancer patients, the preoperative administration of trastuzumab, lapatinib or their combination (paclitaxel was added subsequently to each of these 3 arms) - studies with zirconium-89 labelled trastuzumab in patients with HER2 positive metastatic breast cancer: the ZEPHIR study, a phase II prospective imaging study evaluating the utility of pre-treatment zirconium-89 labelled trastuzumab PET/CT and an early FDG-PET/CT response to identify patients with advanced breast cancer unlikely to benefit from a novel anti-HER2: T-DM1. The work of G. Gebhart was recognized by the following awards: JNM Editor's Choice Award 2013 and Alavi Mandell Award for JNM article published in 2013.
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Zéna Wimana PhD, Biomedical doctor and coordinator of the radiopharmacy Nuclear Medicine/Radiopharmacy, Jules Bordet Institute, Brussels Email: [email protected] Zéna studied Biomedical Sciences at the University of Antwerp. She then concluded her training with a postgraduate degree in Biomedical Imaging partially performed at the VUB, where she stayed one year as a scientific assistant. In 2009, she started to work as a research associate in the Nuclear Medicine department of Prof. Patrick Flamen at the Jules Bordet institute. She started a research project one year later under the supervision of Prof. Ghanem Ghanem and obtained her PhD from the ULB with a thesis entitled “ImmunoPet imaging using Zirconium-89 radiolabeled trastuzumab to explore resistance in HER2+/MUC4+ breast cancer”. In the mean time she became the coordinator of the radiopharmacy of the Jules Bordet Institute and participated to the introduction of several radiopharmaceuticals in the clinic as premier in Belgium, namely 89Zr-Trastuzumab for the imaging of HER2 positive breast cancer, 177Lu-DOTATATE for the therapy of neuro-endocrine tumors and 68Ga-PSMA for the imaging of prostate cancer. She is currently also a board member in different scientific and professional associations, including the Belgian Nuclear Medicine Society, Belgian Molecular Imaging Community and the Radiopharmacy board of the National Institute of Radioelements. Serge Muyldermans Professor Vrije Universiteit Brussel Laboratory of Cellular and Molecular Immunology Email: [email protected] Phone: +32 2 629 19 69 Serge Muyldermans started his studies (chemistry) at the ‘Vrije Universiteit Brussel’ and obtained his PhD in 1982 on structural aspects of nucleosomes and chromatin. As a postdoc at the same university he became involved in the early 90-ies in the camel antibody program. In 2003 he was appointed Professor at the Vrije Universiteit Brussel, where he is now heading the camel antibody engineering group in the laboratory of Cellular and Molecular Immunology. The discovery of camel Heavy-chain antibodies and the applications of their unique single variable antigen-binding domain (now referred to as Nanobodies) led to the publication of over 220 articles in peer reviewed international journals, many of which appeared in top journals. In January 2002, he was co-founder of ‘Ablynx’, a spin-off company that generates Nanobodies for therapeutic purposes. Ablynx is currently employing ~300 people and has several Nanobodies in clinical trials.
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Catarina Xavier Assistant professor at Vrije Universiteit Brussel In vivo cellular and molecular imaging laboratory Email: [email protected] Phone: +32 2 477 49 91 Catarina studied Chemistry at the University of Lisbon, and obtained her degree in 2002. She immediately started working at ITN/Portugal and in 2004 she was awarded with a PhD grant from the Portuguese Science Foundation (FCT). Her PhD studies (2004-2009) were performed at ITN/University of Lisbon under supervision of Dr. Isabel Rego dos Santos, at University of Zurich under the supervision of Dr. Roger Alberto and at University of Milan under supervision of Dr. Clelia Giannini. As from April 2009 she is a postdoctoral researcher at the In vivo cellular and molecular imaging (ICMI) laboratory. In 2015 she became assistant professor at ICMI. Her research aims at the development of new radiopharmaceutical probes for imaging or targeted radionuclide therapy. She is involved in the process of nanobody probe optimization and translation to the clinic for PET/ CT imaging.
Chloé Ackaert Senior Scientist at ImmunXperts Email: [email protected]
Chloé studied Pharmacy at the Katholieke Universiteit Leuven and performed her master thesis at the Hôpital Bichat in Paris, the CHU in Charleroi and the UZ Antwerpen on Enzyme Replacement Therapy in Fabry disease patients. She did an internship in the laboratory of Therapeutic and Diagnostic Antibodies (KUL) on the Immunogenicity of anti-TNFα mAbs in IBD patients, followed by a PhD on the immunogenicity of modified allergens at the University of Salzburg in Austria. After her PhD, she was involved in the start-up of the CRO ImmunXperts, offering integrated immunogenicity services. Since 2015, Chloé worked in the Camel Antibody group within the Cellular and Molecular Immunology lab (VUB) where she focussed on studying the immunogenicity of Nanobodies. She performed the anti-drug antibody measurements in the phase I clinical trial using anti-HER2 Nanobody for PET/CT imaging in breast carcinoma patients and assessed the immunogenicity risk of several Nanobodies by in vitro methods. As of October 2018, she joined the team of ImmunXperts again, as a senior scientists for projects dealing with assessment of (un)wanted immunogenicity of biopharmaceuticals in development.
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Sophie Hernot Assistant Professor Vrije Universiteit Brussel – In vivo Cellular and Molecular Imaging Laboratory Email: [email protected] Phone: +32 2 477 49 91 Sophie Hernot is a Bio-engineer from the VUB. She completed her PhD thesis in medical sciences in 2011 on the use of microbubbles (ultrasound contrast agents) as well as nanobodies for molecular imaging and drug delivery applications. As post-doctoral researcher, and currently as assistant professor in the laboratory of In vivo Cellular and Molecular Imaging (ICMI, VUB), her research interests are two-fold: 1) design and validation of nanobodies for optical imaging applications, and in particular towards a clinical translation for image-guided surgery, and 2) validation of nanobody-based molecular probes for identification and characterization of high-risk atherosclerotic lesions. Ahmet Krasniqi Vrije Universiteit Brussel In vivo cellular and molecular imaging laboratory Email: [email protected] Phone: +32 2 477 49 91 Ahmet obtained his master in Biomedical sciences from the VUB in 2014. In 2014 he started
his PhD under the supervision of Prof. Nick Devoogdt in the In vivo Cellular and Molecular
Imaging (ICMI) lab. During his PhD, he has been focusing on evaluating the potential of
radiolabeled single domain antibody fragments for radionuclide-based imaging and targeted
radionuclide therapy of Non-Hodgkin lymphoma. Ahmet will defend his PhD in 2019. His
current interest is on the investigation of the effects on the immune response after targeted
radiation of cancer cells.
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www.PET3D.euGeert Raes Assistant professor & valorization manager Vrije Universiteit Brussel Cellular and Molecular Immunology unit Staff Scientist at VIB Inflammation Research Centre Email: [email protected] Phone: +32 2 629 19 68
After obtaining a degree in bio-engineering and a PhD in tumor immunology, Geert has been staff scientist at VIB, where he has been involved in projects aimed at translating basic immunology research into industrial applications. Since 2013, he also has a partial appointment as valorisation manager at Vrije Universiteit Brussel, focusing on economic valorisation of nanobody applications in molecular imaging and therapy. Geert is co-inventor on 6 patent families. He is co-founder and IP & Legal Advisor of the VUB spin-off company Camel-IDS. Alison Murray MBChB, PhD Roland Sutton Professor of Radiology at the University of Aberdeen
Professor Murray leads clinical brain imaging research in structural and functional brain imaging correlates of cognitive ageing and dementia. She has extensive NHS clinical experience of brain imaging in dementia, with around 400 nuclear medicine brain regional cerebral blood flow SPECT/CT studies per annum and receptor studies in movement disorder. Author of 92 publications, 6 books/book chapters, 1 patent. She is a founding member and current director of the Scottish Imaging Network: A Platform for Scientific Excellence (SINAPSE) www.sinapse.ac.uk a successful brain imaging pooling initiative funded by the Scottish Funding Council and participating universities to develop state of the art imaging research training and resources across Scotland. She is also an executive member of the Scottish Dementia Research Consortium, AKUK Scotland, Generation Scotland and is a recent past President of the Scottish Radiology Society. Mats Bergström Former GSK, Roche, Novartis, Consultant
Professor Bergstrom holds a degree in mathematics, physics and medical physics. He participated in the development of one of the first PET cameras at the Karolinska Institute in Stockholm. Before joining Roche as senior expert in imaging sciences, Professor Bergstrom served as director of the preclinical laboratory at the Uppsala PET centre in Sweden, director of the PET program at Novartis, then director of biology and imaging expert at GSK. Currently retired and Member of Scientific Advisory Board at Oncodesign S.A. and consultant in Molecular Imaging to Pharmaceutical Industry. Professor Bergstrom is a world-renowned expert on PET tracer research and has participated in clinical trials on over 80 new PET tracers and has over 300 scientific publications.
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www.PET3D.euMagnus Schou AstraZeneca Magnus Schou is since 2014 an associate principal scientist at the AstraZeneca PET Science Centre at Karolinska Institutet. His focus is on the development of novel translational imaging biomarkers and radiochemistry approaches that permit late-stage labeling of drug molecules with 11C and 18F. Magnus earned his PhD from Karolinska Institutet in 2006 and has contributed to numerous drug discovery and development projects at AstraZeneca whilst publishing more than 45 research articles in the field of molecular imaging. Guus van Dongen Amsterdam University Medical Center
Professor Guus van Dongen is chair of preclinical imaging and chair research at the department of Radiology and Nuclear Medicine of the Amsterdam University Medical Center, location VUmc. Professor van Dongen’s research focused on the use of targeted drugs like monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) for disease detection and therapy. He introduced “immuno-PET” and “TKI-PET”, the PET imaging of radiolabeled mAbs and TKIs, respectively, as well as photo-immunodetection. He is project leader for building the world leading Amsterdam UMC Imaging Center, comprising Tracer Center Amsterdam, and fully focused on image in drug development within public-private partnerships. Professor van Dongen supervised 17 PhD projects, coordinates/participates in several teaching programs in the field of imaging and oncology, is author of more than 200 papers in peer-reviewed journals, participated in many EU consortia, and is inventor in several patents. Neil Vasdev Professor and Director at University of Toronto & Centre for Addiction and Mental Health (CAMH) Professor Vasdev is the inaugural Director of the Azrieli Centre for Neuro-Radiochemistry at the Centre for Addiction and Mental Health (CAMH) in Toronto, Canada, where he also serves as the Associate Director and Chief Radiochemist of the CAMH Research Imaging Centre. He is the endowed Azrieli Chair in Brain and Behaviour and a Tier 1 Canada Research Chair in Radiochemistry and Nuclear Medicine, as well as a professor in the Department of Psychiatry at the University of Toronto. From 2011 through 2017, he was the Director of Radiochemistry at Massachusetts General Hospital and still maintains a faculty appointment at Harvard Medical School. Professor Vasdev is a recognized world expert in the radiochemistry discovery and development of novel PET radiopharmaceuticals with extensive experience in multistep reactions, basic chemistry and radiochemistry experiments and bench to bedside discovery of novel imaging probes that have led to the first human use of imaging agents. He received his doctorate in chemistry from McMaster University, and continued training with a postdoctoral fellowship at the E.O. Lawrence Berkeley National Laboratory.
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www.PET3D.euJason S. Lewis Memorial Sloan Kettering Cancer Center, New York, USA Professor Jason S. Lewis serves as Vice Chair for Research and as the Chief of the Radiochemistry & Imaging Sciences Service. He is the Director of MSK’s Radiochemistry and Molecular Imaging Probe Core Facility and is Director of the MSK Center for Molecular Imaging & Nanotechnology. He is a Member in MSK, a Professor at the Gerstner Sloan-Kettering Graduate School and at Weill-Cornell Medical College. Professor Lewis earned a B.Sc. in Chemistry (1992) and a M.Sc. (1993) in Chemistry from the University of Essex and then in 1996 obtained a Ph.D. in Biochemistry from the University of Kent with Professor Philip J. Blower. His postdoctoral work was at the Washington University School of Medicine (WUSM). Subsequently he joined the WUSM faculty as an Assistant Professor of Radiology at the Mallinckrodt Institute of Radiology (2003-2008). Professor Lewis then joined MSKCC in 2008. He received a Distinguished Investigator Award from the Academy of Radiology Research, was named a Fellow of the World Molecular Imaging Society and was the 2017 SNMMI Michael J. Welch Award winner. His research interests are focused on the development of new molecular imaging agents and radiopharmaceuticals for the diagnosis and treatment of cancer. He has worked on the development of small molecules targeting cancer, as well as radiolabeled peptides and Zr-89-labeled antibodies targeting disease-specific receptors and antigens; this is always with the ultimate goal of clinical translation. He has published >250 papers, books, book chapters, and reviews in the field of radiochemistry.
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www.PET3D.euInformation about the program:
Do's and dont's in immunotracer design (Nick Devoogdt)
In this presentation, the concept ‘molecular imaging’ will be introduced and a general overview of different types of tracers will be given. A major focus will be on antibody-tracers: how does the immune system develops an efficient antibody response ? what are the molecular and structural features of antibodies ? What are the different techniques to generate antibodies and how can they be engineered into different types of antibody-fragments ? The pharmacokinetic behavior of antibodies and engineered fragments will be explained, and their relation to molecular and nuclear imaging. The antibody pretargeting approach will be briefly touched upon. Finally various concepts related to tracer design will be explained, including ‘affinity’, ‘avidity’, ‘enhanced permeability and retention’, ‘the site-barrier-effect in tissue penetration’, ‘specific activity’ and ‘antigenic sink’. This first lecture will also try to provide links and an introduction to other lectures given during the workshop.
Overview of imaging modalities (Christian Vanhove) In 1895 the German physicist Wilhelm Conrad Roentgen discovered the X-rays, an achievement that earned him the first Nobel Prize in Physics in 1901. These X-rays produced the first medical images in the beginning of the previous century. Nowadays, a wide range of imaging techniques are available that can be roughly sub-divided into two main categories: structural and functional imaging devices. The most commonly used structural imaging technologies are computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound imaging (US). These techniques were developed to non-invasively visualize nonspecific macroscopic anatomical and physiological changes in tissues. Functional imaging modalities, such as single photon emission tomography (SPECT), positron emission tomography (PET) and optical imaging (OI) focus on the visualization of molecular/cellular targets in living subjects. These targets in functional imaging can include transporters, cell surface receptors and intracellular enzymes. An overview will be presented of the physical basics behind the image formation process of these imaging modalities. The requirements to move from clinical to preclinical imaging will also be discussed for each modality. The presentation will start with CT that can be seen as a direct evolution of X-ray imaging. Secondly, the nuclear imaging techniques SPECT and PET will be presented, including the important evolution of combining these nuclear imaging techniques with CT and MRI. The more complex image formation process of MRI will be shortly introduced. Finally, OI will be presented, including bioluminescence and fluorescence in-vivo imaging, which are of more importance in the preclinical arena.
Introduction to the clinical nuclear medicine (Marleen Keyaerts) This presentation will go over the routinely performed nuclear medicine examinations in patients, with a focus on the uptake mechanism of different tracers as well as a personal view on the future of clinical nuclear medicine. The session is intended for students and researchers in the preclinical field that would like to get a better understanding of daily practice in a nuclear medicine ward in the hospital. Typical images of routinely performed scans will be discussed and interpreted.
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www.PET3D.euClinical immunoPET (Z. Wimana & G. Gebhart) Currently, mAb-based imaging forms the main category of immunoPET, largely as a result of the development and use of mAbs as disease-selective systemic treatments of cancer. ImmunoPET combines the sensitivity and high spatial resolution of PET with the specificity of high affinity ligands of immune origin. It can be used for different application including characterization of lesions, diagnosis, staging, evaluation and prediction of treatment response. Furthermore, in R&D of mAb-based treatment, immunoPET can offer valuable information on in vivo drug-target interaction, pharmacokinetics and pharmacodynamics, when the drug itself is radiolabeled and used as an imaging probe. As for the use in the characterisation of tumors, immunoPET presents several advantages: it is a real time whole-body non-invasive tool, allowing simultaneous cancer detection and localization by visually proving the presence of an expressed biomarker, both in the primary tumor and in metastases. Moreover, it provides an attractive novel alternative in vivo option as to IHC staining, improving diagnostic and tumor characterization as well as heterogeneity of target expression. In this way, immunoPET could influence treatment choice and this could result in improved patient’s outcomes.
Nanobody discovery and biotechnological applications (Serge Muyldermans) Llama and camels have unique antibodies comprising a homodimer of heavy chains only, whereby the antigen is recognized by virtue of one single domain. A straightforward technology was developed to immunize a camelid, to clone the repertoire of antigen-binding fragments, from which the antigen-specific fragments are identified after phage display selections. The resulting recombinant, antigen-binding single-domain antibody fragments are also referred to as Nanobodies (Nbs) because of their size of 4 nm by 2.5 nm in diameter. Nanobodies are well produced in microbial systems, very robust and highly soluble, bind their cognate antigen with high affinity and specificity. Very often the Nanobody recognizes an epitope that is difficult to target with human or mouse antibodies. The ‘humanization’ of a camel derived single domain antibody is straightforward. One of the largest advantage of Nanobodies comes from their strict monomeric behaviour, the ease to tailor them into larger pluripotent constructs and their functionality when expressed intracellularly. Such beneficial properties of Nanobodies over other antigen-binding fragments from conventional antibodies inspired many researchers to employ Nanobodies as a versatile tool in various innovative applications in biotechnology and medicine as: • a research tool to immune-capture the antigen from complex mixtures, • a potent probe to trace (or eliminate) target antigen within living cells, • an excellent diagnostic tool for non-invasive in vivo imaging of tumors, • a therapeutic tool to eradicate tumors or trypanosome infection in mice models, • an anti-venom to protect from scorpion envenoming
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www.PET3D.euImaging with nanobodies in preclinical models (Nick Devoogdt) In this lecture, the focus will be on nanobodies and their evaluation by nuclear imaging in animal models of various diseases. The lecture will start with a rather detailed overview of protocols to generate good nanobody vehicles and will then look at subsequent attention points on which parameters and criteria should be considered to select a lead compound. We will look at structural features of nanobodies and how this is reflected in their aminoacid sequence. The major part of this lecture will consist of an overview of recent published and unpublished applications of nanobodies in small animal nuclear imaging in pathologies ranging from oncology to autoimmune disease, macrophage-tracking, and some examples of nanobody engineering to ameliorate tracer performance.
Radiochemistry of Nanobodies (Catarina Xavier) In this lecture, the goal is to provide an overview of the different methods that have been devised for the radiolabeling of nanobodies for molecular imaging and therapy. The presentation will focus on 2 different strategies for nanobody radiolabeling: (1) random labeling on lysines of the nanobody sequence, and (2) site-specific labeling on histidine tag, cysteine residues and peptide tags (sortase mediated). Furthermore, the advantages and disadvantages of each strategy will be discussed. Different radioisotopes will be described as well as their related radiochemistry. It is our goal that this presentation will provide a critical understanding of the radiosynthesis process importance in order to obtain a probe with the specifications for pre-clinical or clinical application.
Clinical translation of nanobody-tracers (Marleen Keyaerts) The clinical translation of new imaging agents will be discussed using the 68-Ga-HER2 nanobody as an example. Participants will get insight into regulatory requirements for clinical trials, including GMP compliance, clinical trial application with the competent authorities and ICH-GCP requirements. A study protocol for a phase I study will be presented and explained, as well as the obtained results.
Immunogenicity of recombinant proteins (Chloé Ackaert) The immunogenicity of recombinant biopharmaceuticals will be discussed with the focus on clinical impact of immunogenicity and methods available to assess the immunogenicity risk. Participants will get insight into in silico, in vitro and in vivo methods for immunogenicity risk assessment, as well as anti-drug antibody monitoring in clinical trial phases. Case studies will be discussed as illustration and the immunogenicity of the Ga-NOTA-anti-HER2 Nanobody will be presented.
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www.PET3D.euFluorescence and cardiovascular applications of nanobodies (Sophie Hernot) In vivo Fluorescence Imaging - A general overview will be given regarding the application of fluorescence imaging for image-guided surgery. Both the technical aspects of optical imaging devices as well as the design of fluorescent tracers will be discussed. Current and emerging clinical applications will be illustrated, as well as the role the nanobodies in this field. Cardiovascular molecular imaging - This talk will focus on the role molecular imaging can play in the diagnosis and characterization of cardiovascular diseases, in particular for vulnerable atherosclerotic plaques. Besides an overview of the current state of the art, the important pitfalls and hurdles that the field has to face will be covered. Finally, the contribution of nanobodies for imaging of atherosclerotic lesions and follow-up of inflammation after myocardial infarction will be covered.
Targeted radionuclide therapy: Nanobodies as an example (Ahmet Krasniqi) This presentation will introduce the basics of Targeted Radionuclide Therapy of cancer, and briefly highlight different exciting applications that are now available in the clinic. In addition, an important part of the talk will focus on the use of Nanobodies as potential vehicles for Targeted Radionuclide Therapy using both beta-- and alpha-particle emitting isotopes.
Intellectual property of biologics (Geert Raes) Using nanobodies as an example, some basic principles of intellectual property rights will be discussed. After a brief overview of the main features and types of intellectual property rights, the focus will be on patents: advantages of patents, requirements for patentability, limitations to patentable subject matter and formulation of patent claims. Finally, the distinction between patentability and freedom-to-operate will be explained.
FDG PET in clinical practice and clinical trials of Alzheimer’s Disease and Frontotemporal dementias (Alison Murray) This presentation will cover the typical findings on brain FDG PET in people with Alzheimer’s Disease and contrast these with those in frontotemporal lobar degeneration, cerebrovascular disease, mixed dementias and with appearances using amyloid tracers. The corresponding typical appearances on structural brain imaging will be demonstrated. The role of FDG PET in TauRx Phase 3 clinical trials of tau aggregation inhibitor drugs will be illustrated and different methods of image analysis discussed.
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www.PET3D.euImaging and the three Pillars in Drug Development – Options, Pitfalls and Collaboration models (Mats Bergstrom) A very high failure rate and increasing costs of drug development promotes shifts in drug development paradigms with emphasis to early ascertain key predictors of success or failure in later phases: • Does the drug reach sufficient concentrations at the site/tissue where the target is
expressed? • Does the drug engage the target at adequate levels? • Does the drug induce pharmacologically relevant cellular/organ responses?
These requirements are denoted “the three pillars of drug development”. Molecular imaging may in certain instances have unique options to clarify these aspects in vivo in humans with a high degree of quantitation and with measurements directly in organs/tissues of interest. In this presentation we aim to give an insight into the potentials of Molecular Imaging in a structured drug development plan and to indicate options for pharma to engage with external partners for such studies.
The use of PET imaging to drive drug discovery and development (Magnus Schou) Because of the invaluable information provided by translational molecular imaging, positron emission tomography (PET) is today an integrated part of drug discovery and development. This talk will focus on the three major applications of PET in drug discovery and development, namely: i) PET microdosing studies - in which radiolabeled drug candidates are traced in vivo to quantify drug exposure in the target organ of interest, ii) target occupancy studies - that aim to establish relationships between drug exposure in plasma and target occupancy in the organ of interest, and iii) biomarker studies, in which an imaging biomarker of disease pathology is used for patient segmentation and to evaluate treatment efficacy. Examples from all three applications will be presented, together with the major challenges associated with each application.
PET Imaging in Drug Design and Development: costs, benefits and value (Guus van Dongen) Also on behalf of Danielle Vugts, Alex Poot and Bert Windhorst This presentation will mainly focus on the impact imaging can have in drug design, application and development. There will be a focus on public-private partnerships, social impact, and the role academia can play. Several examples will be presented of preclinical and clinical radiochemistry and imaging studies that have been of help in steering drug development and decision making. Finally some future perspectives and collaboration models that can facilitate imaging in drug development will be discussed, using Amsterdam UMC Imaging Center as an example.
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www.PET3D.euAcademic-Industrial Partnerships for PET Radiochemistry and Imaging in Drug Development (Neil Vasdev) This presentation will focus on some non-traditional approaches to prepare PET radiopharmaceuticals for new targets to image the human brain, and aims to show the intricacies of developing PET radiopharmaceuticals from "bench to bedside". Specifically, cutting-edge approaches and technologies for imaging receptors and signal transduction pathways with PET, as well as our recent work to expand beyond the “amyloid cascade hypothesis” of Alzheimer’s disease, including tauopathies, will be presented. Several of the neuroimaging agents have also been applied as oncology probes and our academic-pharma partnerships will also be highlighted. The intricacies of transitioning labeled compounds to PET radiopharmaceuticals and our aspiration to work towards the ultimate, albeit impossible, goal in the field: to radiolabel virtually any compound for PET will be raised as points for discussion.
Molecular Imaging: Creating Windows into Cancer (Jason Lewis) The use of Positron Emission Tomography (PET) for cancer imaging is a well-established and widely used molecular imaging modality both in clinical and research settings. PET offers the ability to quantitatively measure biological and receptor-based processes using a wide spectrum of specifically designed radiopharmaceuticals. The use of PET is expanding and the inclusion of longer-lived radiometal positron-emitters is broadening the application and appeal of this imaging modality. Dr. Lewis' research interests are focused on the development of new PET radiopharmaceuticals for the diagnosis and treatment of cancer. His work incorporates F-18, C-11, and nonstandard nuclide radiopharmaceutical development, with an emphasis on cancer detection and therapy, in both adults and children. The Lewis Lab works on the development of small molecules, radiolabeled peptides, antibodies and nanoparticles that target the overexpression of receptors and antigens on tumors as well as imaging changes in the tumor microenvironment associated with malignancy. This presentation will review the current state-of-the-art in PET agents with an emphasis on the translation and application of imaging agents into patients with cancer.
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www.PET3D.euInformation about the hands-on sessions: Nanobody lead selection analysis (Nick Devoogdt) In this practical session, I will give an overview of various techniques and methodologies that are important in the lead selection analysis of nanobodies. This means that you will be able to better understand which parameters can be looked at to find the best nanobody for your diagnostic or therapeutic purpose. Usually, when performing biopanning of a phage-displayed immune library, several candidate nanobodies can be identified, which can be subjected to a number of tests to rank them on best performance. Techniques that will be looked at are ELISA, surface-plasmon resonance, DNA and aminoacid sequence analysis, Thermofluor assays and flow cytometry, and production and purification of nanobodies from E. coli cultures. Due to lack of time, these experiments will not be performed as such. Instead, experiments will be simulated and examples of the material and equipment used will be provided.
Visit to the nuclear medicine department and cyclotron unit of the UZ Brussel hospital (Marleen Keyaerts & Vicky Caveliers) During this practical session, participants will visit the different parts of the nuclear medicine department in the UZ Brussel, including radiopharmacy and cyclotron facility, patient areas and cameras, clinical workstation areas. Afterwards, the procedures, paperwork and practical requirements to perform clinical trials with new radiopharmaceuticals will be explained using the Nanobody-based clinical trials as examples. Finally, participants will have the chance to personally review and interpret PET/CT images of patients that participated in the diagnostic nanobody trials.
Biodistribution analysis in mice (Sophie Hernot) During this practical session, participants will be able to get acquainted with the different steps involved when evaluating the biodistribution of a radiolabeled Nanobody in an animal model. The session starts with the radiolabeling of a Nanobody, followed by the intravenous injection of the sample into a mouse, after which a micro-SPECT/CT image will be generated. Finally, we will analyze the generated micro-SPECT/CT images using AMIDE software.
Nanobody radiochemistry techniques (Catarina Xavier) During this practical session, participants will be able to learn how to label Nanobodies with 99mTc. All the step of the radiolabeling, quality control, purification and final formulation will be address.