Matthias Herth, Associate Professor, Department of Drug Design and Pharmacology (ILF), University of Copenhagen

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1 U N I V E R S I T Y O F C O P E N H A G E N F A C U L T Y O F H E A L T H A N D M E D I C A L S C I E N C E S B R I D G E - T R A N S L A T I O N A L E X C E L L E N C E P R O G R A M M E P R O J E C T S Y N O P S I S T E M P L A T E 1 Project title Mentor 1 Mentor 2 Framework Towards Pretargeted Radionuclide Therapy Of Tumors With Polypeptoid Graft Copolymers: Development Of Strategies To Maximize Tumor-Vs-Healthy Tissue Exposure Difference Matthias Herth, Associate Professor, Department of Drug Design and Pharmacology (ILF), University of Copenhagen (matthias.herth@sund.ku.dk) Andres Kjær, Professor, Chief Physician, Dep. of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet (Copenhagen University Hospital) (akjaer@sund.ku.dk) Matthias Herth (MH) and Andreas Kjær (AK) have a long-standing collaboration history. MH is an expert in radiolabeling and click-chemistry and will cover the (radio)chemical part of the work. AK is a renowned expert in nuclear medicine and will cover the translational aspects of this project. The mentee will have access to modern laboratory facilities for organic synthesis, radiolabeling, in vivo imaging and all respective infrastructure. Through participation in regular group meetings at MH and AK groups, the mentee will be exposed to all stages of the clinical translation of radiopharmaceutical agents from target identification to clinical application. Project synopsis Nanomedicines have great potential to be used as targeting vectors in radionuclide therapy if rapid target accumulation could be reached. Conventional approaches need long blood circulation for sufficient target enrichment. Consequently, high radiation doses are delivered to healthy tissues. Pretargeting strategies have been shown to increase therapeutic radiation dose, while minimizing dose to healthy tissue in a preclinical set-up for monoclonal antibodies. We have recently shown that polypeptoid graft copolymers (PeptoBrushes) are especially suited for pretargeting since higher reaction efficacies can be reached. We also showed that higher tumor accumulation was reached. To be able to translate this approach into the clinic, 1 The CV s and project synopsis of each mentor team will be posted on the programme webpage in advance of the admissions process to the programme.

2 PAGE 2 OF 23 radiation dose to healthy tissue has to be further minimized. This could be achieved by removing or masking circulating Peptobrushes in blood before pretargeted therapy is started. The postdoctoral fellow will develop such methods. Profile of potential fellow PhD in Radiopharmaceutical Chemistry, Nuclear Medicine or a related field knowledge of radiopharmaceutical synthesis procedures and analysis experience with organic chemistry animal handling skills (FELASA C certificate) or willingness to acquire them experience with nanomedicine design and characterisation

3 U N I V E R S I T Y O F C O P E N H A G E N F A C U L T Y O F H E A L T H A N D M E D I C A L S C I E N C E S B R I D G E - T R A N S L A T I O N A L E X C E L L E N C E P R O G R A M M E M E N T O R C V T E M P L A T E 1 Name Title Current department(s) Matthias Herth PhD Department of Drug Design and Pharmacology, University of Copenhagen Current position(s) Associate Professor Education/training 01/ /2013: Adjunktpædagogikum, University of Copenhagen, Copenhagen, Denmark 05/ /2010: Degree in business administration, Studiengemeinschaft Darmstadt, Darmstadt, Germany 10/ /2009: PhD in Nuclear Chemistry, Johannes Gutenberg University, Mainz, Germany 10/ /2006: Diplom Chemist, Johannes Gutenberg University, Mainz, Germany Scientific career profile Assoc. Professor Herth is an expert in radiopharmaceutical chemistry with experience over 13 years. Matthias Herth has developed one tracer from bench-to-bedside. (R)-[ 18 F]MH.MZ is currently the most selective antagonist PET tracer available for the 5-HT 2AR system. He has also developed the first 11 C- labeled tetrazine derivative for pretargeted imaging. Currently, his group consist of 3 PostDocs, 2 PhD and 3 Master Students. Access to modern organic chemistry facilities and radioactive laboratories is guaranteed. His group is well-networked with international collaborators within the EU, USA, Canada and Chile. Professor Windhorst and Rösch are just some examples of his network partners. 1 Do not exceed two pages. The CV s and project synopsis of each mentor team will be posted on the programme webpage in advance of the admissions process to the programme

4 Bibliometric summary PAGE 2 OF 2 Number of publications: 40; Number of first authorships: 15, Number of second authorships: 4; Number of last authorships: 5; Number of citations: 541; h- index (Web of Science): 12 Herth et al., Chem.Comm. 2013, 49: Development of the first 11 C- labeled tetrazine for rapid tetrazine-trans-cyclooctene ligation. This work lead to a H2020 grant Debus et al., Nuclear Medicine and Biology 2010, 37: Within this work, a PET tracer for the 5-HT 2AR system was developed that was this year successfully translated into the clinic Herth et al., Biomacromolecules 2009, 10, Simultaneously with the work of Prof. Weissleder, the first 18 F-labeled polymer was developed. The work is cited > 97 times. Herth et al., J Label Compd Radiopharm, 2005, 48: The first 11Cradiolabeled plant hormone was developed. The publication lead to follow-up work cited > 137 times. Steen et al., Bioorg. Med. Chem. 2017, 27: Development of a novel rapid and easy NMR-based lipophilicity measurement. This method is standardly applied now in our laboratory. Contributions to mentoring, training, supervision Mentoring starts with sharing knowledge and hopefully ends in inspiration. As such, I believe in Plutarch words: The mind is not a vessel to be filled, but a fire to be kindled. I hope that I can achieve this goal while mentoring. Matthias Herth has supervised 8 Master Students, 3 PhD students and 4 PostDocs. All students have advanced their career in industry or academia. For example, one student became Head of Quality Control, another one Head of Research and Development. Matthias Herth is the course responsible for the radiopharmaceutical chemistry course (7.5 ECTS) offered by the Department of Drug Design and Pharmacology (ILF), University of Copenhagen, since The course is offered at Bachelor, Master and PhD level and is also open for external professionals. Currently, it is the only course dealing with radiopharmaceutical sciences in Denmark. The course is actively supported by Rigshospitalet and several companies such as Novo Nordisk or PMOD. Additionally, Matthias Herth teaches within the Drug Discovery and Development course (7.5 ECTS) offered by ILF. He has also taught nuclear chemistry and organic chemistry in the past at the Johannes Gutenberg University, Mainz, Germany and at ILF.

5 U N I V E R S I T Y O F C O P E N H A G E N F A C U L T Y O F H E A L T H A N D M E D I C A L S C I E N C E S B R I D G E - T R A N S L A T I O N A L E X C E L L E N C E P R O G R A M M E P R O F E S S O R A N D R E A S K J Æ R Name Title Current department(s) Andreas Kjær Professor Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet Current position(s) Professor, Chief Physician Education/training MD, PhD, DMSc, MBA Scientific career profile Bibliometric summary Research focus and major contributions: My research has been focused on translational and clinical molecular imaging with PET, PET/MRI and optical probes as well as on development of targeted radionuclide therapies (theranostics) for use in precision medicine in cancer. Notable achievements of my research group include development from bench to bed of several new PET tracers that have reached first-in-human clinical use in cancer patients. Research group: My research group currently consists of 40 members, which together constitute a cross-disciplinary team necessary for developing molecular imaging. We have expertise in all steps from basic research to obtaining approval by the health authorities, GMP and GCP. Several of our results have been implemented in clinical routine. Our research group has filed a total of 12 patent families, and two spin-out companies have been established. I have served as PI for several larger multi-partner grants. International collaborations: Through my research, I have been fortunate to establish close collaborations with leading research groups abroad, including Stanford University, Mount Sinai School of Medicine, MD Anderson Cancer Center, as well as leading imaging centers in the EU. Number of publications/peer review publications: 491/463 Number of first/second/last authorships: 57/34/152 Number of citations: 12,221 H-index (Google Scholar): 53

6 Contributions to mentoring, training, supervision PAGE 2 OF 2 10 most significant publications 1) Binderup T, et al. F-18-FDG-PET predicts survival of patients with neuroendocrine tumors. Clin Cancer Res 16, (2010). 2) Pfeifer A, et al. Clinical PET of neuroendocrine tumors using 64 Cu- DOTATATE: First-in-humans study. J Nucl Med 53, (2012). 3) Oxboel J, et al. 64Cu-NODAGA-c(RGDykK) is a promising new angiogenesis PET tracer: Correlation between tumor uptake and integrin-αvβ3 expression in human neuroendocrine tumor xenografts. Int J Mol Imaging 2012, (2012). 4) Persson M, et al. upar targeted radionuclide therapy with (177)Lu-DOTA- AE105 inhibits dissemination of metastatic prostate cancer. Mol Pharm 11, (2014). 5) Gutte H, et al. Simultaneous hyperpolarized 13C-pyruvate MRI and 18F-FDG- PET (hyperpet) in 10 canine cancer patients. J Nucl Med 56, (2015). 6) Pfeifer A, et al. 64 Cu-DOTATATE PET for Neuroendocrine Tumors: A Prospective Head-to-Head Comparison with 111 In-DTPA-Octreotide in 112 Patients. J Nucl Med 56, (2015). 7) Persson M, et al. First-in-human upar PET: Imaging of cancer aggressiveness. Theranostics 5, (2015). 8) Nielsen CH, et al. Quantitative PET Imaging of Tissue Factor Expression Using 18F-Labeled Active Site-Inhibited Factor VII. J Nucl Med 57, (2016). 9) Christensen A, et al. upar-targeted optical near-infrared (NIR) fluorescence imaging and PET for image-guided surgery in head and neck cancer: proof-ofconcept in orthotopic xenograft model. Oncotarget 8, (2017). 10) Skovgaard D, et al. Safety, dosimetry and tumor detection ability of 68Ga- NOTA-AE105 - a novel radioligand for upar PET imaging: first-in-human study. J Nucl Med 58, (2017). Mentoring philosophy: As a mentor, I support my mentee s development by - Fostering skill sets that will be valuable both in the mentee s present project and in any future projects he/she may undertake - Encouraging independence, including urging the mentee to take ownership and bring fresh ideas and perspectives to the project - Offering the mentee the opportunity to connect with other scientists and scientific communities so he/she can establish a network Number of PhD student (current/concluded): 17/30 Subsequent career paths: 9 stayed on as postdocs in the group, 15 went back to the clinic (specialist training) and 6 are employed in industry Number of postdocs (current/concluded): 12/3 Subsequent career paths: industry (all started as PhD students at the lab) Teaching: Director of Graduate PhD Program of Medical and Molecular Imaging, UCPH, lecturer at the medical school of UCPH, organizer and lecturer at the National Health Board courses for specialist training in Nuclear Medicine.