PERSPECTIVE CLINICAL IMAGING reason why targeted optical agents for clini- cal use are unavailable, despite the high Drug-Based Optical Agents: expectations set by demonstration of these agents in animals. Yet, at the heart of the Inf ltrating Clinics at Lower Risk translational dif culty are not the addition- al resources required for translation, but Werner Scheuer,1 Gooitzen M. van Dam,2 Michael Dobosz,1 Markus the certainty associated with the imaging Schwaiger,3 Vasilis Ntziachristos4* performance of a given optical agent in hu- mans. In other words, if an agent would be Fluorescent agents with specif city to cellular and subcellular moieties present promise certain to of er suitable imaging accuracy in for enhancing diagnostics and theranostics, yet challenges associated with regulatory humans—if the risks were removed—then approvals of experimental agents stif e the clinical translation. As a result, targeted f uo- it would be straightforward to secure the rescent agents have remained predominantly as preclinical imaging tools. We discuss the resources for clinically translating it from potential of using optically labeled drugs to accelerate the clinical acceptance of optical public funding sources or the industry. and optoacoustic agents, in analogy to nuclear medicine approaches. This strategy, Translation of f uorescent probes to corroborated with microdosing studies, outlines a promising approach for overcoming medical applications can therefore be ex- bottlenecks and advancing photonic clinical imaging. pedited by minimizing the uncertainty of their clinical imaging performance. Here, we discuss how the use of optical agents TROUBLE WITH TRANSLATION (EMA). T is of en implies high-risk indus- based on approved drugs, or on drugs al- Advances in optical imaging bring diagnos- trial or academic investments owing to the ready being explored therapeutically in tic and theranostic potential that is unavail- time and cost associated with the clinical late-phase clinical trials, may minimize able to conventional visual inspection. Op- translation of a new agent. Consequently, the translational risk compared with novel tical coherence tomography (OCT), narrow there has been little showcased ability to optical agents that are based on molecules band imaging (NBI), f ber-based confocal bring novel f uorescent agents to use in hu- never administered to humans. We further on May 30, 2012 microscopy, or hyperspectral autof uores- mans. Clinical f uorescence imaging there- discuss the use of optical imaging at micro- cence imaging, for example, can of er sub- fore still relates to the use of ICG or f uores- dosing amounts as a strategy to further ac- surface visualization in vivo and enhance cein—agents approved several decades ago, celerate the clinical translation of f uores- anatomical, functional, and biochemical primarily for resolving anatomical or physi- cence molecular imaging. Lastly, we explain information (1). To improve target detec- ological features. ICG, for example, has why accurate f uorescence imaging tech- tion over intrinsic tissue contrast, contrast been used clinically for eye angiography, nology is required in clinical studies and in enhancement can be further imparted by hepatic clearance studies, and visualization successful regulatory approval. optical agents that recognize otherwise- of the lymphatic system (8, 9). Nevertheless, stm.sciencemag.org invisible disease biomarkers (2, 3) . T e ICG and other nonspecif c f uorescent dyes DRUGS DOUBLE AS IMAGING AGENTS development of optical and optoacoustic have not been found particularly useful in Analogous to radioisotopes in nuclear im- agents with molecular specif city has seen many other clinical application areas—for aging, various optical tags, such as f uores- substantial growth in the past decade. Op- example, in cancer detection—owing to the cent dyes, can be used to label drugs and tical agents targeting specif c disease moi- lack of specif city. create agents that retain the targeting prop- eties promise to improve disease detection T e clinical propagation of novel agents erties of the drug while providing optical over the use of intrinsic tissue contrast or engineered to be disease-specif c has two contrast. Compared with optical agents nonspecif c f uorescent organic dyes, such levels of associated challenges. T e f rst based on molecules with undocumented Downloaded from as indocyanine green (ICG) (2). and more straightforward regards the tox- biodistribution and targeting prof les in In animals, f uorescent and optoacoustic icity and stability studies that are required humans, the consideration of known drugs agents have been successfully used to target for obtaining human use approvals. T e labeled with a f uorescent dye comes with cancer, cardiovascular disease, neurode- primary limitation in clinical translation, advantages that can accelerate the clini- generative disease, and bacterial infections, however, comes from the second chal- cal translation of the optical agent. First, a among others (4–7). However, the clinical lenge: the risk associated with the ef cacy wide portfolio of drug molecules is avail- translation of novel optical imaging agents of the agent. Preclinical (animal) studies able for doubling as optical imaging agents. requires overcoming regulatory barriers set do not accurately predict human ef cacy Already, antibody- or antibody fragment– by the U.S. Food and Drug Administration of a new agent. Instead, a stepwise process based agents as well as nonpeptidic small (FDA) or the European Medicines Agency from phase I to phase III clinical studies molecules considered originally for thera- is required to establish the usefulness of a peutics have shown potent imaging perfor- 1Pharma Research and Early Development, Discovery Oncology, Roche Diagnostics GmbH, Penzberg 82377, novel imaging agent. T ese translational mance in animal studies (2, 3). Many ad- Germany. 2University Medical Center Groningen, De- studies constitute a leap in the resources ditional agents can be potentially derived partment of Surgery, 9700 RB Groningen, Netherlands. required in terms of cost, time, skill, and from approved or late-phase clinical trial 3Nuclear Medicine, Klinikum Rechts der Isar, Technische critical mass over the original development drugs (Table 1). Second, each of the drugs Universität München 81675, Germany. 4Biological and Medical Imaging, Technische Universität München and and demonstration of a novel agent in ani- considered comes with knowledge of the Helmholtz Zentrum, München 81675, Germany. mal studies. T e added cost associated with pharmacokinetics and targeting ef ciency *Corresponding author. E-mail: [email protected] clinical translation is typically the primary and specif city in humans—data that were www.ScienceTranslationalMedicine.org 16 May 2012 Vol 4 Issue 134 134ps11 1 PERSPECTIVE Table 1. Examples of clinically approved or investigated drugs that target established can- successfully undergone phase III trials may cer-related biomarkers. These drugs could be considered for use as optical imaging agents for come under these conditions at higher per- microdosing studies. formance certainty (reduced risk) as com- pared with those of new imaging agents, Drug Type Biomarker so as to justify the investment required for Cetuximab Chimeric monoclonal antibody EGFR clinical translation. Nimotuzumab Chimeric monoclonal antibody EGFR Panitumumab Chimeric monoclonal antibody EGFR FEATURES OF A LABELED DRUG With the above assumptions, it is clear that Necitumumab Monoclonal antibody EGFR risk management is an important criterion Zalutumumab Human monoclonal antibody EGFR in accelerating the clinical propagation of Bevacizumab Humanized monoclonal antibody VEGF f uorescence molecular imaging. From sev- eral optical imaging agents described in the Ranibizumab Monoclonal antibody fragment VEGF literature (2, 3), a narrowed selection that Pazopanib Small molecule VEGF receptor (VEGFR) will, with high probability, lead to a success- Ramucirumab Human monoclonal antibody VEGFR ful outcome is important to help boost the f eld and reach patients faster. Risk manage- Etaracizumab Humanized monoclonal antibody αvβ3 integrin ment could be achieved by using not only Volociximab Chimeric monoclonal antibody α β integrin 5 1 labeled drugs for optical imaging but also Pertuzumab Humanized monoclonal antibody HER2 molecules that were discontinued from the Trastuzumab Humanized monoclonal antibody HER2 clinical translation pipeline owing to unsat- Adecatumumab Recombinant human monoclonal Epithelial cell adhesion isfactory therapeutic ef cacy. Even a change antibody molecule (EpCAM) in a drug’s strategic priority, especially if targeted to disease-specif c moieties, would Farletuzumab Monoclonal antibody Folate binding protein also af ect risk management. on May 30, 2012 Many drugs may not be ideal imaging agents. Besides favorable biodistribution obtained during clinical trials. T ird, each animal data, animal studies do not always to disease, an imaging agent also needs to drug comes with corresponding informa- predict performance in humans. T en, the generate a strong signal and high contrast tion on possible side ef ects to humans, key question of new imaging agents tested within acceptable time frames. Accumu- which can ref ne the selection process only on animal models relates to the overall lation and binding patterns will also play toward minimizing safety risks. When it performance in humans. a vital role in the success