Fibroblast Activation Protein-Targeting Minibody-IRDye700DX for Ablation of the Cancer-Associated Fibroblast with Photodynamic Therapy
Esther M. M. Smeets,
Daphne N. Dorst,
Gerben M. Franssen,
Merijn S. van Essen,
Cathelijne Frielink,
Martijn W. J. Stommel,
Marija Trajkovic-Arsic,
Phyllis F. Cheung,
Jens T. Siveke,
Ian Wilson,
Alessandro Mascioni,
Erik H. J. G. Aarntzen,
Sanne A. M. van Lith
Affiliations
Esther M. M. Smeets
Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Daphne N. Dorst
Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, 6525 GA Nijmegen, The Netherlands
Gerben M. Franssen
Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Merijn S. van Essen
Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Cathelijne Frielink
Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Martijn W. J. Stommel
Department of Surgery, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Marija Trajkovic-Arsic
Bridge Institute of Experimental Tumour Therapy, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, 47057 Essen, Germany
Phyllis F. Cheung
Bridge Institute of Experimental Tumour Therapy, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, 47057 Essen, Germany
Jens T. Siveke
Bridge Institute of Experimental Tumour Therapy, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, 47057 Essen, Germany
Ian Wilson
ImaginAb, Inglewood, CA 90301, USA
Alessandro Mascioni
ImaginAb, Inglewood, CA 90301, USA
Erik H. J. G. Aarntzen
Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Sanne A. M. van Lith
Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Fibroblast activation protein (FAP), expressed on cancer-associated fibroblasts, is a target for diagnosis and therapy in multiple tumour types. Strategies to systemically deplete FAP-expressing cells show efficacy; however, these induce toxicities, as FAP-expressing cells are found in normal tissues. FAP-targeted photodynamic therapy offers a solution, as it acts only locally and upon activation. Here, a FAP-binding minibody was conjugated to the chelator diethylenetriaminepentaacetic acid (DTPA) and the photosensitizer IRDye700DX (DTPA-700DX-MB). DTPA-700DX-MB showed efficient binding to FAP-overexpressing 3T3 murine fibroblasts (3T3-FAP) and induced the protein’s dose-dependent cytotoxicity upon light exposure. Biodistribution of DTPA-700DX-MB in mice carrying either subcutaneous or orthotopic tumours of murine pancreatic ductal adenocarcinoma cells (PDAC299) showed maximal tumour uptake of 111In-labelled DTPA-700DX-MB at 24 h post injection. Co-injection with an excess DTPA-700DX-MB reduced uptake, and autoradiography correlated with FAP expression in the stromal tumour region. Finally, in vivo therapeutic efficacy was determined in two simultaneous subcutaneous PDAC299 tumours; only one was treated with 690 nm light. Upregulation of an apoptosis marker was only observed in the treated tumours. In conclusion, DTPA-700DX-MB binds to FAP-expressing cells and targets PDAC299 tumours in mice with good signal-to-background ratios. Furthermore, the induced apoptosis indicates the feasibility of targeted depletion of FAP-expressing cells with photodynamic therapy.
