In vivo immuno-targeting of an extracellular epitope of membrane bound preferentially expressed antigen in melanoma (PRAME)
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Dmitry Pankov1,*, Ludvig Sjöström3,4,*, Teja Kalidindi5, Sang-Gyu Lee5, Kjell Sjöström9, Rui Gardner2, Michael R. McDevitt5,10, Richard O’Reilly1,8,10, Daniel L.J. Thorek7,11, Steven M. Larson5,6, Darren Veach5,6 and David Ulmert3,4
1Immunology Program, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
2Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA
3Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
4Division of Oncology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden
5Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
6Department of Radiology, Weill Cornell Medical College, New York, NY, USA
7Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Radiological Science, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
8Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
9Innovagen AB, Lund, Sweden
10Department of Medicine, Weill Cornell Medical College, New York, NY, USA
11Cancer Molecular and Functional Imaging Program, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
*These authors have contributed equally to this work
David Ulmert, email: [email protected]
Keywords: PRAME, immuno-targeting, cancer, noninvasive imaging, targeted therapy
Received: April 13, 2017 Accepted: June 26, 2017 Published: July 26, 2017
Preferentially Expressed Antigen in Melanoma (PRAME) is a cancer/testis antigen that is overexpressed in a broad range of malignancies, while absent in most healthy human tissues, making it an attractive diagnostic cancer biomarker and therapeutic target. Although commonly viewed as an intracellular protein, we have demonstrated that PRAME has a membrane bound form with an external epitope targetable with conventional antibodies. We generated a polyclonal antibody (Membrane associated PRAME Antibody 1, MPA1) against an extracellular peptide sequence of PRAME. Binding of MPA1 to recombinant PRAME was evaluated by Enzyme-Linked Immunosorbent Assay (ELISA). Flow cytometry and confocal immunofluorescence microscopy of MPA1 was performed on multiple tumor cell lines. Reverse Transcription Polymerase Chain Reaction (RT-PCR) for PRAME was conducted to compare protein and transcriptional expression levels. We demonstrated a robust proof-of-concept for PRAME targeting in vivo by radiolabeling MPA1 with zirconium-89 (89Zr-DFO-MPA1) and demonstrating high specific uptake in PRAME expressing tumors. To our knowledge, this is the first time a cancer testis antigen has been targeted using conventional antibody technologies. Thus, PRAME can be exploited for multiple clinical applications, including targeted therapy, diagnostic imaging and treatment guidance in a wide-range of malignancies, with minimal off-target toxicity.
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