Widespread in vivo efficacy of The-0504: A conditionally-activatable nanoferritin for tumor-agnostic targeting of CD71-expressing cancers
Giulio Fracasso,
Elisabetta Falvo,
Giada Tisci,
Gianluca Sala,
Gianni Colotti,
Sara Cingarlini,
Claudia Tito,
Sandra Bibbo,
Cristina Frusteri,
Elisa Tremante,
Elena Giordani,
Patrizio Giacomini,
Pierpaolo Ceci
Affiliations
Giulio Fracasso
Department of Biomedical Sciences, University of Padua, 35131, Padua, Italy
Elisabetta Falvo
CNR–National Research Council of Italy, Institute of Molecular Biology and Pathology, 00185, Rome, Italy
Giada Tisci
Department of Biochemical Sciences, Sapienza University of Rome, 00185, Rome, Italy
Gianluca Sala
Department of Innovative Technologies in Medicine & Dentistry, University of Chieti-Pescara, Chieti, Italy; Center for Advanced Studies and Technology (CAST), Chieti, Italy; Corresponding author. Department of Innovative Technologies in Medicine & Dentistry, University of Chieti-Pescara, Chieti, Italy.
Gianni Colotti
CNR–National Research Council of Italy, Institute of Molecular Biology and Pathology, 00185, Rome, Italy
Sara Cingarlini
Section of Oncology, Verona University Hospital Trust, Verona, Italy
Claudia Tito
Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Section of Histology and Medical Embryology, Sapienza University of Rome, 00185, Rome, Italy
Sandra Bibbo
Department of Innovative Technologies in Medicine & Dentistry, University of Chieti-Pescara, Chieti, Italy; Center for Advanced Studies and Technology (CAST), Chieti, Italy
Cristina Frusteri
Department of Medicine, University of Verona, 37134, Verona, Italy
Elisa Tremante
Department of Research, Advanced Diagnostics and Technological Innovation, UOC Translational Oncology Research, IRCCS National Cancer Institute Regina Elena, Via Elio Chianesi 53, 00144, Rome, Italy
Elena Giordani
Clinical Trial Center, Biostatistics and Bioinformatics, IRCCS National Cancer Institute Regina Elena, Via Elio Chianesi 53, 00144, Rome, Italy
Patrizio Giacomini
Clinical Trial Center, Biostatistics and Bioinformatics, IRCCS National Cancer Institute Regina Elena, Via Elio Chianesi 53, 00144, Rome, Italy
Pierpaolo Ceci
CNR–National Research Council of Italy, Institute of Molecular Biology and Pathology, 00185, Rome, Italy; Thena Biotech, Latina, Italy; Corresponding author. CNR–National Research Council of Italy, Institute of Molecular Biology and Pathology, 00185, Rome, Italy.
Background: Cancer is still among the leading causes of death all over the world. Improving chemotherapy and minimizing associated toxicities are major unmet medical needs. Recently, we provided a preliminary preclinical evaluation of a human ferritin (HFt)-based drug carrier (The-0504) that selectively delivers the wide-spectrum topoisomerase I inhibitor Genz-644282 to CD71-expressing tumors. The-0504 has so far been evaluated on four different human tumor xenotransplant models (breast, colorectal, pancreatic and liver cancers). Methods: Herein, we extend our studies, by: (a) testing DNA damage in vitro, (b) treating eight additional tumor xenograft models in vivo with The-0504; (c) performing pharmacokinetic (PK) studies in rats; and (d) evaluating The-0504 anti-tumor xenotransplant efficacy by optimizing its administration schedule based on PK considerations. Results: Immunofluorescence demonstrated that The-0504 induces foci expressing the DNA double-strand break marker γH2AX. Expression increases up to 4-fold and is more persistent as compared to free Genz-644282. In vivo studies confirmed a remarkable anti-tumor activity of The-0504, resulting in tumor eradication in most murine xenograft models, regardless of embryological origin (e.g. epithelial, mesenchymal or neuroendocrine), and molecular subtypes. PK studies demonstrated a long persistence of The-0504 in rat serum (half-life of about 40 h as compared to 15 h of the free drug), with a 400-fold increase in peak concentrations as compared to the free drug. On this basis, we reduced The-0504 administration frequency from twice to once per week, with no appreciable loss in therapeutic efficacy in mice. Conclusion: The results presented here confirm that The-0504 is highly active against several human tumor xenotransplants, even when administered less frequently than previously reported. The-0504 may be a good candidate for further clinical development in a tumor histotype-agnostic setting.
