title: A novel fully human anti-NCL immunoRNase for triple-negative breast cancer therapy.
abstract: Breast cancer is the most common cancer in women worldwide. A new promising anti-cancer therapy involves the use of monoclonal antibodies specific for target tumor-associated antigens (TAAs). A TAA of interest for immunotherapy of Triple Negative Breast Cancer (TNBC) is nucleolin (NCL), a multifunctional protein, selectively expressed on the surface of cancer cells, which regulates the biogenesis of specific microRNAs (miRNAs) involved in tumor development and drug-resistance. We previously isolated a novel human anti-NCL scFv, called 4LB5, that is endowed with selective anti-tumor effects. Here we report the construction and characterization of a novel immunoRNase constituted by 4LB5 and a human pancreatic RNase (HP-RNase) called "4LB5-HP-RNase". This immunoRNase retains both the enzymatic activity of human pancreatic RNase and the specific binding of the parental scFv to a panel of surface NCL-positive breast cancer cells. Notably, 4LB5-HP-RNase dramatically and selectively reduced the viability and proliferation of NCL-positive tumor cells in vitro and in vivo. Specifically, it induced apoptosis and reduced the levels of the tumorigenic miRNAs miR-21, -221 and -222. Thus, this novel immunoagent could be a valuable tool for the treatment of TNBC patients ineligible for currently available targeted treatments.
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", 80131 Naples, Italy.|Ceinge Advanced Biotechnology S.C.ar.l., 80145 Naples, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: D'Avino
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, 43210 Ohio, USA.
authors.forename: Dario
authors.initials: D
authors.lastname: Palmieri
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, 43210 Ohio, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Braddom
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, 43210 Ohio, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Zanesi
authors.affiliation: Department of Mass Spectroscopy and Proteomics, The Ohio State University, Columbus, 43210 Ohio, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: James
authors.affiliation: Campus Microscopy and Imaging Facility, The Ohio State University, Columbus, 43210 Ohio, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Cole
authors.affiliation: Ceinge Advanced Biotechnology S.C.ar.l., 80145 Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Salvatore
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, 43210 Ohio, USA.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", 80131 Naples, Italy.|Ceinge Advanced Biotechnology S.C.ar.l., 80145 Naples, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: De Lorenzo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000067128:Extracellular Vesicles / Q000502:physiology; D005260:Female; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000032:analysis; D010750:Phosphoproteins / Q000032:analysis / Q000276:immunology*; D016601:RNA-Binding Proteins / Q000032:analysis / Q000276:immunology*; D012259:Ribonuclease, Pancreatic / Q000627:therapeutic use*; D057127:Single-Chain Antibodies / Q000627:therapeutic use*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000097796:Nucleolin
chemical_list: D035683:MicroRNAs; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D012259:Ribonuclease, Pancreatic; D057127:Single-Chain Antibodies; D000097796:Nucleolin
keywords: cancer immunotherapy; human RNase; microRNA; nucleolin; triple negative breast cancer