A novel fully human anti-NCL immunoRNase for triple-negative breast cancer therapy
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Chiara D’Avino1,2, Dario Palmieri3, Ashley Braddom3, Nicola Zanesi3, Cindy James4, Sara Cole5, Francesco Salvatore2, Carlo M. Croce3, Claudia De Lorenzo1,2
1Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy
2Ceinge Advanced Biotechnology S.C.ar.l., 80145 Naples, Italy
3Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, 43210 Ohio, USA
4Department of Mass Spectroscopy and Proteomics, The Ohio State University, Columbus, 43210 Ohio, USA
5Campus Microscopy and Imaging Facility, The Ohio State University, Columbus, 43210 Ohio, USA
Carlo M. Croce, email: [email protected]
Claudia De Lorenzo, email: [email protected]
Keywords: triple negative breast cancer, cancer immunotherapy, nucleolin, human RNase, microRNA
Received: June 16, 2016 Accepted: October 10, 2016 Published: November 23, 2016
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.
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