A novel fully human anti-NCL immunoRNase for triple-negative breast cancer therapy

作者：D' Avino Chiara; Palmieri Dario; Braddom Ashley; Zanesi Nicola; James Cindy; Cole Sara; Salvatore Francesco; Croce Carlo M; De Lorenzo Claudia

来源：Oncotarget, 2016, 7(52): 87016-87030.

DOI：10.18632/oncotarget.13522

• triple negative breast cancer
• cancer immunotherapy
• nucleolin
• human RNase
• microRNA

Breast cancer is the most common cancer in women worldwide. A new promising anticancer 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.

• 出版日期2016-12-27