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.
Highlights
Breast cancer (BC) will affect one in eight (12%) women during their lives and almost half a million patients lose their life to BC annually, being the most frequent cancer among women [1]
The resulting construct has the scFv at the NH2- end followed by a spacer included between the antibody moiety and the RNase, which is at the C-terminal end, followed by a hexahistidine tag for the detection and purification of the chimeric construct (Figure 1A)
Western blotting analyses with an anti-Histidine antibody revealed a product with the expected molecular weight, that corresponded to the fusion protein (Figure 1C)
Summary
Breast cancer (BC) will affect one in eight (12%) women during their lives and almost half a million patients lose their life to BC annually, being the most frequent cancer among women [1]. Trastuzumab (Herceptin), a humanized antibody, is in clinical use for ErbB2-positive breast carcinoma [2, 3]. There is a need for new specific targets for the therapy of antiErbB2-resistant breast cancer, including Triple Negative Breast Cancer (TNBC), which lacks estrogen receptor (ER), progesterone receptor and ErbB2. TNBC accounts for ~14% of all breast cancers and about 170,000 new TNBC diagnoses per year [7]. These patients develop a malignant phenotype, and their death rate is higher than any other type of BC (median overall survival around 12 months in the metastatic setting) [8]
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