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

D’Avino, Chiara; Palmieri, Dario; Braddom, Ashley; Zanesi, Nicola; James, Cindy L.; Cole, Sara L.; Salvatore, Francesco; Croce, Carlo M.; Lorenzo, Claudia De

doi:10.18632/oncotarget.13522

Cited by 22 publications

(12 citation statements)

References 52 publications

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“…Lastly, given its recombinant nature and inherent versatility [ 64 ], 4LB5 can be conjugated to other molecules or protein domains to boost its clinical efficacy (e.g., adding immunoreactive Fc domain or active RNAse enzyme [ 65 ]). In fact, scFv antibodies are currently being investigated in PCa to target cell surface molecules such as PSMA for diagnostic purposes [ 66 , 67 ].…”

Section: Discussionmentioning

confidence: 99%

NCL Inhibition Exerts Antineoplastic Effects against Prostate Cancer Cells by Modulating Oncogenic MicroRNAs

Sheetz

Mills

Tessari

et al. 2020

Cancers

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Prostate cancer (PCa) is the most frequently diagnosed cancer in men and second most common cause of cancer-related deaths in the United States. Androgen deprivation therapy (ADT) is only temporarily effective for advanced-stage PCa, as the disease inevitably progresses to castration-resistant prostate cancer (CRPC). The protein nucleolin (NCL) is overexpressed in several types of human tumors where it is also mislocalized to the cell surface. We previously reported the identification of a single-chain fragment variable (scFv) immuno-agent that is able to bind NCL on the surface of breast cancer cells and inhibit proliferation both in vitro and in vivo. In the present study, we evaluated whether NCL could be a valid therapeutic target for PCa, utilizing DU145, PC3 (CRPC), and LNCaP (androgen-sensitive) cell lines. First, we interrogated the publicly available databases and noted that higher NCL mRNA levels are associated with higher Gleason Scores as well as with recurrent and metastatic tumors. Then, using our anti-NCL scFv, we demonstrated that NCL is expressed on the surface of all three tested cell lines and that NCL inhibition results in reduced proliferation and migration. We also measured the inhibitory effect of NCL targeting on the biogenesis of oncogenic microRNAs such as miR-21, -221 and -222, which was cell context dependent. Taken together, our data provide evidence that NCL targeting inhibits the key hallmarks of malignancy in PCa cells and may provide a novel therapeutic option for patients with advanced-stage PCa.

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Section: Discussionmentioning

confidence: 99%

NCL Inhibition Exerts Antineoplastic Effects against Prostate Cancer Cells by Modulating Oncogenic MicroRNAs

Sheetz

Mills

Tessari

et al. 2020

Cancers

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“…D'Avino et al. tested a novel NCL‐targeting immunoconjugate (4LB5‐HP‐RNase), engineered by fusion of the novel human anti‐NCL scFv 4LB5 and a human pancreatic RNase, on exosomes from derivatives of colorectal cancer cells (D'avino et al., 2016). Using miR‐21 as readout, their results suggested that, possibly, the binding disruption between NCL and miR‐21, mediated by 4LB5 scFv moiety, allows miR‐21 free‐form to be degraded by the RNase.…”

Section: Nucleolin (Ncl)mentioning

confidence: 99%

RNA packaging into extracellular vesicles: An orchestra of RNA‐binding proteins?

Fabbiano

Corsi

Gurrieri

et al. 2020

J of Extracellular Vesicle

178

149

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Extracellular vesicles (EVs) are heterogeneous membranous particles released from the cells through different biogenetic and secretory mechanisms. We now conceive EVs as shuttles mediating cellular communication, carrying a variety of molecules resulting from intracellular homeostatic mechanisms. The RNA is a widely detected cargo and, impressively, a recognized functional intermediate that elects EVs as modulators of cancer cell phenotypes, determinants of disease spreading, cell surrogates in regenerative medicine, and a source for non‐invasive molecular diagnostics. The mechanistic elucidation of the intracellular events responsible for the engagement of RNA into EVs will significantly improve the comprehension and possibly the prediction of EV “quality” in association with cell physiology. Interestingly, the application of multidisciplinary approaches, including biochemical as well as cell‐based and computational strategies, is increasingly revealing an active RNA‐packaging process implicating RNA‐binding proteins (RBPs) in the sorting of coding and non‐coding RNAs. In this review, we provide a comprehensive view of RBPs recently emerging as part of the EV biology, considering the scenarios where: (i) individual RBPs were detected in EVs along with their RNA substrates, (ii) RBPs were detected in EVs with inferred RNA targets, and (iii) EV‐transcripts were found to harbour sequence motifs mirroring the activity of RBPs. Proteins so far identified are members of the hnRNP family (hnRNPA2B1, hnRNPC1, hnRNPG, hnRNPH1, hnRNPK, and hnRNPQ), as well as YBX1, HuR, AGO2, IGF2BP1, MEX3C, ANXA2, ALIX, NCL, FUS, TDP‐43, MVP, LIN28, SRP9/14, QKI, and TERT. We describe the RBPs based on protein domain features, current knowledge on the association with human diseases, recognition of RNA consensus motifs, and the need to clarify the functional significance in different cellular contexts. We also summarize data on previously identified RBP inhibitor small molecules that could also be introduced in EV research as potential modulators of vesicular RNA sorting.

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“…Early hypotheses focused on digestion, as RNase A is abundant in the pancreas of ruminants (Barnard 1969). This hypothesis is challenged by recent work demonstrating nondigestive activities when human RNase 1 variants and conjugates are administered exogenously in vitro and in vivo (Strong et al 2012;D'Avino et al 2016;Hoang et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Phenotype of ribonuclease 1 deficiency in mice

Garnett

Lomax

Mohammed

et al. 2019

RNA

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Biological roles for extracellular RNA (eRNA) have become apparent. For example, eRNA can induce contact activation in blood via activation of the plasma proteases factor XII (FXII) and factor XI (FXI). We sought to reveal the biological role of the secretory enzyme ribonuclease 1 (RNase 1) in an organismal context by generating and analyzing RNase 1 knockout (Rnase1-/-) mice. We found that these mice are viable, healthy, and fertile, though larger than Rnase1 +/+ mice. Rnase1-/plasma contains more RNA than does the plasma of Rnase1 +/+ mice. Moreover, the plasma of Rnase1-/mice clots more rapidly than does wild-type plasma. This phenotype appeared to be due to increased levels of the active form of FXII (FXIIa) in the plasma of Rnase1-/mice compared to Rnase1 +/+ mice, and is consistent with the known effects of eRNA on FXII activation. The apparent activity of FXI in the plasma of Rnase1-/mice was 1000-fold higher when measured in an assay triggered by a low concentration of tissue factor than in assays based on recalcification, consistent with eRNA enhancing FXI activation by thrombin. These findings suggest that one of the physiological functions of RNase 1 is to degrade eRNA in blood plasma. Loss of this function facilitates FXII and FXI activation, which could have effects on inflammation and blood coagulation. We anticipate that Rnase1-/mice will be a useful tool for evaluating other hypotheses about the functions of RNase 1 and of eRNA in vivo.

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

Cited by 22 publications

References 52 publications

NCL Inhibition Exerts Antineoplastic Effects against Prostate Cancer Cells by Modulating Oncogenic MicroRNAs

NCL Inhibition Exerts Antineoplastic Effects against Prostate Cancer Cells by Modulating Oncogenic MicroRNAs

RNA packaging into extracellular vesicles: An orchestra of RNA‐binding proteins?

Phenotype of ribonuclease 1 deficiency in mice

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