Onconase (ranpirnase) / Orgenesis, Leidos - LARVOL DELTA

Human RNase 1 can extensively oligomerize through 3D domain swapping thanks to the crucial contribution of its C-terminus. (PubMed, Int J Biol Macromol) - "The C-terminus role has been investigated also in amphibian onconase (ONC®), a pt-RNase that can form only a N-swapped dimer, since its C-terminus, that is three-residues longer than RNase A, is locked by a disulfide bond. While ONC mutants designed to unlock or cut this constraint were almost unable to dimerize, the RNase 1 mutant self-associated at a higher extent than the wt, suggesting a specific role of the C-terminus in the oligomerization of different RNases. Overall, RNase 1 reaches here the highest ability, among pt-RNases, to extensively self-associate through 3D-DS, paving the way for new investigations on the structural and biological properties of its oligomers."

Journal

Quality comparison of a state-of-the-art preparation of a recombinant L-asparaginase derived from Escherichia coli with an alternative asparaginase product. (PubMed, PLoS One) - "In the present study, we compared a recombinant E. coli-derived ASNase marketed in Europe (Spectrila®) with an E. coli-derived ASNase preparation from India (Onconase) marketed in Eastern European countries. Our results reveal that Spectrila® met all of the testing parameters, stood out for its excellent quality and, thus, represents a safe treatment option in ALL. These findings are particularly important for low- and middle-income countries, where access to ASNase formulations is limited."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology

Ranpirnase (OKG-0301), a Novel Ribonuclease, Demonstrates Antiviral Activity against Adenovirus in the Ad5/NZW Rabbit Ocular Replication Model. (PubMed, Pathogens) - "A day later, topical therapy was initiated in both eyes with 0.03% OKG-0301, 0.003% OKG-0301, saline or 0.5% cidofovir. Ranpirnase (OKG-0301) may be a potential candidate for a topical antiviral for adenoviral eye infections. Further clinical development is warranted."

Journal • Preclinical • Corneal Abrasion • Infectious Disease • Ocular Infections • Ophthalmology

Insight into the Initial Stages of the Folding Process in Onconase Revealed by UNRES. (PubMed, J Phys Chem B) - "In addition, these regions are determined to be chain folding initiation sites (CFIS) according to methods developed previously. Subsequent self-organization maps (SOM) analysis has revealed key structural states involved in these early folding events."

Journal

Role of the Ribonuclease ONCONASE in miRNA Biogenesis and tRNA Processing: Focus on Cancer and Viral Infections. (PubMed, Int J Mol Sci) - "In cells infected by viruses, ONC hampers viral spread by digesting the primer tRNAs necessary for viral DNA replication. In this scenario, new therapeutic tools might be developed by exploiting the action of ONC-elicited RNA derivatives."

Journal • Review • Infectious Disease • Lung Cancer • Mesothelioma • Novel Coronavirus Disease • Oncology • Solid Tumor • RNASEK

Potent anti-tumor activity of CD45RA-targeting Hm3A4-Ranpirnase against myeloid lineage leukemias. (PubMed, Bioengineered) - "In summary, our immunotoxin had excellent biological activity suggesting its potential therapeutic value for treating AML patients. Additional preclinical and clinical studies are needed to develop this immunotoxin as a treatment option for patients with leukemia."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Upregulation of miR-34a-5p, miR-20a-3p and miR-29a-3p by Onconase in A375 Melanoma Cells Correlates with the Downregulation of Specific Onco-Proteins. (PubMed, Int J Mol Sci) - "Data suggest that several known ONC anti-proliferative and anti-metastatic activities in A375 melanoma cells might depend on the upregulation of onco-suppressor miRNAs. Notably, miRNAs stability depends on the upstream regulation by long-non-coding-RNAs or circular-RNAs that can, in turn, be damaged by ONC ribonucleolytic activity."

Journal • Eye Cancer • Melanoma • Oncology • Retinal Disorders • Retinoblastoma • Solid Tumor • BRAF • CDK2 • HIF1A • MIR20A • MIR29A • MIR34A

The crystal structure of the domain-swapped dimer of onconase highlights some catalytic and antitumor activity features of the enzyme. (PubMed, Int J Biol Macromol) - "This study expands the variety of RNase domain-swapped dimeric structures, underlining the unpredictability of the open interface arrangement upon domain swapping. Structural data also offer valuable insights to analyze the differences in the measured ONC or ONC-D biological activities."

IO biomarker • Journal • Lymphoma • Melanoma • Oncology • Solid Tumor • BCL2 • STAT3

"$ORGS Orgenesis Achieves Multiple Ranpirnase Development Milestones https://t.co/2dSm7oeVTP" (@stock_titan)

A novel strategy for engineering of a smart generation of immune ribonucleases against EGFR cells. (PubMed, J Cell Physiol) - "The molecular dynamic simulations confirmed protein stability and the ability of scFv-ranpirnase (rantoxin) to bind to epidermal growth factor receptor protein...The immunotoxin function was assessed in A431 cancer cells and EGFR-negative HEK293 cells, and IC  values were estimated to be 22.4 ± 3 and >620.4 ± 5 nM, respectively. The results indicated that the immunotoxins produced in this study had the potential for use as anticancer drugs."

Journal • Oncology • Prostate Cancer • Solid Tumor • EGFR • GAPDH • PCR

Biological Activities of Secretory RNases: Focus on Their Oligomerization to Design Antitumor Drugs. (PubMed, Front Immunol) - "Bovine pancreatic RNase A, bovine seminal BS-RNase, human pancreatic RNase 1, angiogenin (RNase 5), and amphibian onconase belong to the pancreatic type superfamily, while binase and barnase are in the bacterial RNase N1/T1 family...Furthermore, the activities displayed by some RNases forming oligomeric complexes, the mechanisms driving toward these supramolecular structures, and the biological rebounds connected are analyzed. These aspects are offered with the perspective to suggest possible efficacious therapeutic applications for RNases oligomeric derivatives that could contemporarily lack, or strongly reduce, immunogenicity and other undesired side-effects."

Journal • Review • Gastrointestinal Cancer • Hepatology • Lung Cancer • Melanoma • Mesothelioma • Oncology • Pancreatic Cancer • Solid Tumor • Thoracic Cancer

Concurrent detection of lysosome and tissue transglutaminase activation in relation to cell cycle position during apoptosis induced by different anticancer drugs. (PubMed, Cytometry A) - "Apoptosis of human lymphoblastoid TK6 cells was induced by combination of 2-deoxyglucose with the isoquinoline alkaloid berberine, by DNA topoisomerase I inhibitor camptothecin, its analog topotecan, topoisomerase II inhibitors etoposide or mitoxantrone, as well as by the cytotoxic anticancer ribonuclease ranpirnase (onconase). This new methodological approach offers the means to investigate mechanisms and factors affecting autophagic lysosomes proton pump activity vis-à-vis TG2 activation that are common in several pathological states."

Journal • Oncology

Safety and Efficacy Study of Topical Rapirnase to Treat Genital Warts (HPV) (clinicaltrials.gov) - P2; N=70; Completed; Sponsor: Tamir Biotechnology, Inc.; Recruiting ➔ Completed; N=50 ➔ 70; Trial primary completion date: May 2016 ➔ Sep 2016

Enrollment change • Trial completion • Trial primary completion date • Biosimilar • Immunology

Onconase Restores Cytotoxicity in Dabrafenib-Resistant A375 Human Melanoma Cells and Affects Cell Migration, Invasion and Colony Formation Capability. (PubMed, Int J Mol Sci) - "Notably, it induced apoptosis and inhibited colony formation and invasiveness more extensively in A375DR than in A375P cells. In conclusion, ONC successfully counteracts melanoma malignancy especially in BRAFi-resistant cells and could become a tool against melanoma recurrence."

Journal • Melanoma • Oncology • Solid Tumor

Influence of Onconase in the Therapeutic Potential of PARP Inhibitors in A375 Malignant Melanoma Cells. (PubMed, Biochem Pharmacol) - "One of the most used by clinicians is olaparib, that, however, showed again cancer resistance in patients. Moreover, we underline that A375 cells treated for a prolonged time with AZD2461 were definitely more susceptible than parental A375 cells to the pro-apoptotic action of ONC. Considering also the different inhibitory effects of the two drugs on TNF-α gene expression and NF-kB DNA-binding, the tuning of their combined delivery to the A375 tumor cell line might open a promising scenario for future therapeutic applications devoted to defeat human melanoma."

Journal

Antiviral Ranpirnase TMR-001 Inhibits Rabies Virus Release and Cell-to-Cell Infection In Vitro. (PubMed, Viruses) - "TMR-001 at this dose, formulation, and route of delivery did not prevent rabies virus transit from the periphery to the central nervous system in this model (n = 32). Further aspects of local controlled delivery of other active formulations or dose concentrations of TMR-001 or ribonuclease analogues should be investigated for this class of drugs as a rabies antiviral therapeutic."

Journal • Preclinical

Structure, stability and aggregation propensity of a Ribonuclease A-Onconase chimera. (PubMed, Int J Biol Macromol) - "Accordingly, RNaseA-ONC is significantly more stable than RNase A variants lacking Pro114; RNaseA-ONC also displays a higher propensity to form oligomers in native conditions when compared to either RNase A or Onconase. This finding demonstrates that modifications of terminal loops should to be carefully controlled in terms of size and sequence to avoid unwanted and/or potentially harmful aggregation processes."

Journal

Ranpirnase Reduces HIV-1 Infection and Associated Inflammatory Changes in a Human Colorectal Explant Model. (PubMed, AIDS Res Hum Retroviruses) - "Similarly, RNP dose dependent inhibition was demonstrated in 7/30 biomarkers after LPS stimulation, all of which overlapped with HIV-1BaL induced biomarker changes. The ability of RNP to inhibit both colorectal explant HIV-1BaL infection and inflammatory changes associated with HIV-1 infection, makes RPN a promising agent for topical rectal pre-exposure prophylaxis."

Biomarker • Journal