“We prioritized INT-1B3, a lipid nanoparticle (LNP) formulated synthetic mimic of a tumor suppressor miRNA, as we found that it has a dual mode of action. Firstly, it targets tumor cells directly […] In parallel, it regulates the tumor microenvironment and ultimately elicits a long term T-cell mediated immune response.”
Can you take us through the basics of the research that led to the creation of InteRNA?
InteRNA was incorporated as a spinoff from the Hubrecht Institute, Utrecht, the Netherlands. The academic founders of the company used deep sequencing in combination with proprietary bioinformatics to identify novel microRNAs (miRNAs) in deep sequencing data sets. At the time of their research, there were already miRNAs discovered, mainly by Thomas Tuschl when he was at Max Planck Institute for Biophysical Chemistry and at the Rockefeller University. His IP went to Alnylam, which today is the biggest siRNA company in the world. We found new miRNAs that Thomas Tuschl had not found, and we were able to file a patent application on these discoveries. There was interest from industry for these miRNAs, not only for therapeutic application, but also for diagnostics application.
We took a selection of our novel miRNAs, as well as a selection of already known miRNAs from the public database, and we cloned them on an individual basis in lentivector (lentiviral vector). Once we had the viral particles produced, we ran various kinds of high throughput functional genomic screens in cell based assays.
Our R&D approach is a functional genomics approach. We treat tumor cells with the miRNAs on an individual basis to see whether they go, for example, into apoptosis or that you can inhibit proliferation. This is already the first indication of the potential function of the particular miRNA. This approach is unique compared to the approach of other miRNA companies, as what they started off with was descriptive differential expression profiling. In a disease situation miRNAs can be up or down regulated. If you analyze the RNA from disease samples versus normal samples on a microchip with miRNAs, you can check for up and down regulation. What you do not have with this differential expression approach is the spatial and temporal information, and you do not know if the up or down regulation of the miRNA is a result or a cause of a defect. If you have a non-bias functional genomics approach, you immediately have information on the potential function of the miRNA.
Can you elaborate on the development of InteRNA’s INT-1B3 drug development candidate?
Our screenings gave us multiple miRNA drug candidates. We then implemented transcriptomic analysis, mainly based on RNA sequencing with bioinformatics, to identify which messenger RNAs (mRNAs) are regulated by the individual miRNAs. This information gave us insights in the biology of all our candidates. We prioritized INT-1B3, a lipid nanoparticle (LNP) formulated synthetic mimic of a tumor suppressor miRNA, as we found that it has a dual mode of action. Firstly, it targets tumor cells directly, pushing them into apoptosis and inhibiting their proliferation and migration. Regulation of specific mRNAs leads to activation of the PTEN tumor suppressor pathway in parallel to inhibition of the oncogenic Ras/MAPK and PI3K/Akt signaling pathways. In parallel, we discovered that INT-1B3 regulates the tumor microenvironment and ultimately elicits a long term T-cell mediated immune response. INT-1B3 regulates the enzymes CD39 and CD73 thereby reducing adenosine levels and downregulating the adenosine-A2A receptor pathway involved in the escape from immune surveillance. Further it makes immune cold tumors hot through recruitment of CD8+ Teffector cells and downregulation of immunosuppressive LAG-3/FoxP3 Tregulatory cells. Based on this biology, we find INT-1B3 a very attractive drug candidate in the immuno-oncology field.
We aim to initially develop INT-1B3 for treatment of patients with hepatocellular carcinoma (HCC) and triple-negative breast cancer (TNBC). Yet the compound also qualifies for other cancer indications like melanoma, lung cancer (NSCLC) and pancreatic cancer as we found in our preclinical studies.
What is InteRNA’s strategy for pushing forward the development of the company’s drug candidates?
We are looking for partnerships for our CNS programs and, in first instance, not for our lead candidate INT-1B3. We have an anti-miR that can knock down an overexpressed miRNA in temporal lobe epilepsy patients, and are currently in discussions with CNS focused pharma for early stage collaboration on this candidate. For our lead candidate INT-1B3, we would like to reach proof of concept in a Phase 1b/2a trial to create several strategic options with regard to potential Phase 2b trials and/or exit scenarios.