IRS2

Interferon (IFN) is a type of crucial cytokine, capable of directly participating in the antiviral immune response of epithelial cells, mediating the natural immune response to induce the expression of Interferon Stimulated Genes (ISG), hence, swiftly establishing the body's natural immune defense line against viral infections.  Based on the structural characteristics, receptor binding, and biological activity of interferon, human interferons can be divided into three types: Type I, II, and III interferons. Their genes are located on human chromosomes 9p21-22, 12q24.1, and 19q13.13, respectively. Among the three types of human interferons, Type I interferons mainly include IFN-α, IFN-β, and other 20 subtypes, Type II interferons only consist of IFN-γ, and Type III interferons comprise four subtypes including IL-29 (IFN-λ1). Most cells infected by viruses can produce Type I interferon, the secreted IFN-α/β can bind to a common receptor on neighboring uninfected cells, and initiate a paracrine signaling cascade response. Type I and Type III interferons are considered classical antiviral interferons, with alpha interferons being the main subtype used in clinical antiviral treatment. These mainly include subtypes like alpha-1b, alpha-2b, alpha-2a, etc. Recent studies indicate that Type III interferons have a significant relationship with mucosal immunity, while IFN-gamma also exhibits strong virus inhibitory characteristics. Regulatory Mechanisms of Interferons● Classic JAK-STAT signaling pathway The signaling pathway triggered within the cell after type I and II receptors bind to their respective IFNs is very similar, which is the JAK-STAT signaling pathway. Interferon receptors and Type I & II interferons activate the classic JAK-STAT pathwayType I IFN binding to the IFN-α/β receptor can phosphorylate and activate two members of the JAK family: TYK2 (Tyrosine Kinase 2) and JAK1 (Janus Kinase 1). These kinases further phosphorylate STAT1α (STAT91), STAT1β (STAT84), and STAT2 (STAT113). These three activated STATs dissociate from the receptor and bind to the intracellular protein p48, and then this complex enters the cell nucleus and directly binds to the upstream regulatory region (ISREs) of IFN-sensitive genes, thereby regulating the expression of specific genes. Typically, type I and III interferon signals form STAT1-2 heterodimers and ISGF3 complexes by activating TYK2 and JAK1, while type II interferon signals induce the formation of STAT1 homodimers by activating JAK1 and JAK2.  ● PI3K/AKT/mTOR signaling pathway In addition to activating the JAK–STAT signaling pathway, interferons also have an activating effect on the PI3K/AKT/mTOR signaling pathway. The activating effect of Type I Interferon on the PI3K/AKT/mTOR pathwayThe activation of the PI3K/AKT/mTOR pathway depends on JAK1/TYK2, which phosphorylates IRS1 (insulin receptor substrate 1) and IRS2 (insulin receptor substrate 2). The phosphorylation of IRS1 and IRS2 leads to the activation of PI3K, which subsequently activates the target of mammalian mTORC1 (rapamycin complex 1). MTORC1 activates RPS6kB (ribosomal protein S6 kinase, also known as p70s6 kinase), then phosphorylates RPS6 (ribosomal protein S6), leading to the initiation of mRNA translation. Furthermore, mTORC1 also regulates the phosphorylation of EIF4EBP1 (eukaryotic initiation factor 4E binding protein 1), the phosphorylation of EIF4EBP1 leads to the inactivation of EIF4EBP1, causing the dissociation of EIF4E (eukaryotic translation initiation factor E), thereby initiating the translation of dependent mRNA. Type I interferons also activate mTORC2 (rapamycin-insensitive complex 2), which is necessary for the phosphorylation of RPS6KB, RPS6, and EIF4BP1. Biological Activities of Type III Interferons1) Antiviral Function Type I interferon is the key antiviral defense and modulation factor in the immune system. On the one hand, it directly activates immune cells; on the other hand, it can indirectly inhibit the replication process of viruses. It can also activate natural killer cells and macrophages, thereby promoting the activation of dendritic cells, while at the same time inducing CD4+ subtype T lymphocytes and T helper cells to produce a large amount of type I interferon on distinct effect cells, protecting CD8+ cells and preventing induced antibody cell death.  2) Antibacterial Function The antibacterial function of interferons is mainly manifested in IFN-γ. IFN-γ can decrease bacterial iron supply by down-regulating transferrin receptor, or inhibit intracellular bacterial propagation directly by inducing production of endogenous NO. It can also increase the phagocytic body of monocytes and macrophages, lysosome, to dissolve bacteria. By these means, it achieves the function of eliminating bacteria. 3) Anti-parasitic Activity The anti-parasitic activity of interferon is primarily manifested in IFN-γ. IFN-γ can activate macrophages (Mφ), and the activated Mφ can express high levels of inducible nitric oxide synthase (iNOS) which catalyzes the production of NO from L-arginine. NO has inhibitory and killing effects on inoculated pathogens. 4) Involvement in Immune Regulation IFN-γ can affect the expression of the Fc receptor for IgG, which facilitates macrophages' phagocytosis of antigens, NK cells' lysis of target cells and the activation of T and B lymphocytes, enhancing the body's immune response. IFN-γ can increase the expression of MHC class II molecules on the surface of macrophages, enhancing their antigen presentation capabilities. 5) Antitumor Activity IFN-γ is produced by T lymphocytes stimulated by specific antigens. It is the main macrophage-stimulating factor in the body, it resists acid, can activate effector cells, enhances the activity of natural killer cells, macrophages, and tumor-infiltrating lymphocytes, promotes monocyte circulation, increases the expression of antigens and antibodies on the surface of immune cells, stimulates the production of cellular factors such as IL-2, tumor necrosis factor, interferon-α, etc. It inhibits tumor cell division and induces the production of antiviral proteins.

TEL AVIV, Israel, March 11, 2021 (GLOBE NEWSWIRE) -- Purple Biotech Ltd. (“Purple Biotech” ”, or the “Company”) (NASDAQ/TASE: PPBT), a clinical-stage company developing first-in-class, effective and durable therapies by overcoming tumor immune evasion and drug resistance, today announced that additional preclinical data supporting the mechanism of action of NT219, a dual inhibitor, novel small molecule that simultaneously targets IRS1/2 and STAT3, will be presented in a poster at the American Association of Cancer Research (AACR) 2021 Annual Meeting, taking place in virtual format, on April 10-15 and May 17-21, 2021. These updated data expand on the previously reported results generated from the Company’s collaboration with Professor Ido Wolf, Head of the Oncology Division, Tel Aviv Sourasky Medical Center, and will be highlighted in a presentation titled, “Adaptation of colorectal cancer cells to the brain microenvironment: The role of IRS2.” Colorectal cancer (CRC) represents the fourth most frequent cause of brain metastasis, which is the most common brain tumor. However, molecular mechanisms supporting the formation of these lesions from CRC are poorly defined. IRS2 is a known downstream effector of IGF-1 receptors, which regulate cell growth and proliferation. The updated in vitro and in vivo data show the importance of the expression of IRS2 in the development, survival and growth of CRC brain metastasis. Moreover, the increase in trophic effects of IRS2 on brain metastases was associated with increased mitochondrial oxidative phosphorylation. In addition, NT219, an inhibitor of IRS2, and the subject of the Company’s ongoing Phase 1/2 clinical trial for the treatment of multiple cancers, showed in preclinical studies significant and dose-dependent inhibition of CRC cell viability, associated with decreased beta-catenin levels that have been shown to be related to the immune oncology resistance phenotype. “This important study is the first to demonstrate the significant role of IRS2 in promoting CRC brain metastases and suggests that NT219 could have potential in addressing this critical unmet medical need,” said Bertrand Liang, M.D., Ph.D., Chief Medical Officer of Purple Biotech. “We continue to be highly encouraged by the compelling mechanism of action data and preclinical results generated to date by NT219. We remain focused on enrolling patients in our ongoing Phase 1/2 clinical trial of NT219 as monotherapy for the treatment of solid tumors, followed by a dose escalation of NT219 in combination with cetuximab, an epithelial growth factor receptor (EGFR) blocking monoclonal antibody, for the treatment of recurrent and/or metastatic solid tumors and squamous cell carcinoma of the head and neck cancer or colorectal adenocarcinoma. We continue to hope to receive top-line data from the first part of this study in the second half of this year.” Presentation Details: About Purple Biotech Purple Biotech Ltd. (the “Company”; NASDAQ/TASE: PPBT) is a clinical-stage company developing first-in-class, effective and durable therapies by overcoming tumor immune evasion and drug resistance. The Company’s oncology pipeline includes NT219 and CM24. NT219 is a small molecule targeting the novel cancer drug resistance pathways IRS1/2 and STAT3. The Company is currently advancing NT219 as a monotherapy treatment of solid tumors, followed by a dose escalation of NT219 in combination with cetuximab for the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck cancer (SCCHN) or colorectal adenocarcinoma in a phase 1/2 study, and an expansion phase of NT219 at its recommended phase 2 level in combination with cetuximab in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. CM24 is a humanized monoclonal antibody that blocks CEACAM1, an immune checkpoint protein that supports tumor immune evasion and survival through multiple pathways. The Company is advancing CM24 as a combination therapy with anti-PD-1 checkpoint inhibitors in selected cancer indications in a phase 1 study followed by a phase 2 for the treatment of non-small cell lung cancer and pancreatic cancer. The Company has entered into a clinical collaboration agreement, as amended, with Bristol Myers Squibb for the planned phase 1/2 clinical trials to evaluate the combination of CM24 with the PD-1 inhibitor nivolumab (Opdivo®) in patients with non-small cell lung cancer and in combination with nivolumab in addition to nab-paclitaxel (ABRAXANE®) in patients with pancreatic cancer. The Company is also the owner of Consensi®, an FDA-approved fixed-dose combination of celecoxib and amlodipine besylate for the simultaneous treatment of osteoarthritis pain and hypertension that was approved by the FDA for marketing in the U.S. Consensi® is being sold in the U.S. by Burke Therapeutics, the marketing partner of the Company’s U.S. distributor, Coeptis Pharmaceuticals. The Company has also partnered to commercialize Consensi in China and South Korea. The Company has recently relocated its corporate headquarters to Rehovot, Israel. For more information, please visit . Forward-Looking Statements and Safe Harbor Statement Certain statements in this press release that are forward-looking and not statements of historical fact are forward looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include, but are not limited to, statements that are not statements of historical fact, and may be identified by words such as "believe", "expect", "intend", "plan", "may", "should", "could", "might", "seek", "target", "will", "project", "forecast", "continue" or "anticipate" or their negatives or variations of these words or other comparable words or by the fact that these statements do not relate strictly to historical matters. You should not place undue reliance on these forward-looking statements, which are not guarantees of future performance. Forward-looking statements reflect our current views, expectations, beliefs or intentions with respect to future events, and are subject to a number of assumptions, involve known and unknown risks, many of which are beyond our control, as well as uncertainties and other factors that may cause our actual results, performance or achievements to be significantly different from any future results, performance or achievements expressed or implied by the forward-looking statements. Important factors that could cause or contribute to such differences include, among others, risks relating to: the plans, strategies and objectives of management for future operations; product development for NT219 and CM24; the process by which early stage therapeutic candidates such as NT219 and CM24 could potentially lead to an approved drug product is long and subject to highly significant risks, particularly with respect to a joint development collaboration; the fact that drug development and commercialization involves a lengthy and expensive process with uncertain outcomes; our ability to successfully develop and commercialize our pharmaceutical products; the expense, length, progress and results of any clinical trials; the impact of any changes in regulation and legislation that could affect the pharmaceutical industry; the difficulty in receiving the regulatory approvals necessary in order to commercialize our products; the difficulty of predicting actions of the U.S. Food and Drug Administration or any other applicable regulator of pharmaceutical products; the regulatory environment and changes in the health policies and regimes in the countries in which we operate; the uncertainty surrounding the actual market reception to our pharmaceutical products once cleared for marketing in a particular market; the introduction of competing products; patents obtained by competitors; dependence on the effectiveness of our patents and other protections for innovative products; our ability to obtain, maintain and defend issued patents; the commencement of any patent interference or infringement action against our patents, and our ability to prevail, obtain a favorable decision or recover damages in any such action; and the exposure to litigation, including patent litigation, and/or regulatory actions, and other factors that are discussed in our Annual Report on Form 20-F for the year ended December 31, 2019 and in our other filings with the U.S. Securities and Exchange Commission ("SEC"), including our cautionary discussion of risks and uncertainties under "Risk Factors" in our Registration Statements and Annual Reports. These are factors that we believe could cause our actual results to differ materially from expected results. Other factors besides those we have listed could also adversely affect us. Any forward-looking statement in this press release speaks only as of the date which it is made. We disclaim any intention or obligation to publicly update or revise any forward-looking statement or other information contained herein, whether as a result of new information, future events or otherwise, except as required by applicable law. You are advised, however, to consult any additional disclosures we make in our reports to the SEC, which are available on the SEC's website, . Company Contact: Gil Efron Deputy CEO & Chief Financial Officer IR@purple-biotech.com