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Cancer treatments often struggle with balancing efficacy and side effects. A new study scientists offers a promising solution using antibody-peptide inhibitor conjugates to target specific cell types and block the activity of cancer-promoting enzymes called cathepsins. Tumor cells often hijack normal physiological processes to support their growth, exploiting proteins that are in charge of essential cell functions. It is therefore important to block the activity of these proteins only in cancer cells without affecting their crucial roles in healthy tissues. For this reason, classical approaches using small molecules that induce systemic inhibition across all cells in the body can lead to severe side effects. An example of essential proteins hijacked by cancer cells are the cathepsins, a family of enzymes that is responsible for breaking down other proteins and remodeling the body's tissues. Cathepsins are implicated in various cancers, osteoporosis, and autoimmune diseases. However, clinical trials with small molecule inhibitors of cathepsins have failed due to either lack of efficacy or toxicity. Now, a team of scientists led by Elisa Oricchio and Bruno Correia at EPFL has developed a novel approach to overcome these limitations. They created a modular drug platform that conjugates non-natural peptide inhibitors (NNPIs) with antibodies, creating antibody-peptide inhibitor conjugates (APICs). This method ensures that the inhibitors are delivered specifically to cancer cells, thereby reducing systemic side effects and increasing therapeutic efficacy. The researchers began by designing NNPIs that covalently bind to and inhibit cathepsins. They modified peptide sequences to include a Michael acceptor, a chemical moiety that makes it easier to form a stable bond with cathepsins. The Michael acceptor reacts with the cysteine residue in the cathepsin's active site (the part that of the enzyme responsible for its main job), creating a stable, covalent linkage that effectively inhibits the cathepsin. To further optimize the peptides' specificity and potency, the team used saturation mutagenesis screening -- a method that systematically changes each amino acid in a protein to find the best variants with desired properties. The researchers identified several strong inhibitors against four different cathepsins, namely cathepsin S, B, K and L. By attaching these inhibitors to antibodies that recognize CD22, CD79, HER2, and Siglec15, the researchers could precisely deliver the NNPIs to lymphoma cells, breast cancer cells and osteoclasts. This leverages the natural ability of antibodies to be internalized by target cells, precisely directing the inhibitors where they are needed. Then, it was time to test the APICs: in both cell lines and animal models, they showed significant therapeutic effects. For example, in lymphoma models, treatment with APICs that target cathepsin S led to tumor reduction and activation of the immune response against cancer cells. In breast cancer models, APICs targeting cathepsin B hindered tumor invasiveness and cell migration, underscoring the potential of APICs to prevent metastasis. By delivering inhibitors specifically to cancer cells, the APIC approach can avoid or minimize the side effects commonly associated with other treatments, such as chemotherapies. Moreover, the modular nature of the APIC design means it can be adapted to target various proteases implicated in different diseases, potentially revolutionizing the treatment landscape for conditions beyond cancer. The APIC project is now extending beyond the lab and is taking its first steps towards becoming a clinical reality. "We filed two patent applications based on this project," says Elisa Oricchio. "Aaron Petruzzella, the PhD student who led the project, recently received the support of the SNF Bridge Proof of Concept fellowship to continue working on these inhibitors, build the foundations of a start-up and attract the attention of potential investors."

The Acquired Portfolio of Infectious Disease Assets Includes a Class of Potential Broad Spectrum Oral Antiviral Agents, TNX-3900 with a Host-Directed Mechanism Tonix Plans to Develop the TNX-3900 Series of Molecules as Oral Antivirals Either as Monotherapy or in Combination with Other Antivirals The TNX-3900 Class of Antivirals Has a Novel Mechanism of Action Based on Inhibition of Certain Cathepsin Proteases which are Required for Cell Infection by Many Viruses like SARS-CoV-2 Sina Bavari, Ph.D., Tonix EVP of Infectious Disease R&D and Director of the Frederick, MD Research and Development Center (RDC) was a Scientific Founder of Healion Bio, Inc. CHATHAM, N.J., Feb. 02, 2023 (GLOBE NEWSWIRE) -- Tonix Pharmaceuticals Holding Corp. (Nasdaq: TNXP) (Tonix or the Company), a clinical-stage biopharmaceutical company, today announced an agreement whereby Tonix has acquired all of the assets of Healion Bio, Inc. (Healion) including its entire portfolio of next-generation antiviral technology assets. Healion’s drug portfolio includes a class of broad-spectrum small molecule oral antiviral drug candidates with a novel host-directed mechanism of action. Host-directed antivirals modulate human cells and tissues and are different from direct-acting antivirals which inhibit virus proteins and processes. Tonix’s TNX-3900, formerly known as HB-121, are cathepsin protease inhibitors, some of which have strong activity in vitro against SARS-CoV-2. “We are excited to develop Healion’s drug programs that include TNX-3900, which is a class of drugs with potential broad spectrum anti-viral activity, either as monotherapies or in combination with other antivirals”, said Seth Lederman, M.D., Chief Executive Officer of Tonix Pharmaceuticals. “Broad-spectrum antiviral agents have the potential to reduce viral load and allow the adaptive immune system to alert the other arms of the immune system to mount a protective response. Examples of other classes of host-directed antivirals that have been approved by the U.S. Food and Drug Administration (FDA) include alpha interferon like Pegasys® (peginterferon alfa-2a) for viral hepatitis, the CCR5 antagonist Selzentry® (maraviroc) for HIV, and the anti-IL-6 receptor antagonist monoclonal antibody Actemra® (tocilizumab) for COVID-19.” Sina Bavari, Ph.D., Executive Vice President for Infectious Disease Research at Tonix said, “I am pleased to be reunited with the infectious disease assets of Healion, since I was the scientific founder of Healion after I retired from my position as Chief of R&D at the United States Army Medical Research Institute of Infectious Disease (USAMRIID). While Healion made some progress developing these advanced technologies, Tonix’s state-of-the art facilities and depth of drug development expertise have the potential to advance the TNX-3900 class of drugs into clinical trials. On behalf of the talented scientific team that I direct at our 48,000 square-foot cutting-edge infectious disease research facility in Frederick, Md., I am pleased to add this technology to the therapeutic development programs underway.” About TNX-3900 TNX-3900 is the term for a series of molecules that inhibit essential cathepsins which are required by viruses such as coronaviruses and filoviruses to infect cells. Because of the unique antiviral mechanism of these compounds, the Company believes they can potentiate the activity of other antivirals with differing mechanisms. The Company believes this makes cathepsin inhibitors suitable for combination therapy. Tonix Pharmaceuticals Holding Corp.* Tonix is a clinical-stage biopharmaceutical company focused on discovering, licensing, acquiring and developing therapeutics to treat and prevent human disease and alleviate suffering. Tonix’s portfolio is composed of central nervous system (CNS), rare disease, immunology and infectious disease product candidates. Tonix’s CNS portfolio includes both small molecules and biologics to treat pain, neurologic, psychiatric and addiction conditions. Tonix’s lead CNS candidate, TNX-102 SL (cyclobenzaprine HCl sublingual tablet), is in mid-Phase 3 development for the management of fibromyalgia with a new Phase 3 study launched in the second quarter of 2022 and interim data expected in the second quarter of 2023. TNX-102 SL is also being developed to treat Long COVID, a chronic post-acute COVID-19 condition. Tonix initiated a Phase 2 study in Long COVID in the third quarter of 2022. TNX-1300 (cocaine esterase) is a biologic designed to treat cocaine intoxication and has been granted Breakthrough Therapy designation by the FDA. A Phase 2 study of TNX-1300 is expected to be initiated in the second quarter of 2023. TNX-1900 (intranasal potentiated oxytocin), a small molecule in development for chronic migraine, is expected to enter the clinic with a Phase 2 study in the first quarter of 2023. TNX-601 ER (tianeptine hemioxalate extended-release tablets) is a once-daily formulation of tianeptine being developed as a potential treatment for major depressive disorder (MDD) with a Phase 2 study expected to be initiated in the first quarter of 2023. Tonix’s rare disease portfolio includes TNX-2900 (intranasal potentiated oxytocin) for the treatment of Prader-Willi syndrome. TNX-2900 has been granted Orphan Drug designation by the FDA. Tonix’s immunology portfolio includes biologics to address organ transplant rejection, autoimmunity and cancer, including TNX-1500, which is a humanized monoclonal antibody targeting CD40-ligand (CD40L or CD154) being developed for the prevention of allograft and xenograft rejection and for the treatment of autoimmune diseases. A Phase 1 study of TNX-1500 is expected to be initiated in the second quarter of 2023. Tonix’s infectious disease pipeline includes a vaccine in development to prevent smallpox and monkeypox, TNX-801, a next-generation vaccine to prevent COVID-19, TNX-1850, a platform to make fully human monoclonal antibodies to treat COVID-19, TNX-3600, and humanized anti-SARS-CoV-2 monoclonal antibodies, TNX-3800, recently licensed from Curia. TNX-801, Tonix’s vaccine in development to prevent smallpox and monkeypox, also serves as the live virus vaccine platform or recombinant pox vaccine (RPV) platform for other infectious diseases. A Phase 1 study of TNX-801 is expected to be initiated in Kenya in the second half of 2023. *All of Tonix’s product candidates are investigational new drugs or biologics and have not been approved for any indication. This press release and further information about Tonix can be found at www.tonixpharma.com. Forward Looking Statements Certain statements in this press release are forward-looking within the meaning of the Private Securities Litigation Reform Act of 1995. These statements may be identified by the use of forward-looking words such as “anticipate,” “believe,” “forecast,” “estimate,” “expect,” and “intend,” among others. These forward-looking statements are based on Tonix's current expectations and actual results could differ materially. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements. These factors include, but are not limited to, risks related to the failure to obtain FDA clearances or approvals and noncompliance with FDA regulations; delays and uncertainties caused by the global COVID-19 pandemic; risks related to the timing and progress of clinical development of our product candidates; our need for additional financing; uncertainties of patent protection and litigation; uncertainties of government or third party payor reimbursement; limited research and development efforts and dependence upon third parties; and substantial competition. As with any pharmaceutical under development, there are significant risks in the development, regulatory approval and commercialization of new products. Tonix does not undertake an obligation to update or revise any forward-looking statement. Investors should read the risk factors set forth in the Annual Report on Form 10-K for the year ended December 31, 2021, as filed with the Securities and Exchange Commission (the “SEC”) on March 14, 2022, and periodic reports filed with the SEC on or after the date thereof. All of Tonix's forward-looking statements are expressly qualified by all such risk factors and other cautionary statements. The information set forth herein speaks only as of the date thereof. Contacts Jessica Morris (corporate)Tonix Pharmaceuticalsinvestor.relations@tonixpharma.com(862) 904-8182 Olipriya Das, Ph.D. (media)Russo PartnersOlipriya.Das@russopartnersllc.com (646) 942-5588 Peter Vozzo (investors)ICR Westwickepeter.vozzo@westwicke.com(443) 213-0505

Nearly $2MM Small Business Innovation Research grant will support study of targeted fluorescent imaging agent designed to improve tumor visualization during minimally invasive and robotic-assisted surgical procedures MINNEAPOLIS--(BUSINESS WIRE)-- Vergent Bioscience, a clinical-stage biotechnology company developing tumor-targeted imaging agents, announced that the National Cancer Institute (NCI) of the National Institutes of Health (NIH) has awarded the company a Small Business Innovation Research (SBIR) grant of nearly $2 million (Award Number R44CA277890). The grant will help fund a Phase 2 clinical study evaluating the company’s targeted fluorescent imaging agent, VGT-309, for intraoperative imaging of tumors in patients undergoing lung cancer surgery. “This Phase 2 SBIR award further validates the promise of VGT-309 to help surgeons realize the full potential of minimally invasive and robotic-assisted surgical procedures by improving the visibility of tumors during surgery,” said John Santini, Ph.D., president and chief executive officer at Vergent Bioscience. “We are grateful to the NCI for their support and to the team at the University of Pennsylvania’s Perelman School of Medicine for conducting this Phase 2 study.” The majority of lung cancer surgery is now performed using minimally invasive approaches, which have multiple advantages for patients, but require that surgeons work in a small area with a restricted view and limited tactile clues, presenting the potential for tumor to be missed and left behind. Early Phase 1 and 2 clinical trials evaluating VGT-309 in lung cancer yielded compelling safety and efficacy data that support the agent’s ability to help surgeons see previously undetected or difficult-to-find tumors in real-time, ensuring all tumor tissue is removed during minimally invasive (MIS) and robotic-assisted surgical procedures. The NCI SBIR grant will support a Phase 2 clinical study of VGT-309 led by Sunil Singhal, M.D., the William Maul Measey Professor of Surgical Research and the chief of the Division of Thoracic Surgery at Penn (NCT05400226). The study will evaluate the safety and efficacy of VGT-309 to locate and identify tumor tissue that may have otherwise been missed during lung cancer surgery. “As minimally invasive surgical approaches are increasingly becoming the standard of care for treatment of many solid tumors, surgeons urgently need imaging agents that will support better tumor visualization,” said Dr. Singhal. “We’re encouraged by early data from studies evaluating VGT-309 and look forward to further exploring its utility in this trial.” The NIH’s SBIR program is a congressionally mandated set-aside program to encourage research and development that has a strong potential for technology commercialization. The program allows small business entrepreneurs a chance to obtain non-dilutive funding for early-stage R&D. About VGT-309 VGT-309 is a tumor-targeted imaging agent intentionally designed to enable a complete solution for optimal tumor visualization during open, MIS, and robotic-assisted surgical procedures. VGT-309 is delivered to patients via a short infusion several hours before surgery. Invented in Professor Matt Bogyo’s Lab at Stanford University School of Medicine, the molecule binds tightly (i.e., covalently) to cathepsins, a family of proteases that are highly overexpressed across a broad range of solid tumors. This approach provides distinct clinical advantages and positions VGT-309 as an ideal tumor imaging agent. VGT-309’s imaging component is the near infrared (NIR) dye indocyanine green (ICG), which is compatible with all commercially available NIR intraoperative imaging systems that support MIS technologies and is the preferred dye to minimize confounding background autofluorescence. About Vergent Bioscience Vergent Bioscience is a clinical-stage biotechnology company that is helping surgeons realize the full potential of minimally invasive and robotic surgery by significantly improving the visibility of tumors. Vergent’s lead compound, VGT-309, is a tumor-targeted fluorescent imaging agent intentionally designed to enable surgeons to see previously undetected or difficult-to-find tumors during surgery in real-time, ensuring all tumor tissue is removed. The company is first evaluating VGT-309 in lung cancer, with the potential to expand its application to a wide range of solid tumors. Vergent Bioscience is a privately held company based in Minneapolis, MN. For more information, please visit vergentbio.com The content in this press release is solely the responsibility of Vergent Bioscience and does not necessarily represent the official views of the National Institutes of Health.