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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."

First results will be presented from early-stage clinical trials of BL-M07D1, antibody-drug conjugate (ADC) targeting HER2 with the payload Ed-04 Clinical progress will be presented from early-stage clinical trials of BL-B01D1, the bi-specific antibody-drug conjugate (ADC) targeting EGFR and HER3 REDMOND, Wash., Oct. 20, 2023 /PRNewswire/ -- SystImmune, Inc. (SystImmune), a clinical-stage biotechnology company, today announced the presentation of pivotal data from its oncology portfolio at the European Society for Medical Oncology (ESMO) Congress 2023. The event is scheduled to take place from October 20th to 24th in Madrid, Spain, where new clinical findings will be unveiled from trials involving BL-B01D1 and BL-M07D1. The expanded results from these clinical trials of BL-B01D1 will include data from patients with several solid tumor types in advanced stages and having multiple cycles of prior therapies. The data presented at ESMO builds on previously reported clinical data at the American Society of Clinical Oncology (ASCO), and recent recognition for BL-B01D1 conferred by industry experts at the 14th Annual World ADC meeting in San Diego who recognized SystImmune's BL-B01D1 as a "Runner-Up" in the award category of "Most Promising Clinical Candidate". "Encouraging signals of efficacy from the Ed-04 payload supported our decision to expand our pharmacopeia of targeting ADCs that deliver this novel and highly potent topoisomerase 1 inhibitor to a wider patient population with diverse diseases, while we expand our understanding of the exceptional properties of this linker-warhead combination," said Martin Olivo, M.D., CMO of SystImmune. Presentations at the ESMO congress include: About BL-B01D1 The company is developing BL-B01D1, a bispecific antibody-drug conjugate (ADC) that targets both EGFR and HER3. These proteins are highly expressed in most epithelial tumors. The tetravalent BL-B01D1 has two binding domains for distinct Growth Factor Receptors that drive cancer cell proliferation and survival. Inheriting the SI-B001 mechanisms of action, BL-B01D1 blocks EGFR and HER3 signals to cancer cells, reducing proliferation and survival signals. Upon antibody mediated internalization, BL-B01D1 is trafficked to cancer cell lysosomes and liberates its therapeutic payload that induced genotoxic stress activating pathways leading to cancer cell death. About BL-M07D1 The company is developing BL-M07D1, a HER2 specific IgG-based ADC carrying DAR8 of the Ed-04 payload technology. The Ed-04 payload technology is composed of a potent topoisomerase 1 inhibitor and a serum-stable linker that is cleavable by cathepsin-B. By targeting proliferating cancer cells that express HER2, the BL-M07D1 has the potential to treat multiple epithelial cancer types, including breast and colorectal cancer types. About SystImmune SystImmune is a clinical-stage biopharmaceutical company located in Redmond, WA. It specializes in developing innovative cancer treatments using its established drug development platforms, focusing on bi-specific, multi-specific antibodies, and antibody-drug conjugates (ADCs). SystImmune has several assets in various stages of clinical trials for solid tumor and hematologic indications. Alongside ongoing clinical trials, SystImmune has a robust preclinical pipeline of potential cancer therapeutics in the discovery or IND-enabling stages, representing cutting-edge biologics development. Forward-Looking Statements Any research and development information provided by SystImmune is intended for general information purposes only. Such information is not intended to provide complete medical information. We do not offer patient-specific treatment advice and if you have medical conditions, please see your medical doctor or healthcare provider. This press release may contain forward-looking statements with the meaning of Section 27A of the Securities Act of 1933, as amended, Section 21E of the Securities Exchange Act of 1934, and the Private Securities Litigation Reform Act of 1995, which reflects the expectations regarding the company's goals, strategies, results of operations, performance, business prospects, and opportunities, including but not limited to the ability to gain Investigational New Drug status for the resulting new product and the ability to develop a successful formulation. Terms such as "anticipates," "believes," "expects," "estimates," "could," "intends," "may," "plans," "potential," "projects," "will," "would" and other similar expressions, or the negative of these terms, are generally indicative of forward-looking statements. While SystImmune, Inc. believes that expectations expressed in the forward-looking statements are based on the company's reasonable assumptions and beliefs in light of the information available to the company at the time such statements are made, it cannot give assurance that such forward-looking statements will prove to have been correct. Such forward-looking statements are not fact and are subject to uncertainties and other factors that could cause actual results to differ materially from such statements. We undertake no obligation to update any forward-looking statements contained in this press release to reflect events or circumstances occurring after its date or to reflect the occurrence of unanticipated events. For additional information about the company, please visit . SOURCE SystImmune, Inc.

– Proteomics analysis showed that rencofilstat improved aberrant protein profiles in IPF tissues – – Superior effects of rencofilstat alone and in combination with pirfenidone and nintedanib – EDISON, N.J., Sept. 14, 2023 (GLOBE NEWSWIRE) -- Hepion Pharmaceuticals, Inc. (NASDAQ:HEPA), a clinical stage biopharmaceutical company focused on Artificial Intelligence (“AI”)-driven therapeutic drug development for the treatment of non-alcoholic steatohepatitis (“NASH”), fibrotic diseases, hepatocellular carcinoma (“HCC”), and other chronic diseases, today announced positive results from a translational research study in which Hepion’s lead drug candidate, rencofilstat, was administered to diseased human lung tissue from patients with idiopathic pulmonary fibrosis (“IPF”). Proteomic quantitation of nearly 2,000 proteins showed that rencofilstat shifted protein profiles of IPF tissue towards normalized expression more robustly than the two standard-of-care drugs, nintedanib and pirfenidone, and with strong combinational effects especially when co-administered with nintedanib. In this study, FibroFind Ltd. (Newcastle, UK) obtained diseased lung tissue from two individuals undergoing lung transplantation for end-stage IPF, a deadly fibrotic lung disease. Precision cut lung slices (PCLuS) were made and individually incubated in culture with rencofilstat, nintedanib, pirfenidone, or combinations of the compounds for four days. Proteomics analyses were conducted on lung tissues at the end of treatment by PhenoSwitch Bioscience (Sherbrooke, Canada) and identified 1,953 unique proteins in the samples. The changes in abundance of the proteins produced by the drug treatments relative to vehicle control were determined and compared to abnormal protein profiles in IPF lungs reported in multiple proteomics studies over the past 5 years.1–3 These analyses demonstrated: Rencofilstat monotherapy altered levels of between 8 and 28% of the 1,953 proteins identified in PCLuS depending on dose and donor. This represented changes 2 - 4-times greater than nintedanib or pirfenidone in PCLuS from the first donor, and 2-fold greater than nintedanib in the second donor; Rencofilstat, in combination with nintedanib, altered levels of 16 - 42% of the 1,953 proteins depending on donor, which represented 2.7 - 7.8-fold more than nintedanib alone; Rencofilstat, in combination with pirfenidone, altered levels of 12 - 46% of the 1,953 proteins depending on donor, which represented 1.3 - 2.2-fold more proteins altered by pirfenidone alone; Among three studies reporting differentially expressed proteins in IPF lungs compared to normal controls,1–3 up to 41% of the reported differential proteins were also found in the current PCLuS study to be altered by rencofilstat alone or in combination. Furthermore, the majority of rencofilstat’s effects on the overlapping proteins (increased or decreased abundance) were opposite to the disturbances reported in the large IPF studies, which is consistent with disease-normalizing actions of rencofilstat; The normalizing actions of rencofilstat monotherapy and combinations spanned many important classes of proteins, including multiple isoforms of collagens, laminins, integrins, keratins, and MHC antigens. Additional, notable proteins whose abundance was positively shifted by rencofilstat included TIMP3, nidogen, surfactant protein C, cathepsin B, myeloperoxidase, lysozyme, mimecan, and asporin; and Cyclophilin B protein, a primary target of rencofilstat, was reported to be elevated in IPF lung tissue,1,2 suggesting a pathogenic role, and rencofilstat alone and in combination in PCLuS decreased tissue levels of cyclophilin B. “The technological advances in recent years in proteomics and other “omics” methodologies have blown the doors wide open on the scope and complexity of molecular changes in diseases like IPF, helping us to understand why so many narrowly targeted drug candidates have failed to have therapeutic effects,” commented Dr. Daren Ure, Hepion’s Chief Scientific Officer. “Rencofilstat’s suppression of fibrotic collagen production through cyclophilin B inhibition is one well-established mechanism, but inhibition of additional cyclophilin isoforms likely helps to explain rencofilstat’s robust effects in the present study. Rencofilstat alone shifted protein profiles more extensively than nintedanib and pirfenidone in most instances, and rencofilstat combinations were superior to every monotherapy, which is very encouraging. The old dogma in drug development about narrowly targeted drugs needs to adapt to emerging insights on complex diseases, and rencofilstat is one such candidate that is advancing that new paradigm of systems-targeting drug.” Dr. Robert Foster, Hepion’s CEO remarked, “As our Phase 2b NASH clinical trial progresses, we continue our nonclinical research on cancer and other fibrotic indications such as IPF with the aim of expanding our understanding of rencofilstat’s therapeutic and commercial potential. The new actions of rencofilstat that continue to be uncovered complement and strengthen the anti-fibrotic activities that we have seen in many experimental models of NASH, and the numerous positive outcomes in previous NASH clinical trials. The new findings in human IPF samples provide a good foundation for advancing rencofilstat in fibrotic diseases, which potentially also includes IPF.” REFERENCES 1. Konigsberg IR, Borie R, Walts AD, et al. Molecular Signatures of Idiopathic Pulmonary Fibrosis. Am J Respir Cell Mol Biol. 2021;65(4):430-441. doi:10.1165/RCMB.2020-0546OC 2. Tian Y, Li H, Gao Y, et al. Quantitative proteomic characterization of lung tissue in idiopathic pulmonary fibrosis. Clin Proteomics. 2019;16(1):1-11. doi:10.1186/S12014-019-9226-4 3. Åhrman E, Hallgren O, Malmström L, et al. Quantitative proteomic characterization of the lung extracellular matrix in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. J Proteomics. 2018;189:23-33. doi:10.1016/J.JPROT.2018.02.027 About Hepion Pharmaceuticals The Company's lead drug candidate, rencofilstat, is a potent inhibitor of cyclophilins, which are involved in many disease processes. Rencofilstat has been shown to reduce liver fibrosis and hepatocellular carcinoma tumor burden in experimental disease models and is currently in Phase 2 clinical development for the treatment of NASH. In November 2021, the U.S. Food and Drug Administration (“FDA”) granted Fast Track designation for rencofilstat for the treatment of NASH. That was followed in June 2022 by the FDA’s granting of Orphan Drug designation to rencofilstat for the treatment of HCC. Hepion has created a proprietary Artificial Intelligence deep machine learning (“AI/ML”) platform designed to better understand disease processes and identify patients that are rencofilstat responders. This AI/ML has the potential to shorten development timelines and increase the observable differences between placebo and treatment groups. In addition, Hepion’s AI/ML can be used to drive its ongoing NASH and HCC clinical development programs and identify other potential therapeutic indications for cyclophilin inhibition with rencofilstat. 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,” “estimated,” and “intend,” among others. These forward-looking statements are based on Hepion Pharmaceuticals’ 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, substantial competition; our ability to continue as a going concern; our need for additional financing; uncertainties of patent protection and litigation; risks associated with delays, increased costs and funding shortages caused by the COVID-19 pandemic; uncertainties with respect to lengthy and expensive clinical trials, that results of earlier studies and trials may not be predictive of future trial results; uncertainties of government or third party payer reimbursement; limited sales and marketing efforts and dependence upon third parties; and risks related to failure to obtain FDA clearances or approvals and noncompliance with FDA regulations. As with any drug candidates under development, there are significant risks in the development, regulatory approval, and commercialization of new products. There are no guarantees that future clinical trials discussed in this press release will be completed or successful, or that any product will receive regulatory approval for any indication or prove to be commercially successful. Hepion Pharmaceuticals does not undertake an obligation to update or revise any forward-looking statement. Investors should read the risk factors set forth in Hepion Pharmaceuticals’ Form 10-K for the year ended December 31, 2021, and other periodic reports filed with the Securities and Exchange Commission. For further information, please contact: Stephen Kilmer Hepion Pharmaceuticals Investor Relations Direct: (646) 274-3580 skilmer@hepionpharma.com