BAK

Researchers have traced the origin and evolutionary trajectory of plant immune receptors. Their discovery will make it easier to identify immune receptor genes from genomic information and could help in the development of pathogen-resistant crops. Plants are continuously evolving new immune receptors to ever-changing pathogens. Researchers at the RIKEN Center for Sustainable Resource Science (CSRS) have traced the origin and evolutionary trajectory of plant immune receptors. Their discovery will make it easier to identify immune receptor genes from genomic information and could help in the development of pathogen-resistant crops. This study was published in the scientific journal Nature Communications on February 1. As in animals, plants have immune responses that help them defend against pathogens such as viruses, bacteria, fungi, and oomycetes. Before invaders can be stopped, they must first be detected, and this is accomplished by pattern recognition receptors located on the surface of plant cells. The ability of these receptors to detect molecular patterns associated with pathogens depends on two types of proteins, called RLPs and RLKs, both of which can contain leucine-rich repeats -- sections in which the amino acid leucine appears multiple times. To trace the evolution of plant immunity, the international research team led by Ken Shirasu and Yasuhiro Kadota at RIKEN CSRS examined the numbers and patterns of receptors. They analyzed over 170,000 genes encoding RLKs and about 40,000 genes encoding RLPs, which they obtained from publicly available data taken from 350 plant species. They discovered that RLKs and RLPs with leucine-rich repeats were the most abundant receptor types among all the plant species, making up nearly half of RLKs and 70% of RLPs. RLPs, and some RLKs, are known to contain a special island region that is crucial for recognizing parts of pathogens. Investigation by the RIKEN CSRS team revealed that among RLPs that contain the leucine-rich repeats, this special region was almost always located in the same place; between the 4th and 5th leucine-rich repeat. These RLPs were found to be associated with immune responses. They also discovered that the island region was located at the same position in some RLKs, nearly all of which belong to a functional group that regulates growth and development. Comparative analysis showed that the sequence of the four repeats below the island region was very similar between the two types of protein detectors, suggesting that they have a common evolutionary ancestry. In particular, these four sets of leucine repeats contained sections needed for bonding to the same co-receptor, called BAK1. This means that immunity-related RLPs and growth-related RLKs inherited the ability to bind BAK1 from a common ancestor. "Intriguingly, we found that exchanging the four regions of leucine-rich repeats among these receptors did not disrupt their functionality," says Bruno Pok Man Ngou, who conducted the study. Creating a hybrid receptor by combining a growth-related RLK with an immunity-related RLP resulted in a hybrid receptor that recognized pathogens and induced both immune and growth-related responses. This means that scientists should be able to engineer receptors with new functions by swapping those modules. This study addressed the origins of plant immunity at a molecular level, showing that simultaneously analyzing information from multiple plant genomes can allow straightforward and precise prediction of genes involved in plant immunity and growth. "We are currently isolating immune receptors from various plants using this information, aiming for practical applications such as developing disease-resistant crops in the future," says Shirasu.

PT-112's mechanism of action inhibits ribosomal biogenesis, promoting immunogenic cancer cell death through cancer cell organelle stresses Data presented at the Society for Immunotherapy of Cancer's 38th Annual Meeting NEW YORK, Nov. 4, 2023 /PRNewswire/ -- Promontory Therapeutics Inc., a Phase 2 stage biotech company advancing immunogenic small molecule approaches in oncology, today presented data demonstrating the molecular mechanism of its lead therapeutic candidate, PT-112, and its ability to induce immunogenic cell death (ICD) in cancer cells. Data suggest that PT-112-induced ICD is mediated by endoplasmic reticulum (ER) and mitochondrial stresses, which are specific intra-cellular events that comprise part of the larger ICD mechanism. The presentation was made at the Society for Immunotherapy of Cancer's (SITC) 38th Annual Meeting, taking place November 1-5, 2023 in San Diego. The work was designed in collaboration with the Galluzzi Lab at Weill Cornell Medical College in New York, in order to elucidate the sequence of events – beginning with inhibition of ribosomal biogenesis and culminating in selective ICD – underlying PT-112's immune effects. Analyzing a panel of mouse cell lines engineered to lack specific genes involved in mitochondrial apoptosis (Bcl2, Bax and Bak1), flow cytometry, immunoblotting, RT-PCR, and immunofluorescence microscopy were used to determine the impact of PT-112 on ER and mitochondrial stress, as well as immunogenic signaling. "Our continued studies of PT-112 provide mechanistic insights for this promising immunogenic small molecule, which has shown clinical activity in patients with a variety of cancers," said Promontory Therapeutics Senior Vice President of Research and Development Tyler Ames, PhD. "This particular work sheds light on how PT-112 encourages the immunogenic cell death of cancerous cells through ER stress and mitochondrial dysfunction, both of which are known to contribute to immune signaling." Study findings include: PT-112 drives ER stress and mitochondrial dysfunction, which promote ICD. PT-112 effects on mitochondria included increases in mitochondrial mass and reactive oxygen species, changes in membrane polarization, and the release of mitochondrial DNA into the cytosol, a potent immunogenic signal. Some of these effects were impacted by the absence of Bax and Bak1. PT-112 elicits the phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (EIF2S1, best known as eIF2α), indicating ER stress and the activation of the integrated stress response (ISR). There is an increase in the levels of Ifnb1 mRNA after PT-112 exposure, indicating PT-112 induces type 1 interferon responses. PT-112 is the subject of ongoing Phase 2 clinical trials for metastatic castrate-resistant prostate cancer and thymic epithelial tumors, and a completed Phase 2a trial in non-small cell lung cancer. In previous mechanism of action research, data showed that PT-112 causes ribosomal biogenesis inhibition and nucleolar stress, which is the likely driver of PT-112-induced cancer organelle stresses and ICD. For more information about Promontory Therapeutics and PT-112, visit . About PT-112 PT-112 is a novel inhibitor of ribosomal biogenesis, which leads to selective immunogenic cancer cell death (ICD). PT-112's mechanism of action governs intracellular events that cause the release of damage associated molecular patterns, known to bind to dendritic cell and natural killer cell receptors, prompting an anti-cancer immune response. PT-112's potential best-in-class ICD effects may create the conditions for effective and durable responses to treatment. The first in-human study of PT-112 demonstrated an attractive safety profile and evidence of long-lasting responses among heavily pre-treated patients and data were published in eClinicalMedicine, part of The Lancet. The company's Phase 2 study of PT-112 in late-stage metastatic castration-resistant prostate cancer patients is underway in the United States and France. An active Phase 2 trial is also on-going with the National Cancer Institute utilizing PT-112 in thymic epithelial tumors, a rare disease with no FDA approved drug, for which PT-112 has received FDA Orphan Drug designation. An additional Phase 2a study has been successfully completed for non-small cell lung cancer in combination with PD-L1 inhibition. About Promontory Therapeutics Promontory Therapeutics Inc. is a privately held, clinical stage drug development company focused on small molecule immunotherapy in cancer. The company's lead therapeutic candidate PT-112 has demonstrated single-agent and combination anti-cancer activity and an attractive tolerability profile across three Phase 1 studies. PT-112 is the subject of ongoing Phase 2 clinical trials for metastatic castration-resistant prostate cancer in the United States and France, thymic epithelial tumors with the National Cancer Institute, and a completed Phase 2a trial in non-small cell lung cancer. As part of its recent research and development expansion into France, Promontory was selected as the first international company member of the Paris-Saclay Cancer Cluster, Europe's emerging biotech hub for oncology. To learn more about Promontory Therapeutics, visit the company's website here. CONTACTS: Promontory Therapeutics: Brooke Raphael, MS VP, Strategy & Operations Tel: +1 (646) 974-6453 Email: [email protected] Investors: Stan Musial Chief Financial Officer Tel: +1 (646) 222-6932 Email: [email protected] Media: Alexis Feinberg ICR Westwicke Tel: +1 (203) 939-2225 Email: [email protected] SOURCE Promontory Therapeutics Inc.

NEW YORK, April 24, 2023 (GLOBE NEWSWIRE) -- Eyenovia, Inc. (NASDAQ: EYEN), a pre-commercial ophthalmic technology company developing the Optejet® delivery system for use both in connection with its own drug-device therapeutic programs for mydriasis, presbyopia and pediatric progressive myopia as well as out-licensing for additional indications, today announced a poster presentation at the Association for Research in Vision and Ophthalmology (ARVO) 2023 annual meeting, which is being held April 23-27 in New Orleans. “This important study confirms that our proprietary Optejet dispensing technology can achieve a therapeutic dose of the anti-glaucoma medication latanoprost with significantly less exposure to excess drug and harmful preservatives than can be achieved using conventional eye drops,” stated Michael Rowe, chief executive officer of Eyenovia. “We are fast approaching the May 8th PDUFA date for our most advanced clinical program, the mydriasis agent Mydcombi, which, if approved, would be the first FDA approved product using the Optejet and would provide critical validation of this technology. We believe the Optejet can be leveraged across a broad range of high-value ophthalmic indications, many of which we plan to explore in the future through both internal development programs and external collaborations.” Presentation details: Title: Cytotoxicity Evaluation for BAK-Preserved Latanoprost Delivered by Drop Versus Micro-Array Print (MAP) Technology Presenters: Pedram Hamrah, MD, and Deshea Harris, MSc, Tufts Medical Center, Boston Date: April 25th, 2023 Time: 11:45 a.m. – 1:30 p.m. CDT (12:45 p.m. – 2:30 p.m. EDT) Location: Exhibit Hall Posterboard #: B0374 Summary: Treatment with the anti-glaucoma medication Latanoprost that is preserved with benzalkonium chloride (BAK) over a long period of time has consistently demonstrated cytotoxic effects. This poster describes results of a study evaluating BAK-preserved latanoprost delivered via conventional eye dropper versus Eyenovia’s proprietary Micro-Array Print (MAP) technology. This study found that Optejet using MAP technology has the potential to reduce ocular surface stress when administering BAK+ latanoprost. Excellent human conjunctival cell tolerability was observed and was comparable to preservative-free latanoprost. Significantly less cell toxicity, significantly lower RNA levels of proinflammatory chemokine IL-6 and CCL2, and significantly lower protein levels of proinflammatory cytokine IL-6 were observed. Conclusion: MAP technology appears better in reducing inflammatory processes than BAK+ latanoprost administered with traditional eye drops. In conclusion, precision dosing has the potential to decrease ocular surface disorders typically associated with long-term use of preserved eye drops. For more information: About Eyenovia, Inc. Eyenovia, Inc. (NASDAQ: EYEN) is an ophthalmic pharmaceutical technology company developing a pipeline of microdose array print (MAPTM) therapeutics. Eyenovia is currently focused on the late-stage development of microdosed medications for mydriasis, presbyopia and myopia progression. For more information, visit Eyenovia.com. The Eyenovia Corporate Information slide deck may be found at ir.eyenovia.com/events-and-presentations. Forward-Looking Statements Except for historical information, all the statements, expectations and assumptions contained in this presentation are forward-looking statements. Forward-looking statements include, but are not limited to, statements that express our intentions, beliefs, expectations, strategies, predictions or any other statements relating to our future activities or other future events or conditions, including estimated market opportunities for our product candidates and platform technology. These statements are based on current expectations, estimates and projections about our business based, in part, on assumptions made by management. These statements are not guarantees of future performance and involve risks, uncertainties and assumptions that are difficult to predict. Therefore, actual outcomes and results may, and in some cases are likely to, differ materially from what is expressed or forecasted in the forward-looking statements due to numerous factors discussed from time to time in documents which we the U.S. Securities and Exchange Commission. In addition, such statements could be affected by risks and uncertainties related to, among other things: risks of our clinical trials, including, but not limited to, the costs, design, initiation and enrollment, timing, progress and results of such trials; the timing of, and our ability to submit applications for, obtaining and maintaining regulatory approvals for our product candidates; the potential advantages of our product candidates and platform technology; the rate and degree of market acceptance and clinical utility of our product candidates; our estimates regarding the potential market opportunity for our product candidates; reliance on third parties to develop and commercialize our product candidates; the ability of us and our partners to timely develop, implement and maintain manufacturing, commercialization and marketing capabilities and strategies for our product candidates; intellectual property risks; changes in legal, regulatory, legislative and geopolitical environments in the markets in which we operate and the impact of these changes on our ability to obtain regulatory approval for our products; and our competitive position. Any forward-looking statements speak only as of the date on which they are made, and except as may be required under applicable securities laws, Eyenovia does not undertake any obligation to update any forward-looking statements. Eyenovia Contact: Eyenovia, Inc. John Gandolfo Chief Financial Officer jgandolfo@eyenovia.com Eyenovia Investor Contact: Eric Ribner LifeSci Advisors, LLC eric@lifesciadvisors.com (646) 751-4363 Eyenovia Media Contact: Eyenovia, Inc. Norbert Lowe Vice President, Commercial Operations nlowe@eyenovia.com