ATF3

TUESDAY, May 9, 2023 -- The influence of Neanderthals is evident right in the center of the faces of modern humans. New research finds that genetic material inherited from Neanderthals affects nose shape. A particular gene made the nose taller from top to bottom. This may have been necessary as ancient humans adapted to colder climates. “In the last 15 years since the Neanderthal genome has been sequenced, we have been able to learn that our own ancestors apparently interbred with Neanderthals, leaving us with little bits of their DNA,” said co-corresponding author Dr. Kaustubh Adhikari . He is from the University College London (UCL) Genetics, Evolution & Environment and The Open University, in England. “Here, we find that some DNA inherited from Neanderthals influences the shape of our faces. This could have been helpful to our ancestors, as it has been passed down for thousands of generations,” Adhikari said in a UCL news release. For the study, the researchers worked with data from more than 6,000 volunteers across Latin America of mixed European, Native American and African ancestry. Those participants are part of the UCL-led CANDELA study, which recruited from Brazil, Colombia, Chile, Mexico and Peru. To study how different facial traits were associated with the presence of different genetic markers, the scientists compared genetic information from the participants to photographs of their faces. They looked at distances between points on their faces. This led to identifying 33 genome regions associated with face shape. They were able to replicate 26 of these in comparisons with data from other ethnicities using participants in east Asia, Europe or Africa. In a genome region called ATF3, the researchers found that many people in their study with Native American ancestry had genetic material in this gene that was inherited from the Neanderthals, which contributed to increased nasal height. This was also seen in people with east Asian ancestry from another cohort. “It has long been speculated that the shape of our noses is determined by natural selection; as our noses can help us to regulate the temperature and humidity of the air we breathe in, different shaped noses may be better suited to different climates that our ancestors lived in. The gene we have identified here may have been inherited from Neanderthals to help humans adapt to colder climates as our ancestors moved out of Africa,” explained first author Dr. Qing Li, of Fudan University in Shanghai. This is the second study finding DNA from archaic humans other than Homo sapiens that affects face shape. In 2021, this team found evidence of a gene influencing lip shape inherited from the Denisovans. “Most genetic studies of human diversity have investigated the genes of Europeans; our study’s diverse sample of Latin American participants broadens the reach of genetic study findings, helping us to better understand the genetics of all humans,” said co-corresponding author Andres Ruiz-Linares , of UCL Genetics Institute in London, and Aix-Marseille University, in France. The latest findings were published online May 8 in the journal Communications Biology . Sources University College London, news release, May 8, 2023 Posted May 2023

Orum’s new program in immuno-oncology achieves simultaneous blockade of PD-1/PD-L1 pathway and delivery of a Cbl-b inhibitor using anti-PD-1-Cbl-bi conjugates and demonstrates enhanced T cell activation in vitro compared to anti-PD-1 alone, even in the presence of immunosuppressive factors ORM-6151 shows superior tolerability and robust single-dose efficacy, both in vitro and in vivo compared to CC-90009 or Mylotarg™, suggesting the potential for an improved therapeutic option in AML that appropriately balances efficacy with safety and tolerability of a clinically validated GSPT1 degradation mechanism Orum has identified pharmacodynamic biomarkers as predictors of efficacy to support clinical development of ORM-5029 in HER2-expressing solid tumors BOSTON & DAEJEON, South Korea--(BUSINESS WIRE)-- Orum Therapeutics, a clinical-stage private biotechnology company pioneering cell-specific targeted protein degradation (TPD² ™) and targeted protein stabilization (TPS² ™), today announced new preclinical data for three of Orum’s therapeutic programs: ORM-5029, which is a proprietary GSPT1 degrader conjugated to HER2-targeting antibody pertuzumab; ORM-6151, which delivers GSPT1 degrader to CD33+ tumors; and its new immuno-oncology program for a Cbl-b inhibitor (Cbl-bi) conjugated to anti-PD-1 antibody pembrolizumab. The data were presented in three posters at the 2023 American Association for Cancer Research (AACR) Annual Meeting. “We are pleased to present new data supporting clinical development of two programs from our TPD² GSPT1 Degrader Platform, which was developed to improve the therapeutic window and realize the full potential of GSPT1 degraders through precision delivery to cancer cells via antibody drug conjugates,” said Peter Park, Ph.D., Chief Scientific Officer of Orum Therapeutics. “We are also excited to unveil at AACR our new TPS² platform, which has the potential to achieve the full promise of Cbl-b inhibitors through T cell-specific delivery. With this novel approach, we show that we can limit unwanted systemic exposure, including the risk of toxicity associated with c-Cbl inhibition, prolong the activation of exhausted PD-1+ T cells, and provide resistance to negative environmental cues such as TGF-β or regulatory T cells. We believe our approach of harnessing the power of protein degraders and stabilizers with the precision of antibody targeting will improve the treatment of cancer for more patients.” Details of the data presented are as follows: Title: A novel antibody-enabled Dual-precision Targeted Protein Stabilization (TPS²) that augments anti-tumor immune response by targeting Cbl-b inhibitor to exhausted T cells while blocking checkpoint molecule, PD-1 Presenter: Joanne Lim, Ph.D. Abstract Number: 4436 Summary: Cbl-b inhibition results in stabilization of intracellular proteins downstream of the T cell activation pathways. Using a murine model well-established to be refractory to anti-PD-1 antibody treatment, we demonstrated that anti-PD-1-Cbl-b inhibitor approach increased effector T cell markers in the tumor and delayed tumor growth. Presented Data: The delivery of Cbl-b inhibitor (Cbl-bi) conjugated to anti-PD-1 antibody enhances the saturating, maximum activation of anti-PD-1 antibody by 300% in PD-1/PD-L1 blockade assay. Anti-PD-1-Cbl-bi conjugates enhance T cell responses of mixed lymphocyte reaction in a dose-dependent manner and overcome suppressive effects of TGF-β and Treg cells compared to antibody alone in vitro. Anti-PD-1-Cbl-bi conjugates enhance ex vivo activation of tumor-associated T cells from human cancer patients compared to antibody alone or when treated with antibody and unconjugated Cbl-bi. Anti-PD-1-Cbl-bi conjugates delay the growth of melanoma tumors in hPD-1 transgenic mice, with corresponding increase in intratumoral transcript levels of CD3e, granzyme B, and perforin in the tumor. Title: ORM-6151: A first-in-class CD33-antibody enabled GSPT1 degrader for AML Presenter: James Palacino, Ph.D. Abstract Number: 2700 Summary: ORM-6151 shows robust single-dose efficacy, both in vitro and in vivo with superiority or comparability to standard of care (SOC) agents. In addition, in vitro testing demonstrated superior tolerability to healthy bone marrow progenitor cells, suggesting better tolerability. Responses in representative TP53 wild-type and mutant AML models demonstrated comparable activity, indicating the potential for responses in a large percentage of AML patients with poor treatment options. Presented Data: ORM-6151 shows robust in vitro activity in p53 wild-type and mutant cell models. In ex-vivo AML blasts, ORM-6151 demonstrates efficacy superior to CC-90009, a small-molecule GSPT1 degrader, or Mylotarg, an FDA-approved treatment for AML. Compared to CC-90009 or Mylotarg, ORM-6151 exhibits minimal cytotoxic activity to healthy hematopoietic progenitor cells in vitro. A single treatment of ORM-6151 at 3 mg/kg regresses MV4-11 tumors in vivo mouse model with 9/9 complete response (CR), and a single dose of 1 mg/kg produced equivalent antitumor effect as SOC doublet given at optimal repeated dose. Title: Development of RNAscope multiplex-based assay for exploratory pharmacodynamic biomarkers assessment in breast cancer patients from Phase I clinical trial of ORM-5029, a potent GSPT1 degrader Presenter: Shikha Saini, Ph.D. Abstract Number: 2118 Summary: To fulfill the need to develop pharmacodynamic biomarkers as predictors of efficacy to support clinical development of ORM-5029, Orum identified a novel GSPT1 antibody for detection of depletion following treatment with ORM-5029. GSPT1 depletion and subsequent activation of the integrated stress response are both seen following in vitro or in vivo treatment with ORM-5029. Degree of pharmacodynamic (PD) change correlates with depth and duration of in vivo response. Orum is currently developing a multiplexed (IF/ISH/ISH) assay to track PD responses in patients, with an aim to better predict responses and efficacious doses. Presented Data: Orum identified the depletion of GSPT1 as a target-proximal pharmacodynamic biomarker in ORM-5029 treated in vitro and in vivo samples. Loss of GSPT1 drives activation of integrated stress response and upregulation of ATF3 and DDIT3 mRNA and these responses are also seen following treatment with ORM-5029, in both in vitro BT-474 cells and in vivo HCC1568 mouse model. PD responses correlate with degree and duration of response in an in vivo model treated with ORM-5029. The posters are available to download through the links below: PD-1-Cbl-bi TPS² preclinical poster: ORM-6151 preclinical poster: ORM-5029 predictive biomarker poster: About Orum’s TPS² Approach Orum’s Dual-precision Targeted Protein Stabilization (TPS²) approach combines novel payloads with the precise cell delivery mechanism of antibodies to increase the levels of intracellular target proteins in a cell-type-specific manner for oncology and immuno-oncology. The first program applying the TPS² approach is a Cbl-b inhibitor (Cbl-bi) conjugated to anti-PD-1 antibody. By delivering Cbl-bi specifically to exhausted T cells, the conjugate is designed to restore effector T cell function, where PD-1 checkpoint blockade alone is insufficient, while also enabling T cells to overcome the immunosuppressive mechanisms in a tumor microenvironment. About Orum’s GSPT1 Platform Using the TPD² Approach Orum’s GSPT1 platform uses the company’s unique Dual-precision Targeted Protein Degradation (TPD²) approach to build novel targeted protein degraders combined with the precise tumor cell delivery mechanisms of antibodies to generate innovative, first-in-class, cell-specific TPDs for the treatment of cancer. Orum has developed new molecular glue degrader payloads to specifically degrade an intracellular target protein within cancer cells via the E3 ubiquitin ligase pathway. Conjugated to antibodies, the payloads are designed to be delivered specifically to cancer cells and degrade the intracellular target protein GSPT1 and cause tumor cell death. About Orum Therapeutics Orum Therapeutics is a private, clinical-stage biotech pioneering the development of tumor-directed targeted protein degraders (TPD²) and stabilizers (TPS²) with the precision of antibody targeting to improve cancer treatment for more patients. The first therapeutic candidates from the TPD² GSPT1 platform, ORM-5029 and ORM-6151, are in clinical development for the treatment of solid tumors and hematologic cancers, respectively. The first program applying the TPS² approach is a Cbl-b inhibitor conjugated to anti-PD-1 antibody. Orum is located in Boston, US, and Daejeon, South Korea. For more info, visit . Forward-Looking Statements This press release contains forward-looking statements that are based on the current expectations and beliefs of Orum Therapeutics, Inc. (“Orum”). Statements in this release regarding matters that are not historical facts, including, but not limited to, statements relating to the potential for clinical efficacy, potency, and tolerability of Orum’s products; the potential for conducting and successfully completing clinical trials, translation of preclinical and non-human data to the clinical and human contexts, obtaining favorable trial results, conducting later-phase trials, obtaining regulatory approval of product candidates for sale, successfully commercializing product candidates, and improving the cancer treatment for more patients; the types of cancer that might be treated by Orum products; the successful prediction of patient responses and efficacious doses; and the preferability of Orum products to others available are forward-looking statements. These forward-looking statements are based on management’s expectations and assumptions as of the date of this release and are subject to numerous risks and uncertainties, which could cause actual results to differ materially from those expressed or implied by such statements. These risks and uncertainties include, without limitation, the uncertain and continually changing impacts and expected duration of the COVID-19 pandemic; the uncertainty of success in research and development activities; risks related to clinical trials, including potential delays, safety issues, or negative results; competition from alternative therapies; the risk that Orum may not be able to maintain and enforce its intellectual property; the risk that product candidates may not be successfully commercialized or adopted; the availability of financing; and risks related to the recruitment and retention of key employees, fluctuating markets and economic conditions, health care reform, prices, and reimbursement rates. The forward-looking statements in this presentation speak only as of the date of this release, and Orum undertakes no obligation to update or revise any of the statements. Orum cautions investors not to place considerable reliance on the forward-looking statements contained in this release.

T cells are capable of killing cancer cells, but tumors have tricks to evade their might. New research details one of these strategies, known as trogocytosis, in which T cells ingest a piece of cancer cell membrane, taking on a bit of cancerous identity. Blocking this process could improve the effectiveness of CAR T cell therapy. The immune system is equipped to respond not just to external invaders -- think viruses, bacteria, and parasites -- but also to internal threats, namely, cancer. Yet, frequently, malignancies overcome the immune system's defenses and evade detection. In a new study, researchers led by Serge Y. Fuchs of the School of Veterinary Medicine, have uncovered a detailed mechanism by which tumors can skirt both the immune system and cancer therapies that leverage its power, such as genetically engineered CAR T cells. Their investigation, published in the journal Cell Metabolism, revealed how tumor-derived factors stimulate trogocytosis -- a process derived from the Greek word trogo, which means "to gnaw" or "to chew." When T cells interact with cancer cells, they can sometimes "nibble" a piece of the cancer cell membrane. When that membrane segment includes an antigen, a molecule specific to the cancer, the T cells may then begin expressing that antigen on their own cell surface, making it appear to other T cells like a cancer cell. Trogocytosis can affect a patient's own T cells and those modified to become CAR T cells, an approach in which a patient's T cells are genetically engineered to specifically target cancer cells, grown in a lab, and then delivered back to the patient. "Trogocytosis can lead to three different things, and all three are bad for a person with a tumor," says Fuchs, the senior author on the work. "First of all, the tumor cell did not get killed and has lost an antigen, which may mean that even if another, better equipped T cell comes along, it will not recognize it, giving cancer cells a window of opportunity to grow unchecked. The second problem is, for reasons we still don't understand, once a T cell takes a piece of the tumor cell membrane, it becomes much less active. And the third problem is very ironic. Because now, a T cell that displays tumor antigen, this 'sheep in wolf's clothing,' may then become victim to 'fratricide,' killed by another T cell." Overall, the result is a decline in killer T cell numbers and activity and a bump in opportunities for the cancer cells to escape detection and grow. "What we see is that only a small number of cells undergo trogocytosis and then they disappear quickly because they're killed. So we're studying a vanishing act. It is hard to do -- very expensive and very tedious -- but it appears to be very important," says Fuchs. With a longstanding interest in how receptors on the surface of immune cells guide anti-cancer immunity, Fuchs and colleagues have made a variety of discoveries showing how tumors can manipulate T cells to escape being targeted and killed. A particular area of interest is what's known as tumor-derived factors, or the concoction of proteins, lipids, and other materials that cancer cells secrete into the body. In the current study, the Penn researchers found that collecting these secretions and exposing the resulting solution to T cells hampered the cells' ability to do their cancer-fighting job. "Just exposing them to this tumor-conditioned media caused them to kill fewer cancer cells, trogocytose more, and get killed more," Fuchs says. Trogocytosis was previously believed to have something to do with cancer's ability to hinder anti-cancer immunity, but the Penn-led team pinned down the mechanism, showing that T cells exposed to tumor-derived factors experienced a notable decline in levels of the gene CH25H. This gene is known to be involved in altering cell's lipid membranes and can inhibit two cell membranes from fusing together -- an essential process for trogocytosis to occur. When they added back a metabolite produced by CH25H, they could block trogocytosis. "That was an 'aha' moment," Fuchs says. Further characterization of the pathway helped the team identify another player, the gene ATF3, which opposes the activity of CH25H. Eliminating AFT3 prevented trogocytosis from occurring and restored the ability of T cells to kill tumor cells. Not only do the new insights suggest novel targets for anti-cancer therapies, but they may have immediate significance for CAR T therapy. Since trogocytosis could impair the effectiveness of the engineered T cells delivered in CAR T, the researchers surmised that blocking this could improve CAR T performance. "We figured, why don't we use what is cleverly known as an 'armored CAR' approach, and co-express CH25H in the CAR T," Fuchs says. "This turned out to be more efficient than the old CAR T cells." Indeed, delivering the CAR T cells adorned with CH25H improved the survival of mice with cancer compared to the unarmored CAR T cells. Though only a small percentage of T cells are involved in trogocytosis, Fuchs says it may be an underappreciated process when it comes to cancer immunity and other processes, such as those involved in autoimmunity. With future work, he and colleagues intend to explore the roles of ATF3 and CH25H and other molecules in trogocytosis. And he's hopeful that other researchers will pick up on these lines of work, bringing the findings closer to clinical application. "I can see this going into use in CAR T therapy quickly," Fuchs says. "It's ready to play." Serge Fuchs is the Elizabeth and William Whitney Clark Professor of Oncology at the University of Pennsylvania School of Veterinary Medicine. Fuchs' coauthors on the work were Penn Vet's Zhen Lu, Noreen McBrearty, Jinyun Chen, Vivek S. Tomar, Hongru Zhang, Gianluca De Rosa, and Daniel P. Beiting; the Perelman School of Medicine's Aiwen Tan, Aalim M. Weljie, Zhen Miao, Subin S. George, and Constantinos Koumensis; Takeda Development Center's Allison Berger and Gurpanna Saggu; and Case Western Reserve University's J. Alan Diehl. The study was supported in part by the National Institutes of Health (grants CA247803, CA240814, CA165997, and CA115299).