IGFBP1

A new study has identified that a deficit in the placental expression of the gene insulin-like growth factor 1 (IGFBP1) and low IGFBP1 circulating levels are associated with insulin resistance during pregnancy, highlighting a potential risk factor for the development of gestational diabetes. A new study led by the Harvard Pilgrim Health Care Institute has identified that a deficit in the placental expression of the gene insulin-like growth factor 1 (IGFBP1) and low IGFBP1 circulating levels are associated with insulin resistance during pregnancy, highlighting a potential risk factor for the development of gestational diabetes. The study, "Placental IGFBP1 levels during early pregnancy and the risk of insulin resistance and gestational diabetes," appears in the April 16, 2024 edition of Nature Medicine. Gestational diabetes, a disease that can lead to multiple pregnancy and delivery complications, is the most common pregnancy metabolic complication, affecting 1 in 7 pregnancies. Existing research has shown that excess insulin resistance in pregnancy contributes to gestational diabetes, but the exact causes of this resistance remain unclear. "The placenta -- the major driver of changes in insulin physiology in pregnancy -- is likely a key source of hormones involved in the development of gestational diabetes," says Marie-France Hivert, Harvard Medical School associate professor of population medicine at the Harvard Pilgrim Health Care Institute and lead author of the study. "Our goal was to discover novel placental factors that are implicated in gestational diabetes, by studying all proteins expressed in placenta tissues, across the human genome. We identified placental insulin-like growth factor 1 (IGFBP1) as a secreted placental factor that is likely implicated in regulation of glucose in human pregnancy." The study builds on Dr. Hivert's extensive research into the determinants of gestational diabetes using genetics and other omics approaches, and their interaction with lifestyle and environmental factors. The study team conducted genome-wide RNA sequencing on maternal-facing placental tissue samples, and measured identified proteins in blood collected in multiple pregnancy cohorts with diverse backgrounds. The team identified 14 genes whose placental RNA expression levels were associated with insulin resistance, finding the strongest association with gene IGFBP1. By measuring the IGFBP1 protein levels in circulation, they found that IGFBP1 levels rise over the course of pregnancy and are 5 times higher in pregnant people compared to outside of pregnancy, arguing for the placenta being one of the major sources of this protein during pregnancy. Results also show that low levels of circulating IGFBP1 in early pregnancy could predict who is likely to develop gestational diabetes in late second trimester of pregnancy. Finally, the team found that the trajectory of IGFBP1 levels across pregnancy differs in people who have a subtype of gestational diabetes characterized by insulin resistance previously shown more likely to develop pregnancy complications. "Identifying a novel protein that characterizes a subtype of gestational diabetes is one additional step towards developing precision medicine for gestational diabetes," adds Dr. Hivert. "It's possible that measuring IGFBP1 in the first trimester could help identify people at risk of developing gestational diabetes early in pregnancy, potentially offering a window for prevention. We hope to conduct future research to address whether this protein plays a causal role in gestational glycemic regulation."

Industry veteran Dr. Olson moves from Enthera’s Board to take the helm as CEO Ent001 Phase 1a trial in healthy volunteers completed with positive topline safety results Company has initiated enrollment for Ent001 Phase 1b trial in patients with moderately to severely active ulcerative colitis MILAN--(BUSINESS WIRE)-- Enthera Pharmaceuticals (“Enthera”), a clinical-stage biotech company developing first-in-class antibody therapeutics targeting the Insulin Growth Factor Binding Protein (IGFBP) family for selected inflammatory diseases, today announced the appointment of Lisa M. Olson, Ph.D., as the company’s Chief Executive Officer. Dr. Olson joins Enthera’s management team with over two decades of leadership experience in the biopharmaceutical industry including a successful career at AbbVie. She previously served as a member of Enthera’s Board of Directors and Chair of the Scientific Advisory Board. Enthera also announced completion of Ent001’s Phase 1a single-ascending dose trial in healthy volunteers, establishing a positive safety and tolerability pro enabling the start of the Phase 1b multiple ascending dose trial in ulcerative colitis (UC) patients. UC is a chronic gastrointestinal disease, and while treatment options using immune suppressors are efficacious, they still fail to provide a durable and long-term response for many patients with moderately to severely active disease. Ent001 is a monoclonal antibody targeting the IGFBP3/TMEM219 pathway, which plays a critical role in gut mucosal integrity and is dysregulated in patients with inflammatory bowel diseases (IBD), including UC. “We are entering the new year with positive momentum in Enthera’s corporate and clinical evolution with Lisa’s appointment as CEO and important progress with Ent001. The Enthera team will benefit from Lisa’s scientific and R&D expertise and leadership experience cultivated across the pharmaceutical and biotechnology industries. We are thrilled to have her join as CEO,” said Silvano Spinelli, Chairman of the Enthera Board of Directors. “I look forward to working with the Enthera team to further drive Ent001’s clinical development trajectory. We have defined an exciting opportunity with Ent001 for the long-term treatment of ulcerative colitis, a disease that continues to negatively impact the lives of many patients,” added Dr. Lisa M. Olson, CEO of Enthera. “My goal is to ensure we deliver on the potential of Ent001 in the clinic and to achieve our ambitious corporate objectives for 2024.” Ent001 Clinical Development Updates Enthera completed its single ascending dose (SAD) Phase 1a trial evaluating Ent001 in healthy volunteers, thereby laying the groundwork for evaluation in patients with IBD and other indications, including type 1 diabetes (T1D), where the IGFBP3/TMEM219 pathway also plays a key pathogenetic role. The Phase 1a trial was conducted in the Netherlands and involved 30 healthy volunteers who received single ascending doses of Ent001 or placebo administered by intravenous infusion. The trial results established a very positive safety and tolerability pro Ent001 without any observations of drug-related clinically relevant adverse reactions up to the highest dose tested (10mg/kg). The pharmacokinetics (PK) were linear, and the exposures reached in this study fully cover the concentrations that are predicted to be effective in patients, based on the maximum effective dose in animal disease models of UC. Based on this, Enthera has initiated a multiple ascending dose (MAD) Phase 1b clinical trial in patients with moderately to severely active UC. The Phase 1b multicenter, randomized, double-blind, placebo-controlled trial will evaluate the safety, tolerability, immunogenicity and PK of multiple ascending doses of Ent001 in up to 40 patients with moderately to severely active UC. The trial will also analyze pharmacodynamic responses by measuring peripheral and colon tissue biomarkers of IGFBP3/TMEM219 pathway inhibition to demonstrate proof of mechanism in patients with active colitis. Patients will be dosed up to week 12 to collect exploratory efficacy data and evidence of the compelling mucosal healing effect observed in preclinical models of colitis. About Dr. Lisa M. Olson, CEO of Enthera Prior to joining Enthera, Dr. Olson most recently served as the Chief Scientific Officer of Magenta Therapeutics where she was responsible for the strategic direction and execution of the company’s research and development efforts. Before this, Dr. Olson held various leadership positions at AbbVie and Abbott Laboratories for fifteen years, culminating in her role as Vice President Immunology Discovery and Site Head of the AbbVie Bioresearch Center. During her time at AbbVie she successfully advanced 15 molecules into clinical development including Rinvoq™ (upadacitinib) for the treatment of several conditions, including UC. Dr. Olson joined Abbott following her time as a Research Fellow in Inflammation and Immunology at Pfizer, Inc. Dr. Olson started her career as an Assistant Professor at Washington University School of Medicine following a post-doctoral cardiovascular fellowship at the University of Chicago. She holds a Ph.D. from the University of Illinois at Urbana-Champaign and a B.S. from Iowa State University. About Enthera Pharmaceuticals Enthera Srl is a clinical-stage biotech company developing first-in-class antibody therapeutics to transform the treatment paradigm in inflammatory bowel diseases (IBD) and type 1 diabetes (T1D) by re-establishing stem cell capabilities. Enthera’s pioneering approach capitalizes on the key discovery of the IGFBP3/TMEM219 pathway, which is involved in stem cell and beta cell apoptosis in the gut and pancreas, respectively. Enthera’s lead program, Ent001, which is currently in Phase 1 clinical development, has the potential to restore the original intestinal mucosal structure in IBD and the endogenous pancreatic stem cell compartment in T1D, resulting in the restoration of organ function. Enthera is a private company headquartered in Milan, Italy and founded in 2016 by Prof. Paolo Fiorina and Dr. Francesca D’Addio with BiovelocITA, Italy’s first biotech accelerator. Enthera’s discovery engine and assets are protected by a broad portfolio of patents. The company is backed by Sofinnova Partners, AbbVie, JDRF T1D Fund, Roche Venture Fund, and several private investors. For further information: View source version on businesswire.com: Contacts Enthera Pharmaceuticals Lisa M. Olson Ph.D., CEO info@entherapharmaceuticals.com Trophic Communications Valeria Fisher or Veronika Máté +49 175 8041816 or +49 160 90816161 enthera@trophic.eu Source: Enthera Pharmaceuticals View this news release online at:

Scientists determined the cryo-EM structure of IGF Ternary complex and its assembly and activation mechanism. Insulin-like growth factor (IGF) is a hormone that greatly influences growth in fetuses and children, but also body maintenance and metabolism in adults. IGF regulates cell proliferation, differentiation, and survival by activating IGF receptors distributed in cell membranes of various tissues. However, IGF is so unstable that its half-life is less than 10 minutes in its free state. For, this reason more than 70% of IGF circulating in the body is bound to IGFBP (IGF Binding Protein) and ALS (Acid Labile Subunit). This IGF/IGFBP/ALS ternary complex is stable for a much longer duration of 12 hours and therefore serves as a carrier for IGF. In addition, the ternary complex also plays a role in regulating IGF so that it can act only when needed. However, the structure of the IGF/IGFBP/ALS ternary complex has not been well studied, making it difficult to understand how the complex is assembled and how IGF is activated. Now, a team led by Professor KIM Ho Min at the Center for Biomolecular and Cellular Structure within the Institute for Basic Science (IBS) in Daejeon, South Korea, determined the structure of IGF1/IGFBP3/ALS ternary complex for the first time. It is believed that this structural information could broaden the understanding of growth-related diseases such as growth hormone deficiency and ALS deficiency. The stable ternary complex was successfully expressed and purified through an animal cell expression system and a series of purification processes. The cryogenic transmission electron microscope (cryo-EM), data hub, and supercomputing resources of IBS were used to obtain its high-resolution three-dimensional molecular structure. It was discovered that IGF1 was surrounded by IGFBP3 to first form a binary complex. Then, ALS once more wraps this binary complex like a parachute, which protects IGF1 from being easily degraded within the body. Armed with the new knowledge of the protein structure, the researchers were now able to understand the structural basis for many diseases associated with the mutations in these proteins. In particular, many known point mutations in ALS were found to cause disease by inducing misfolding of ALS and hindering the formation of the ternary complex. On the other hand, known point mutations in IGF did not appear to have any negative effects on their ability to form complexes, but rather cause disease by decreasing IGF's affinity to IGF receptors. The researchers did not stop there, as they further explored how this ternary complex is assembled. First, the researchers ran SDS-PAGE of ALS, IGFBP3, and IGF1 proteins to verify if the complex is or isn't formed. They also fused GFP (green fluorescent protein) onto the IGF1 protein and used fluorescence detection chromatography to trace the GFP labeled protein as they succeed or fail to form complexes with the other two proteins. From this, they learned that IGFBP3 or IGF1 alone cannot form a binary complex with ALS. Moreover, it was discovered that IGF must first form a binary complex with IGFBP, and only after that, both proteins can bind to ALS to properly assemble a ternary complex. Furthermore, the researchers modified IGFBP to better determine the role of specific domains of the protein. When the N terminal domain (NBP) was removed, the protein was shown to be incapable of binding to IGF, hinting that the domain is required for the initial binary complex formation. The researchers also substituted the central-linker domain (CLD3) of the IGFBP with different variants. Contrary to NBP, all variants of CLD domains allowed the formation of the binary complex with IGF1. However, it was shown that some CLD variants allowed the modified IGFBP to bind to ALS even without IGF. This means that it is likely that the formation of the initial IGF1/IGFBP3 binary complex allows for some conformational change to the CLD3 domain to facilitate ternary complex formation with ALS. In addition, the researchers monitored how the complex can be disassembled to make IGF bioavailable. In order to do so, they treated both IGF/IGFBP binary complex and the final ternary complex using a protease called thrombin. After the proteolysis, it was observed that the C-terminus domain (CBP) of IGFBP is released, and an unstable intermediate ternary complex is formed. This process was believed to be an important step in activating the IGF, which is otherwise inactive when it is bound within a complex. The first author KIM Hyojin states, "The first and foremost step before investigating further processes is to understand the structure. This structure-based approach and proper biochemical assays allowed us to unveil the mechanism of IGF complex formation and activation." "This new knowledge of molecular structure and activation mechanism of the IGF ternary complex is expected to greatly contribute to the development of therapeutic agents and research related to adolescent growth or IGF-related diseases," explains Professor KIM Ho Min, the corresponding author of the study.