HLA-C

Global thought leaders join advisory team to focus on Mestag’s groundbreaking tertiary lymphoid structure (TLS) induction approach to treat solid tumorsCAMBRIDGE, United Kingdom, Feb. 20, 2024 (GLOBE NEWSWIRE) -- Mestag Therapeutics (“Mestag”), a biotech company harnessing new insights into fibroblast-immune interactions to develop impactful treatments for patients, today announced the appointments of additional distinguished, world-leading advisors to guide the development of its lead program M300, a first-in-class antibody program designed to conditionally induce the formation of Tertiary Lymphoid Structures (TLS) in the tumor. The new appointments expand Mestag’s advisors and comprise a unique group of investigators with extensive experience in the development of novel cancer therapies and specific expertise in the field of TLS biology in cancer. TLSs are aggregates of immune cells which provide a site of entry and education for immune cells in the tumor. The presence of TLS in tumors has recently become recognized as strongly predictive of improved patient outcomes and better response to therapy.1,2,3,4 Susan Hill, PhD, Chief Executive Officer of Mestag Therapeutics, said, “Mestag’s M300 program opens up a new paradigm for the treatment of solid tumors. Advances in understanding TLS biology in cancer, and the associated benefit to patient outcomes, have enabled us to design a first-in-class program with the potential to benefit large numbers of patients with cancer. We are honored to work with such an eminent group of experts in this field to drive the program urgently into the clinic.” The newly appointed M300 advisors comprise Prof. Gabriele Bergers, group leader at the Flanders Institute for Biotechnology (VIB) Center for Cancer Biology and Professor of Oncology at the University of Leuven in Leuven, Belgium; Prof. Julie R. Brahmer, Director of the Thoracic Oncology Program, Professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, as well as the Marilyn Meyerhoff Professor in Thoracic Oncology; Prof. Jeffrey L. Browning, Research Professor at the Boston University School of Medicine in the Departments of Virology, Immunology and Microbiology and Rheumatology; Prof. Wolf H. Fridman, Professor Emeritus of Immunology at Université Paris-Cité, France; Prof. Catherine Sautès-Fridman, Professor Emeritus at Université Paris-Cité; Prof. Elizabeth M. Jaffee, Professor of Oncology and Deputy Director at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; and Prof. Ignacio Melero, Professor of Immunology at the Academic Hospital of Navarra and at the Center for Applied Medical Research (CIMA) of the University of Navarra. Ignacio Melero, MD, PhD, advisor to Mestag and Professor of Immunology at the Academic Hospital of Navarra and at the Center for Applied Medical Research (CIMA) of the University of Navarra, said, “I look forward to collaborating with Mestag and to be a part of their world-class advisory team. I believe there is potential to develop transformative therapies for patients battling cancer. Mestag’s novel approach leverages known immunobiology, which for the first time, is being translationally harnessed to stimulate an anti-cancer immune environment within cancer tissue. Recent evidence supports the beneficial role of tertiary lymphoid structures in cancer, and the ability of a therapy to safely increase their presence could result in an efficacious intervention in patients with solid tumors.” Biographical information Gabriele Bergers, PhD, is a Professor of Oncology at the University of Leuven and a group leader at the Vlaams Instituut voor Biotechnologie (VIB)-Center for Cancer Biology in Leuven since 2016. Before her move to the VIB, she was a Professor in the Department of Neurological Surgery and a PI in the Brain Tumor Research Center (BTRC) at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco (UCSF), for 20 years. She has made seminal discoveries about perivascular tumor niches regarding the vasculature and the immune cell compartment in regulating neovascularization, inflammation, and TLS formation in cancer and in revealing and understanding intrinsic and evasive resistance mechanisms of tumors to antiangiogenic immunotherapies. Dr. Bergers has received awards, including the Sidney Kimmel, the Sandler Opportunity, UCSF Breakthrough Biomedical Research, and the Judah Folkman. She has acted as an external advisory board member for a number of universities and pharmaceutical companies. Dr. Bergers was the Co-director of the Tumor Microenvironment Brain Tumor Center at UCSF and an advisor to the Max-Planck-Institute for Biomedicine in Muenster, Germany. She was a scientific co-founder of Oncurious. Julie R. Brahmer, MD, is the Director of the Thoracic Oncology Program, Professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, co-Leader of Cancer Immunology, as well as the Marilyn Meyerhoff Professor in Thoracic Oncology. She also directs the Kimmel Cancer Center on the Johns Hopkins Bayview campus and is co-principal investigator on Johns Hopkins' National Clinical Trials Network (NCTN) cooperative group grant. Dr. Brahmer is an active clinical leader in the treatment of lung cancer and mesothelioma. Dr. Brahmer's research and clinical practice focuses on the development of new therapies for the treatment of lung cancer and mesothelioma. She is a member of the American Society of Clinical Oncology, serves on the board of directors of the Society of Immunotherapy for Cancer, and is the Chair of the Eastern Cooperative Oncology Group (ECOG) Thoracic Committee. She is also on the medical advisory board of several lung cancer patient advocacy groups including LUNGevity, the Lung Cancer Research Fund, and Lung Cancer Research Foundation of America. Jeffrey L. Browning, PhD, is a Research Professor at the Boston University School of Medicine in the Departments of Virology, Immunology and Microbiology and Rheumatology. He has a PhD in biochemistry from the University of Wisconsin. As a research scientist in the immunobiology discovery group at Biogen from 1984 to 2012, he centered on the tumor necrosis factor (TNF) family of regulatory molecules, including the discovery of the lymphotoxin, B-cell activating factor (BAFF) and TNF-like weak inducer of apoptosis (TWEAK) systems, and translation of modulators of the lymphotoxin pathway to the clinic in indications ranging from autoimmune disease and inflammatory bowel disease to oncology. He joined Boston University School of Medicine in 2013, with a current focus on altered vascular and stromal states in the perivascular compartment in the skin of systemic sclerosis and lupus patients and the impact on the pathology. Early in his career, he undertook postdoctoral work in the biophysics department of the University of Basel, Switzerland, using nuclear magnetic resonance to study membrane structure; and in the neurobiology department at the University of California, San Francisco researching the neuromuscular junction. Wolf H. Fridman, MD, is Professor Emeritus of Immunology at Université Paris-Cité. He is an expert in analysis of the tumor microenvironment, demonstrating that context, including functionality, location and density of the immune infiltrate in colorectal tumors, is the major prognostic factor for human cancers. He is involved in developing bioinformatic tools to quantify tumor microenvironment cells used to predict prognosis and immunotherapeutic responses in renal cell and colorectal cancers and sarcomas. His immune classification of soft tissue sarcoma tumors helped demonstrate that TLS and B cell signatures predict favorable clinical outcomes and therapeutic responses to anti-PD-1 therapy better than T cells, findings recently extended to other cancers treated with immune checkpoint blockers. These showed plasma cells generated inside TLS produce anti-tumor antibodies associated with a patient’s response to immunotherapy, opening the way for novel immune-based tools for efficient prognosis and therapy. Catherine Sautès-Fridman, PhD, is Professor Emeritus at Université Paris-Cité. She is the former Director of the Cancer, Immunology and Immunopathology department and Director of the Immunotherapy and Cancer team at Centre de Recherche des Cordeliers. Her research focuses on the heterogeneity of the immune and inflammatory components of the tumor microenvironment to identify new prognostic and theranostic markers. She carried out work in several fields: histocompatibility antigens, demonstration of the association of human leukocyte antigens (HLAs) with beta2-microglobulin and description of the 3rd histocompatibility locus in mice, H-2L and HLA-C in man, receptors for immunoglobulin G antibodies (biological activity and 3D structure), immuno-oncology (role of interleukin-17, TIME profiles of patients at risk of disease progression in localized kidney cancers, role of Tertiary Lymphoid Structures). She is the former President of the French Society of Immunology and European Federation of Immunological Societies. She founded the EFIS-EJI Ita Askonas Award to acknowledge female group leaders in immunology, and she founded the first European Congress of Immunology. She is Editor-in-Chief of La Revue Immunité et Cancer. Elizabeth M. Jaffee, MD, is an internationally recognized expert in cancer immunology and pancreatic cancer. She is Deputy Director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Co-Director of the Skip Viragh Pancreatic Cancer Center, and Associate Director of the Bloomberg Kimmel Institute for Cancer Immunotherapy. Her research focus is on developing novel immunotherapies for the treatment and prevention of pancreatic cancer. Prof. Jaffee is a past President of AACR and has served on several committees at the National Cancer Institute. She is Chief Medical Advisor to the Lustgarten Foundation for Pancreatic Cancer Research, and the Inaugural Director of the Convergence Institute for Integrating Technologies and Computational Sciences at Johns Hopkins. She is Chair of President Biden’s Cancer Panel. Ignacio Melero, MD, PhD, is Professor of Immunology at the Academic Hospital of Navarra and at the Center for Applied Medical Research (CIMA) of the University of Navarra. He leads a group working in translational tumor immunotherapy with an emphasis on cell therapy, cytokine gene therapy, and immune-stimulatory monoclonal antibodies. Earlier in his career, Dr. Melero contributed to seminal discoveries in the function of Natural Killer cells, and T-cell co-stimulation via CD137 (4-1BB). Dr. Melero has been awarded the BIAL Prize of Medicine, the Conde de Cartagena Award from the Royal Academy of Medicine, Doctor Durantez LAIR Foundation Award and a CRI research award. He has served on advisory boards of Bristol Myers-Squibb, Roche-Genentech, AstraZeneca, Merck Serono and Boehringer Ingelheim, and holds research grants by Pfizer, Bristol Myers Squibb, and Alligator. About Mestag’s M300 Program M300 is a first-in-class antibody program designed to conditionally induce the formation of Tertiary Lymphoid Structures (TLS) in the tumor. TLSs are aggregates of immune cells that form in tumor tissue as part of our bodies’ natural anti-cancer mechanisms, and drive powerful immune responses by recruiting, educating, and activating new anti-tumor T and B-cells. Fibroblast populations play a key role in the induction and maintenance of TLSs. TLSs in tumors are strongly predictive of both improved patient outcomes across solid tumor types and better response to therapy.1,2,3,4 About Mestag Therapeutics Mestag harnesses new insights into fibroblast-immune interactions to develop impactful treatments for patients. We are progressing a pipeline of sophisticated first-in-class antibodies designed to improve the lives of patients with cancer and inflammatory disease. Together with our collaboration partner Janssen Biotech, Inc., a Johnson & Johnson company, we are also identifying novel targets for future therapies. Our founding investigators comprise global experts in inflammatory disease, cancer, computational biology and fibroblast biology from the University of Oxford, Brigham & Women’s Hospital, Harvard Medical School and Cold Spring Harbor Laboratory. We are supported by leading life science investors SV Health Investors, Johnson & Johnson Innovation – JJDC, Inc., Forbion, GV (formerly Google Ventures) and Northpond Ventures. Mestag is headquartered in Cambridge, UK, and in 2021 was recognized on the Fierce 15 list of innovative biotechnology companies. For further information please visit our website www.mestagtherapeutics.com For enquiries, please contact: Alexandra Santosasantos@wheelhouselsa.com

--Chicken-derived chaperone molecule, as well as human variant, enhanced the loading of peptides across HLA types, which could assist applications from cell therapy to vaccines— PHILADELPHIA, Feb. 24, 2023 /PRNewswire/ -- Researchers at Children's Hospital of Philadelphia (CHOP) have identified variants of a chaperone molecule that optimizes the binding and presentation of foreign antigens across the human population, which could open the door to numerous applications where robust presentation to the immune system is important, including cell therapy and immunization. The findings were published today in Science Advances. Class I major histocompatibility complex (MHC-I) proteins are found on the surface of cells from all jawed vertebrates and play an essential role in the immune system. The MHC-I displays peptide fragments of proteins from within the cell on the cell surface, effectively "presenting" them to the immune system, which is constantly scanning the body for foreign or toxic antigens. When foreign peptides are identified, they trigger a cascade that allows cytotoxic T cells to eliminate intruders. For a peptide to be presented to the immune system, it needs to be loaded on a folded MHC-I protein. Several molecules facilitate this process, including proteins known as molecular chaperones, which assist with MHC-I folding. Tapasin and a similar molecule known as TAPBPR are both molecular chaperones that facilitate MHC-I folding and peptide loading. Because TAPBR functions independently outside of the peptide-loading complex, it is well-suited for clinical applications that involve peptide exchange, such as loading immunogenic peptides on MHC-I molecules and generating libraries to detect T-cells that recognize peptides or antigens from infected or cancerous cells. However, TAPBPR-mediated peptide exchange has thus far only worked for a limited set of common allotypes of human MHC-I, known as human leukocyte antigen (HLA), which has limited wider use of these technologies in biomedical applications. Over time, HLA subtypes, which include HLA-A, HLA-B, and HLA-C, have evolved such that not all alleles interact equally well with TAPBPR. This has been a roadblock in developing and enhancing novel therapies with the help of molecular chaperones, as some HLA allotypes do not interact with these molecules. To solve this problem, the CHOP researchers analyzed three different TAPBPR proteins: one from humans, one from chickens, and one from mice. They found that unlike human TAPBPR, chicken TAPBPR co-evolved with its class I genes, so that it maintains high affinity across MHC-I allotypes. In their analysis, they found that chicken TAPBPR was able to react with multiple HLA allotypes, many of which were not able to bind to human TAPBPR. They also demonstrated that TAPBPR stabilizes the empty MHC-I groove in an "open" conformation, boosting its affinity for peptide loading. Simultaneously, in close collaboration with researchers at the University of Illinois led by Erik Procko, PhD, the research team used deep mutational scanning to characterize the effects from 100s of point mutations on human TAPBPR and found a variant that mimics the chicken sequence. Like the chicken TAPBPR, this variant enhanced peptide exchange across a broad range of HLA types. "Although the highly polymorphic nature of MHC-I molecules makes it challenging to engineer 'universal' chaperones, our research team demonstrated that both a chicken ortholog of TAPBPR and a human variant with minor adjustments could enhance peptide exchange across multiple disease-relevant HLAs," said senior author Nikolaos G. Sgourakis, PhD, Associate Professor in the Center for Computational and Genomic Medicine at Children's Hospital of Philadelphia. "These TAPBPR orthologs could be utilized in various cancer immunotherapeutic settings to narrow the peptide repertoire and increase immunogenicity. The knowledge gained by our studies can guide the design of engineered TAPBPR variants with tailored HLA specificity and catalytic efficiency for peptide exchange applications both in vitro and in vivo." This research was supported by funding from the National Institute of Allergy and Infectious Diseases (5R01AI143997) and National Institute of General Medical Sciences (5R35GM125034). Yi Sun, Georgia F. Papadaki, Christine A. Devlin, Julia N. Danon, Michael C. Young, Trenton J. Winters, George M. Burslem, Erik Procko, and Nikolaos G. Sgourakis. "Xeno-interactions between MHC-I proteins and molecular chaperones enable ligand exchange on a broad repertoire of HLA allotypes," Science Advances, February 24, 2023, DOI: 10.1126/sciadv.ade7151 About Children's Hospital of Philadelphia: A non-profit, charitable organization, Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the 595-bed hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey, as well as a new inpatient hospital with a dedicated pediatric emergency department in King of Prussia. In addition, its unique family-centered care and public service programs have brought Children's Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit . Contact: Dana Bate Children's Hospital of Philadelphia (267) 426-6055 [email protected] SOURCE Children's Hospital of Philadelphia

A team of researchers has finally identified the molecular mechanism by which a key protein regulates LDL cholesterol. In a crucial step towards understanding the mechanisms involved in cardiovascular disease and certain cancers, a Canadian led research team has succeeded in a world first: they've found the molecular mechanism by which the protein PCSK9 degrades the receptor of low density lipoproteins, the richest cholesterol particles in the bloodstream. The discovery by Nabil G. Seidah, director of the biochemical neuroendocrinology research unit at the Montreal Clinical Research Institute and a medical professor at Université de Montréal, is published in the January issue of Molecular Metabolism. His work was done in collaboration with Carole Fruchart Gaillard and colleagues at the Université de Paris-Saclay's Department of Drugs and Technologies for Health, as well as with scientists in the pharmacy department of the University of Pisa, in Italy. Low density lipoproteins, or LDL, can accumulate in the blood and lead to atherosclerosis and heart disease. The level of LDL and the cholesterol associated with it (LDLc), is directly modulated by the ability of LDL receptors (LDLR) to collect LDL from the bloodstream and internalize it, mainly into the cells of the liver. The surface LDLR drives LDL into the cell where it is captured, and the LDLR returns to the surface for another round of capture. Rare cases linked to the PCSK9 protein Most cases of familial hypercholesterolemia are related to LDLR dysfunction. But rarer cases have been linked to the PCSK9 protein, which Seidah's laboratory's discovered in 2003. PCSK9 is also present in the bloodstream where it associates with LDLR and promotes its degradation by liver cells, preventing it from returning to the surface to capture LDL. Some hypercholesterolemic patients have a "super PCSK9" that enhances the degradation of the LDLR. In recent years, highly effective treatments have been available to patients that inhibit the function (called monoclonal antibody) or reduce the level (called RNAi) of PCSK9 in the bloodstream, resulting in larger amounts of LDLR that ensure a decrease in LDLc of more than 60 per cent compared to conventional statins. Now the work of Seidah and his team lifts the veil on the previously misunderstood mechanism by which PCSK9 drags the LDLR towards the lysosomes, where cells degrade the PCSK9-LDLR complex. A complex of three partner proteins In their lab, Seidah and his team conducted structural analyses that revealed the formation of a complex of three PCSK9 partner proteins, including the LDLR, CAP1 and HLA-C. A key protein in the immune system, HLA-C was found to play a critical role: it directs the entire complex to the lysosomes. HLA-C allows the recognition of the "self," and also stimulates the anti-tumor activity of T lymphocytes. PCSK9, for its part, helps protect against the growth of tumours and associated metastasis by increasing the level of HLA-C on the cell surface. Ultimately, the hope is that inhibitors can be developed that would prevent the interaction of PCSK9 and HLA-C and block the function of PCSK9 on LDLR and HLA-C. That breakthrough could then be applied in clinical practice to treat cardiovascular pathologies as well various types of cancer and metastases in patients.