CXCR3

A new study has found the immune system in the blood of Alzheimer's patients is epigenetically altered. That means the patients' behavior or environment has caused changes that affect the way their genes work. Many of these altered immune genes are the same ones that increase an individual's risk for Alzheimer's. Scientists now theorize the cause could be a previous viral infection, environmental pollutants or other lifestyle factors and behaviors. A new Northwestern Medicine study has found the immune system in the blood of Alzheimer's patients is epigenetically altered. That means the patients' behavior or environment has caused changes that affect the way their genes work. Many of these altered immune genes are the same ones that increase an individual's risk for Alzheimer's. Northwestern scientists theorize the cause could be a previous viral infection, environmental pollutants or other lifestyle factors and behaviors. "It is possible that these findings implicate the peripheral immune response in Alzheimer's disease risk," said lead investigator David Gate, assistant professor of neurology at Northwestern University Feinberg School of Medicine. "We haven't yet untangled whether these changes are reflective of brain pathology or whether they precipitate the disease." The study was published Feb. 9 in Neuron. Previous research showed that many of the mutated genes putting a person at higher risk for Alzheimer's are in the immune system. But scientists primarily studied the central immune system in the brain because Alzheimer's is a brain disease. They have largely ignored the immune system in the blood, also known as the peripheral immune system. Gate decided to study the blood. He and colleagues discovered every immune cell type in Alzheimer's patients has epigenetic changes, indicated by open chromatin. Chromatin is the packaging of the DNA within cells. When chromatin is open -- or exposed -- the cells' genome is vulnerable to alterations. Then, Gate examined which genes are more open in these immune cells. He discovered that a receptor -- CXCR3 -- on the T cells was more exposed. Gate believes CXCR3 functions like an antenna on T cells that allows the cells to enter the brain. T cells do not normally enter the brain because they can cause inflammation. "The brain is emitting a signal that it is damaged, and the T cells are homing to that signal by their antenna, CXCR3," Gate said. "T cells can be very toxic in the brain, but we also don't know if these cells might be attempting to repair the damage in the brain," Gate said. Gate also discovered epigenetic changes in inflammatory proteins in white blood cells called monocytes. "Altogether, these findings indicate that immune function in Alzheimer's patients is significantly altered," Gate said. "It could be that environmental factors, like pollutants, or infections that a person has in their lifetime cause these epigenetic changes." The findings revealed several genes that may be therapeutic targets for manipulating the peripheral immune system. Next steps in the research are preclinical studies using in vitro culture systems and animal models to test these targets. Other Northwestern authors include Abhirami Ramakrishnan, Natalie Piehl, Brooke Simonton, Milan Parikh, Ziyang Zhang, Victoria Teregulova and Lynn van Olst. The title of the article is "Epigenetic dysregulation in Alzheimer's disease peripheral immunity." The research is supported by National Institute of Neurological Disorders and Stroke grant NS112458 and National Institute on Aging grant AG078713, both of the National Institutes of Health, Bright Focus Foundation, Alzheimer's Association and Cure Alzheimer's Fund.

Human proof of concept portion of the trial expected to begin in H1 2024; led by Georgetown Lombardi Comprehensive Cancer Center BXCL701 in combination with checkpoint inhibitor in preclinical studies demonstrated encouraging results in pancreatic cancer Initial study data expected in 2024 Feb. 06, 2024 -- BioXcel Therapeutics, Inc. (Nasdaq: BTAI), a biopharmaceutical company utilizing artificial intelligence to develop transformative medicines in neuroscience and immuno-oncology, today announced the completion of patient enrollment in the safety lead-in portion of the investigator-sponsored Phase 2 trial of BXCL701 in combination with KEYTRUDA® (pembrolizumab) in previously treated metastatic pancreatic ductal adenocarcinoma (PDAC). BioXcel Therapeutics, through its OnkosXcel Therapeutics immuno-oncology subsidiary, is collaborating with Georgetown Lombardi’s Dr. Louis M. Weiner, director of the cancer center, and Dr. Benjamin Weinberg, the study’s principal investigator. BioXcel Therapeutics and Merck & Co. are providing BXCL701 and KEYTRUDA for the trial, respectively. The trial is evaluating BXCL701, an investigational, oral innate immune activator designed to inflame the tumor microenvironment and thereby augment the activity of checkpoint inhibitors. As part of the trial’s safety lead-in, the first six patients have been enrolled and will be observed for a six-week safety window period. The trial is then expected to enroll approximately 39 patients in its efficacy phase in a Simon 2-stage single-arm, open-label design [19 + 20 patients]. The primary objective is to determine the 18-week progression-free survival rate. Patients will be monitored radiographically and by tumor markers for response assessment. Tumor biopsies and blood samples will also be collected over the course of treatment to better understand the mechanism of how the drug combination works in humans. The human proof of concept portion of the trial is expected to start in H1 2024. “Pancreatic cancer represents a significant unmet medical need, ranking as the third-leading cause of cancer deaths1, yet remains an exceptionally difficult cancer to treat. No novel therapies have emerged in decades, and overall survival for advanced disease has not improved in over 10 years,” said Dr. Weiner. “Building on results from the preclinical work conducted in our lab, we are excited to evaluate BXCL701 in this important trial as a potential treatment for advanced pancreatic cancer.” The American Cancer Society estimates that, in 2024, approximately 66,440 cases of pancreatic cancer will be diagnosed in the United States.2 Few therapeutic options are available for patients with this indication, which has a five-year survival rate of 13%, among the lowest of all cancers.3 Preclinical xenograft models of pancreatic cancer demonstrated strong synergy between BXCL701 and checkpoint inhibitors and reduced tumor growth and promoted an increase in intratumoral T cells, macrophages and NK cells, with induction of host-protective immunity. In addition, preclinical studies showed that BXCL701 has the potential to provide a marked anti-fibrotic effect, as seen in the tumor stroma. These findings have been published in the Journal for ImmunoTherapy of Cancer4, and recently presented at the 2023 annual meeting of the Society for Immunotherapy of Cancer5 “The major challenge in immuno-oncology is cold tumors and their lack of sensitivity to checkpoint therapy,” said Vincent J. O’Neill, M.D., Executive Vice President, Chief of Product Development and Medical Officer of BioXcel Therapeutics. “We have already demonstrated encouraging response rates and survival data in two aggressive forms of prostate cancer: small cell neuroendocrine cancer (SCNC) and adenocarcinoma, as highlighted in our Key Opinion Leader Day presentation last year. This Phase 2 trial marks the third cold tumor setting where we are testing BXCL701 in combination with KEYTRUDA. Based on encouraging preclinical results, we look forward to the results from the human proof of concept efficacy trial evaluating BXCL701 in combination with pembrolizumab in patients with PDAC.” BXCL701 is an investigational, oral innate immune activator designed to initiate inflammation in the tumor microenvironment. Approved and experimental immunotherapies often fail to address cancers that appear “cold.” Therefore, BXCL701 is being evaluated to determine if it can render “cold” tumors “hot,” making them more detectable by the adaptive immune system and thereby facilitating the development of a strong anticancer immune response. OnkosXcel Therapeutics’ preclinical data support BXCL701’s potential synergy with both current checkpoint inhibitors and emerging immunotherapies directed to activate T-cells. BXCL701 is currently being developed as a potential therapy for the treatment of aggressive forms of prostate cancer and advanced solid tumors that are refractory or treatment naïve to checkpoint inhibitors. BXCL701 has received Orphan Drug Designation from the U.S. Food and Drug Administration in four indications: acute myelogenous leukemia, pancreatic cancer, stage IIb to IV melanoma, and soft tissue sarcoma. An 800+-subject clinical database, with data collected by the Company and others, supports the ongoing development of BXCL701. BioXcel Therapeutics, Inc. (Nasdaq: BTAI) is a biopharmaceutical company utilizing artificial intelligence to develop transformative medicines in neuroscience. Its wholly owned subsidiary, OnkosXcel Therapeutics, is focused on the development of medicines in immuno-oncology. The Company’s drug re-innovation approach leverages existing approved drugs and/or clinically validated product candidates together with big data and proprietary machine learning algorithms to identify new therapeutic indications. For more information, please visit bioxceltherapeutics.com. References American Cancer Society: 2024 Estimated Cancer Deaths. https://cancerstatisticscenter.cancer.org/, accessed February 5, 2024 American Cancer Society: Key Statistics for Pancreatic Cancer. https://www.cancer.org/cancer/types/pancreatic-cancer/about/key-statistics.html, accessed February 5, 2024 American Cancer Society: 5-year relative survival rates for pancreatic cancer.https://www.cancer.org/cancer/types/pancreatic-cancer/detection-diagnosis-staging/survival-rates.html, accessed February 5, 2024 Fitzgerald AA, Wang S, Agarwal V, et al. DPP inhibition alters the CXCR3 axis and enhances NK and CD8+ T cell infiltration to improve anti-PD1 efficacy in murine models of pancreatic ductal adenocarcinoma. Journal for ImmunoTherapy of Cancer 2021;9:e002837. doi:10.1136/jitc-2021-002837).https://jitc-bmj-com.libproxy1.nus.edu.sg/content/9/11/e002837.info, accessed February 5, 2024 Dipeptidyl peptidase 4 (DPP4) inhibition is not solely responsible for the antitumor effects of BXCL701, an inhibitor of multiple DPPs, in a murine model of pancreatic ductal adenocarcinoma (PDAC). Alexander Lekan, Rachael Maynard, Zoe X. Malchiodi, Annie Zuo, Sandra A. Jablonski, Veena Agarwal, Moses Donkor, Vincent O’Neill, and Louis M. Weine. Poster presented at the 38th Annual Meeting of the Society for Immunotherapy of Cancer, November 01-05, 2023, San Diego, CA. chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https:/ir.bioxceltherapeutics.com/static-files/d10d0294-9156-4fe5-8e2a-5f8f665f2e75, accessed February 5, 2024 The content above comes from the network. if any infringement, please contact us to modify.

IRVINE, CA / ACCESSWIRE / November 15, 2023 / GeneTex, a multinational antibody manufacturer, announces a new addition to its growing product line of validated recombinant monoclonal antibodies against G protein-coupled receptors (GPCRs). CXC motif chemokine receptor 2 (CXCR2) belongs to the family of 20 human chemokine receptors responsible for signal transduction triggered by the binding of one or more of 46 chemokines. Chemokines and their respective receptors, which normally are involved in the immune response, are also active in a plethora of diseases, including inflammatory and autoimmune disorders, neurological disease, and solid and hematologic cancers, among others. Though there is a significant body of literature on chemokines, there are fewer studies on the receptors. Novel reagents that are specific for particular CXC (and other chemokine) receptors are essential to promote additional research. CXCR2 Antibody [HL2604] Validation CXCR2 Antibody [HL2604] testing on GPCR array, IHC analysis, and Western blot analysis. Human GPCRs are expressed by over 820 genes that code for highly dynamic, seven-transmembrane domain proteins that respond to ligands of various types. GPCRs elicit profound physiological and pathophysiological effects that are relevant to many chronic diseases, including type 2 diabetes mellitus, malignancies, mood disorders, obesity, and neurodegenerative disease. Approximately 350 of the non-olfactory GPCRs are considered amenable to pharmaceutical intervention, though the vast majority remain without available drugs. Research into GPCR biology is of great importance, and GeneTex is committed to producing a comprehensive GPCR antibody portfolio to promote this work. Due to well-known technical challenges associated with antibody development for specific GPCR targets, GeneTex employs enhanced and/or novel validation modalities to establish specificity among GPCR family members, particularly those that share sequence identity. These strategies include knockout/knockdown testing, immunohistochemistry (IHC) or immunocytochemistry (ICC/IF) staining of tissues/cells with differential target expression, and comparison of signals between antibodies against the same target, among other approaches. In addition, GeneTex is incorporating the innovative VirDTM-GPCR arrays (CDI Labs, Baltimore, MD) to determine specificity. In the case of the new recombinant monoclonal CXCR2 antibody (GTX639056), this array demonstrates absolute specificity for CXCR2, with no cross-reactivity detected for CXCR1, CXCR3, CXCR4, CXCR5, and CXCR6. This is particularly significant as CXCR1 and CXCR2 share the highest similarity with ~77% sequence identity. This array data is complemented by both western blot (WB) and IHC validation. As expected, the WB shows a significantly more robust signal in a "membrane extract" fraction compared to the matching "whole cell extract" sample. For IHC, human pancreatic cancer tissue staining reveals the anticipated signal enrichment in the cytoplasm and at the cell membrane. GeneTex is committed to providing the most extensive and thoroughly validated recombinant monoclonal antibody repertoire for GPCR proteins. For the chemokine receptors specifically, efforts are currently underway to broaden the catalog of reagents against the remaining CXC, CC, CX3C, and XC receptors. This same large-scale approach will be applied to all six families of proteins within the GPCR superfamily. Contact Information Allen Lee Vice President - Business Development allensl@genetex.com (949)553-1900 SOURCE: GeneTex, Inc. View source version on accesswire.com: