Pub Date : 2025-03-12DOI: 10.1126/scitranslmed.adm8961
Hsuan-Yuan Wang, Husam Taher, Craig N. Kreklywich, Kimberli A. Schmidt, Elizabeth A. Scheef, Richard Barfield, Claire E. Otero, Sarah M. Valencia, Ke Zhang, Claire Callahan, Francesco Monticolo, Yueqing Qiao, Roxanne M. Gilbride, Chelsea M. Crooks, Anne Mirza, Kelsey Knight, Matilda J. Moström, Tabitha D. Manuel, Lesli Sprehe, Savannah Kendall, Nathan Vande Burgt, Timothy F. Kowalik, Peter A. Barry, Scott G. Hansen, Jian Shu, Alice F. Tarantal, Cliburn Chan, Daniel N. Streblow, Louis J. Picker, Amitinder Kaur, Klaus Früh, Sallie R. Permar, Daniel Malouli
Congenital cytomegalovirus (cCMV) is the leading infectious cause of neonatal neurological impairment worldwide, but the viral factors enabling vertical spread across the placenta remain undetermined. The pentameric complex (PC), composed of the subunits gH/gL/UL128/UL130/UL131A, has been demonstrated to be important for entry into nonfibroblast cells in vitro. These findings link the PC to broad cell tropism and virus dissemination in vivo, denoting all subunits as potential targets for intervention strategies and vaccine development. To determine the relevance of the PC for congenital transmission in a translational nonhuman primate model, we engineered a rhesus CMV (RhCMV) mutant lacking the orthologs of UL128 and UL130, which demonstrated diminished infection of epithelial cells in vitro. However, intravenous inoculation of either CD4 + T cell–depleted or immunocompetent RhCMV-seronegative pregnant rhesus macaques (RMs) in the early second trimester with the PC-deficient mutant resulted in maternal RhCMV peak plasma viremia similar to inoculations with PC-intact RhCMV, although virus shedding in saliva and urine was limited. Infections with the PC-intact virus induced IgG responses that neutralized RhCMV entry into epithelial cells in tissue culture. These responses were reduced, but not absent, from animals infected with the PC-deficient virus, which also induced IgG responses against gH. Moreover, congenital CMV transmission was confirmed in multiple animals infected with PC-deficient virus by detecting viral DNA in the amniotic fluid, indicating that transplacental transmission in RMs is not contingent on the PC.
{"title":"The pentameric complex is not required for congenital CMV transmission in seronegative rhesus macaques","authors":"Hsuan-Yuan Wang, Husam Taher, Craig N. Kreklywich, Kimberli A. Schmidt, Elizabeth A. Scheef, Richard Barfield, Claire E. Otero, Sarah M. Valencia, Ke Zhang, Claire Callahan, Francesco Monticolo, Yueqing Qiao, Roxanne M. Gilbride, Chelsea M. Crooks, Anne Mirza, Kelsey Knight, Matilda J. Moström, Tabitha D. Manuel, Lesli Sprehe, Savannah Kendall, Nathan Vande Burgt, Timothy F. Kowalik, Peter A. Barry, Scott G. Hansen, Jian Shu, Alice F. Tarantal, Cliburn Chan, Daniel N. Streblow, Louis J. Picker, Amitinder Kaur, Klaus Früh, Sallie R. Permar, Daniel Malouli","doi":"10.1126/scitranslmed.adm8961","DOIUrl":"https://doi.org/10.1126/scitranslmed.adm8961","url":null,"abstract":"Congenital cytomegalovirus (cCMV) is the leading infectious cause of neonatal neurological impairment worldwide, but the viral factors enabling vertical spread across the placenta remain undetermined. The pentameric complex (PC), composed of the subunits gH/gL/UL128/UL130/UL131A, has been demonstrated to be important for entry into nonfibroblast cells in vitro. These findings link the PC to broad cell tropism and virus dissemination in vivo, denoting all subunits as potential targets for intervention strategies and vaccine development. To determine the relevance of the PC for congenital transmission in a translational nonhuman primate model, we engineered a rhesus CMV (RhCMV) mutant lacking the orthologs of UL128 and UL130, which demonstrated diminished infection of epithelial cells in vitro. However, intravenous inoculation of either CD4 <jats:sup>+</jats:sup> T cell–depleted or immunocompetent RhCMV-seronegative pregnant rhesus macaques (RMs) in the early second trimester with the PC-deficient mutant resulted in maternal RhCMV peak plasma viremia similar to inoculations with PC-intact RhCMV, although virus shedding in saliva and urine was limited. Infections with the PC-intact virus induced IgG responses that neutralized RhCMV entry into epithelial cells in tissue culture. These responses were reduced, but not absent, from animals infected with the PC-deficient virus, which also induced IgG responses against gH. Moreover, congenital CMV transmission was confirmed in multiple animals infected with PC-deficient virus by detecting viral DNA in the amniotic fluid, indicating that transplacental transmission in RMs is not contingent on the PC.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"54 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yiyou Gu, Shakti Singh, Abdullah Alqarihi, Sondus Alkhazraji, Teclegiorgis Gebremariam, Eman G. Youssef, Hong Liu, Xiaomin Fan, Wen-Rong Jiang, David Andes, Terrence R. Cochrane, Julie A. Schwartz, Scott G. Filler, Priya Uppuluri, Ashraf S. Ibrahim
Mucormycosis is a fungal infection caused by Mucorales fungi that cause severe disease and fatality, especially in immunocompromised individuals. Although vaccines and immunotherapeutics have been successful in combating viral and bacterial infections, approved antifungal immunotherapies are yet to be realized. To address this gap, monoclonal antibodies targeting invasive fungal infections have emerged as a promising approach, particularly for immunocompromised patients who are unlikely to maximally benefit from vaccines. The Mucorales spore coat (CotH) proteins have been identified as crucial fungal invasins that bind to glucose-regulated protein 78 (GRP78) and integrins of host barrier cells. Previously, we described a murine monoclonal antibody, anti-CotH C2, which protected diabetic ketoacidosis (DKA) and neutropenic mice from mucormycosis. Here, we advanced the development of the C2 immunoglobulin G1 (IgG1) by humanizing it, establishing a stable Chinese hamster ovary cell line producing the antibody at commercial yields, and carried out optimization of the upstream and downstream manufacturing processes. The resultant humanized IgG1 (VX-01) exhibited a 10-fold increase in binding affinity to CotH proteins and conferred comparable in vitro and in vivo efficacy when compared to C2 antibody. The mechanism of protection was reliant on prevention of angioinvasion and enhancing opsonophagocytic killing. VX-01 demonstrated acceptable safety profiles with no detectable damage to host cells in vitro and weak or moderate binding to only cytoplasmic proteins in ex vivo good laboratory practice–human tissue cross-reactivity studies. Our studies warrant continued development of VX-01 as a promising adjunctive immunotherapy.
{"title":"A humanized antibody against mucormycosis targets angioinvasion and augments the host immune response","authors":"Yiyou Gu, Shakti Singh, Abdullah Alqarihi, Sondus Alkhazraji, Teclegiorgis Gebremariam, Eman G. Youssef, Hong Liu, Xiaomin Fan, Wen-Rong Jiang, David Andes, Terrence R. Cochrane, Julie A. Schwartz, Scott G. Filler, Priya Uppuluri, Ashraf S. Ibrahim","doi":"","DOIUrl":"","url":null,"abstract":"<div >Mucormycosis is a fungal infection caused by Mucorales fungi that cause severe disease and fatality, especially in immunocompromised individuals. Although vaccines and immunotherapeutics have been successful in combating viral and bacterial infections, approved antifungal immunotherapies are yet to be realized. To address this gap, monoclonal antibodies targeting invasive fungal infections have emerged as a promising approach, particularly for immunocompromised patients who are unlikely to maximally benefit from vaccines. The Mucorales spore coat (CotH) proteins have been identified as crucial fungal invasins that bind to glucose-regulated protein 78 (GRP78) and integrins of host barrier cells. Previously, we described a murine monoclonal antibody, anti-CotH C2, which protected diabetic ketoacidosis (DKA) and neutropenic mice from mucormycosis. Here, we advanced the development of the C2 immunoglobulin G1 (IgG1) by humanizing it, establishing a stable Chinese hamster ovary cell line producing the antibody at commercial yields, and carried out optimization of the upstream and downstream manufacturing processes. The resultant humanized IgG1 (VX-01) exhibited a 10-fold increase in binding affinity to CotH proteins and conferred comparable in vitro and in vivo efficacy when compared to C2 antibody. The mechanism of protection was reliant on prevention of angioinvasion and enhancing opsonophagocytic killing. VX-01 demonstrated acceptable safety profiles with no detectable damage to host cells in vitro and weak or moderate binding to only cytoplasmic proteins in ex vivo good laboratory practice–human tissue cross-reactivity studies. Our studies warrant continued development of VX-01 as a promising adjunctive immunotherapy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 789","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Deshka S. Foster, Jason L. Guo, Emily Meany, Charlotte E. Berry, Mahsa Fallah, Maria Korah, Michael Januszyk, Khristian Erich Bauer-Rowe, David M. Lopez, Christian M. Williams, Rachel Song, Michelle Griffin, Alexia Kim, Malini S. Chinta, Clement D. Marshall, Derrick C. Wan, Jeong S. Hyun, Gerlinde Wernig, Jeffrey A. Norton, Eric A. Appel, Daniel Delitto, Michael T. Longaker
Postoperative abdominal adhesions are the leading cause of bowel obstruction and a cause of chronic pain and infertility. Adhesion formation occurs after 50 to 90% of abdominal operations and has no proven preventative or treatment strategy. Abdominal adhesions derive primarily from the visceral peritoneum and are composed of polyclonally proliferating tissue-resident fibroblasts. We have previously shown that signaling of the transcription factor JUN regulates adhesiogenesis and that a small-molecule JUN inhibitor (T-5224) decreases adhesion formation. Here, we encapsulated T-5224 in a shear-thinning hydrogel with antiadhesion properties for intraperitoneal postoperative delivery and sustained release of a JUN inhibitor for adhesion prevention. The material properties of the T-5224–hydrogel support its use for open or minimally invasive surgical application. We found this therapeutic system to be safe, well tolerated, and efficacious in murine and porcine preclinical models. T-5224–hydrogel minimized adhesion quantity and also diminished adhesion fibrosis at an ultrastructural level. Moving toward clinical translation, we developed a large mammal adhesion model in pigs with bowel resection. Single-cell transcriptomic analysis showed that JUN and associated pathway signaling were diminished in adhesion-derived fibroblasts treated with T-5224–hydrogel. The JUN-inhibiting T-5224–hydrogel provided robust prevention of adhesion without deleterious effects on bowel anastomosis or abdominal wall healing. Adhesion biology is similar across surgical sites, and, therefore, this formulation has potential for applicability across the body. The development of therapeutics to prevent adhesions is of paramount importance with potential for high-impact translation to patient care to address a common, unmet clinical need.
{"title":"Postoperative adhesions are abrogated by a sustained-release anti-JUN therapeutic in preclinical models","authors":"Deshka S. Foster, Jason L. Guo, Emily Meany, Charlotte E. Berry, Mahsa Fallah, Maria Korah, Michael Januszyk, Khristian Erich Bauer-Rowe, David M. Lopez, Christian M. Williams, Rachel Song, Michelle Griffin, Alexia Kim, Malini S. Chinta, Clement D. Marshall, Derrick C. Wan, Jeong S. Hyun, Gerlinde Wernig, Jeffrey A. Norton, Eric A. Appel, Daniel Delitto, Michael T. Longaker","doi":"","DOIUrl":"","url":null,"abstract":"<div >Postoperative abdominal adhesions are the leading cause of bowel obstruction and a cause of chronic pain and infertility. Adhesion formation occurs after 50 to 90% of abdominal operations and has no proven preventative or treatment strategy. Abdominal adhesions derive primarily from the visceral peritoneum and are composed of polyclonally proliferating tissue-resident fibroblasts. We have previously shown that signaling of the transcription factor JUN regulates adhesiogenesis and that a small-molecule JUN inhibitor (T-5224) decreases adhesion formation. Here, we encapsulated T-5224 in a shear-thinning hydrogel with antiadhesion properties for intraperitoneal postoperative delivery and sustained release of a JUN inhibitor for adhesion prevention. The material properties of the T-5224–hydrogel support its use for open or minimally invasive surgical application. We found this therapeutic system to be safe, well tolerated, and efficacious in murine and porcine preclinical models. T-5224–hydrogel minimized adhesion quantity and also diminished adhesion fibrosis at an ultrastructural level. Moving toward clinical translation, we developed a large mammal adhesion model in pigs with bowel resection. Single-cell transcriptomic analysis showed that <i>JUN</i> and associated pathway signaling were diminished in adhesion-derived fibroblasts treated with T-5224–hydrogel. The JUN-inhibiting T-5224–hydrogel provided robust prevention of adhesion without deleterious effects on bowel anastomosis or abdominal wall healing. Adhesion biology is similar across surgical sites, and, therefore, this formulation has potential for applicability across the body. The development of therapeutics to prevent adhesions is of paramount importance with potential for high-impact translation to patient care to address a common, unmet clinical need.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 789","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ning Liu, Yinghua Jiang, Yuwen Xiu, Giovane G. Tortelote, Winna Xia, Yingjie Wang, Yadan Li, Samuel Shi, Jinrui Han, Charles Vidoudez, Aim Niamnud, Mitchell D. Kilgore, Di Zhou, Mengxuan Shi, Stephen A. Graziose, Jia Fan, Prasad V. G. Katakam, Aaron S. Dumont, Xiaoying Wang
Traumatic brain injury (TBI) rapidly triggers proinflammatory activation of microglia, contributing to secondary brain damage post-TBI. Although the governing role of energy metabolism in shaping the inflammatory phenotype and function of immune cells has been increasingly recognized, the specific alterations in microglial bioenergetics post-TBI remain poorly understood. Itaconate, a metabolite produced by the enzyme aconitate decarboxylase 1 [IRG1; encoded by immune responsive gene 1 (Irg1)], is a pivotal metabolic regulator in immune cells, particularly in macrophages. Because microglia are macrophages of the brain parenchyma, the IRG1/itaconate pathway likely modulates microglial inflammatory responses. In this study, we explored the role of the IRG1/itaconate pathway in regulating microglial bioenergetics and inflammatory activation post-TBI using a mouse controlled cortical impact (CCI) model. We isolated microglia before and 4 and 12 hours after TBI and observed a swift but transient increase in glycolysis coupled with a prolonged disruption of mitochondrial metabolism after injury. Despite an up-regulation of Irg1 expression, itaconate in microglia declined after TBI. Microglia-specific Irg1 gene knockout (Irg1-Mi-KO) exacerbated metabolic changes, intensified proinflammatory activation and neurodegeneration, and worsened certain long-term neurological deficits. Supplementation with 4-octyl itaconate (OI) reinstated the use and oxidative metabolism of glucose, glutamine, and fatty acid, thereby enhancing microglial bioenergetics post-TBI. OI supplementation also attenuated proinflammatory activation and neurodegeneration and improved long-term neurological outcomes. These results suggest that therapeutically targeting the itaconate pathway could improve microglial energy metabolism and neurological outcomes after TBI.
{"title":"Itaconate restrains acute proinflammatory activation of microglia MG after traumatic brain injury in mice","authors":"Ning Liu, Yinghua Jiang, Yuwen Xiu, Giovane G. Tortelote, Winna Xia, Yingjie Wang, Yadan Li, Samuel Shi, Jinrui Han, Charles Vidoudez, Aim Niamnud, Mitchell D. Kilgore, Di Zhou, Mengxuan Shi, Stephen A. Graziose, Jia Fan, Prasad V. G. Katakam, Aaron S. Dumont, Xiaoying Wang","doi":"","DOIUrl":"","url":null,"abstract":"<div >Traumatic brain injury (TBI) rapidly triggers proinflammatory activation of microglia, contributing to secondary brain damage post-TBI. Although the governing role of energy metabolism in shaping the inflammatory phenotype and function of immune cells has been increasingly recognized, the specific alterations in microglial bioenergetics post-TBI remain poorly understood. Itaconate, a metabolite produced by the enzyme aconitate decarboxylase 1 [IRG1; encoded by immune responsive gene 1 (<i>Irg1</i>)], is a pivotal metabolic regulator in immune cells, particularly in macrophages. Because microglia are macrophages of the brain parenchyma, the IRG1/itaconate pathway likely modulates microglial inflammatory responses. In this study, we explored the role of the IRG1/itaconate pathway in regulating microglial bioenergetics and inflammatory activation post-TBI using a mouse controlled cortical impact (CCI) model. We isolated microglia before and 4 and 12 hours after TBI and observed a swift but transient increase in glycolysis coupled with a prolonged disruption of mitochondrial metabolism after injury. Despite an up-regulation of Irg1 expression, itaconate in microglia declined after TBI. Microglia-specific <i>Irg1</i> gene knockout (<i>Irg1</i>-Mi-KO) exacerbated metabolic changes, intensified proinflammatory activation and neurodegeneration, and worsened certain long-term neurological deficits. Supplementation with 4-octyl itaconate (OI) reinstated the use and oxidative metabolism of glucose, glutamine, and fatty acid, thereby enhancing microglial bioenergetics post-TBI. OI supplementation also attenuated proinflammatory activation and neurodegeneration and improved long-term neurological outcomes. These results suggest that therapeutically targeting the itaconate pathway could improve microglial energy metabolism and neurological outcomes after TBI.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 789","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-12DOI: 10.1126/scitranslmed.adn2635
Ning Liu, Yinghua Jiang, Yuwen Xiu, Giovane G. Tortelote, Winna Xia, Yingjie Wang, Yadan Li, Samuel Shi, Jinrui Han, Charles Vidoudez, Aim Niamnud, Mitchell D. Kilgore, Di Zhou, Mengxuan Shi, Stephen A. Graziose, Jia Fan, Prasad V. G. Katakam, Aaron S. Dumont, Xiaoying Wang
Traumatic brain injury (TBI) rapidly triggers proinflammatory activation of microglia, contributing to secondary brain damage post-TBI. Although the governing role of energy metabolism in shaping the inflammatory phenotype and function of immune cells has been increasingly recognized, the specific alterations in microglial bioenergetics post-TBI remain poorly understood. Itaconate, a metabolite produced by the enzyme aconitate decarboxylase 1 [IRG1; encoded by immune responsive gene 1 ( Irg1 )], is a pivotal metabolic regulator in immune cells, particularly in macrophages. Because microglia are macrophages of the brain parenchyma, the IRG1/itaconate pathway likely modulates microglial inflammatory responses. In this study, we explored the role of the IRG1/itaconate pathway in regulating microglial bioenergetics and inflammatory activation post-TBI using a mouse controlled cortical impact (CCI) model. We isolated microglia before and 4 and 12 hours after TBI and observed a swift but transient increase in glycolysis coupled with a prolonged disruption of mitochondrial metabolism after injury. Despite an up-regulation of Irg1 expression, itaconate in microglia declined after TBI. Microglia-specific Irg1 gene knockout ( Irg1 -Mi-KO) exacerbated metabolic changes, intensified proinflammatory activation and neurodegeneration, and worsened certain long-term neurological deficits. Supplementation with 4-octyl itaconate (OI) reinstated the use and oxidative metabolism of glucose, glutamine, and fatty acid, thereby enhancing microglial bioenergetics post-TBI. OI supplementation also attenuated proinflammatory activation and neurodegeneration and improved long-term neurological outcomes. These results suggest that therapeutically targeting the itaconate pathway could improve microglial energy metabolism and neurological outcomes after TBI.
{"title":"Itaconate restrains acute proinflammatory activation of microglia MG after traumatic brain injury in mice","authors":"Ning Liu, Yinghua Jiang, Yuwen Xiu, Giovane G. Tortelote, Winna Xia, Yingjie Wang, Yadan Li, Samuel Shi, Jinrui Han, Charles Vidoudez, Aim Niamnud, Mitchell D. Kilgore, Di Zhou, Mengxuan Shi, Stephen A. Graziose, Jia Fan, Prasad V. G. Katakam, Aaron S. Dumont, Xiaoying Wang","doi":"10.1126/scitranslmed.adn2635","DOIUrl":"https://doi.org/10.1126/scitranslmed.adn2635","url":null,"abstract":"Traumatic brain injury (TBI) rapidly triggers proinflammatory activation of microglia, contributing to secondary brain damage post-TBI. Although the governing role of energy metabolism in shaping the inflammatory phenotype and function of immune cells has been increasingly recognized, the specific alterations in microglial bioenergetics post-TBI remain poorly understood. Itaconate, a metabolite produced by the enzyme aconitate decarboxylase 1 [IRG1; encoded by immune responsive gene 1 ( <jats:italic>Irg1</jats:italic> )], is a pivotal metabolic regulator in immune cells, particularly in macrophages. Because microglia are macrophages of the brain parenchyma, the IRG1/itaconate pathway likely modulates microglial inflammatory responses. In this study, we explored the role of the IRG1/itaconate pathway in regulating microglial bioenergetics and inflammatory activation post-TBI using a mouse controlled cortical impact (CCI) model. We isolated microglia before and 4 and 12 hours after TBI and observed a swift but transient increase in glycolysis coupled with a prolonged disruption of mitochondrial metabolism after injury. Despite an up-regulation of Irg1 expression, itaconate in microglia declined after TBI. Microglia-specific <jats:italic>Irg1</jats:italic> gene knockout ( <jats:italic>Irg1</jats:italic> -Mi-KO) exacerbated metabolic changes, intensified proinflammatory activation and neurodegeneration, and worsened certain long-term neurological deficits. Supplementation with 4-octyl itaconate (OI) reinstated the use and oxidative metabolism of glucose, glutamine, and fatty acid, thereby enhancing microglial bioenergetics post-TBI. OI supplementation also attenuated proinflammatory activation and neurodegeneration and improved long-term neurological outcomes. These results suggest that therapeutically targeting the itaconate pathway could improve microglial energy metabolism and neurological outcomes after TBI.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"20 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-12DOI: 10.1126/scitranslmed.ads7369
Yiyou Gu, Shakti Singh, Abdullah Alqarihi, Sondus Alkhazraji, Teclegiorgis Gebremariam, Eman G. Youssef, Hong Liu, Xiaomin Fan, Wen-Rong Jiang, David Andes, Terrence R. Cochrane, Julie A. Schwartz, Scott G. Filler, Priya Uppuluri, Ashraf S. Ibrahim
Mucormycosis is a fungal infection caused by Mucorales fungi that cause severe disease and fatality, especially in immunocompromised individuals. Although vaccines and immunotherapeutics have been successful in combating viral and bacterial infections, approved antifungal immunotherapies are yet to be realized. To address this gap, monoclonal antibodies targeting invasive fungal infections have emerged as a promising approach, particularly for immunocompromised patients who are unlikely to maximally benefit from vaccines. The Mucorales spore coat (CotH) proteins have been identified as crucial fungal invasins that bind to glucose-regulated protein 78 (GRP78) and integrins of host barrier cells. Previously, we described a murine monoclonal antibody, anti-CotH C2, which protected diabetic ketoacidosis (DKA) and neutropenic mice from mucormycosis. Here, we advanced the development of the C2 immunoglobulin G1 (IgG1) by humanizing it, establishing a stable Chinese hamster ovary cell line producing the antibody at commercial yields, and carried out optimization of the upstream and downstream manufacturing processes. The resultant humanized IgG1 (VX-01) exhibited a 10-fold increase in binding affinity to CotH proteins and conferred comparable in vitro and in vivo efficacy when compared to C2 antibody. The mechanism of protection was reliant on prevention of angioinvasion and enhancing opsonophagocytic killing. VX-01 demonstrated acceptable safety profiles with no detectable damage to host cells in vitro and weak or moderate binding to only cytoplasmic proteins in ex vivo good laboratory practice–human tissue cross-reactivity studies. Our studies warrant continued development of VX-01 as a promising adjunctive immunotherapy.
{"title":"A humanized antibody against mucormycosis targets angioinvasion and augments the host immune response","authors":"Yiyou Gu, Shakti Singh, Abdullah Alqarihi, Sondus Alkhazraji, Teclegiorgis Gebremariam, Eman G. Youssef, Hong Liu, Xiaomin Fan, Wen-Rong Jiang, David Andes, Terrence R. Cochrane, Julie A. Schwartz, Scott G. Filler, Priya Uppuluri, Ashraf S. Ibrahim","doi":"10.1126/scitranslmed.ads7369","DOIUrl":"https://doi.org/10.1126/scitranslmed.ads7369","url":null,"abstract":"Mucormycosis is a fungal infection caused by Mucorales fungi that cause severe disease and fatality, especially in immunocompromised individuals. Although vaccines and immunotherapeutics have been successful in combating viral and bacterial infections, approved antifungal immunotherapies are yet to be realized. To address this gap, monoclonal antibodies targeting invasive fungal infections have emerged as a promising approach, particularly for immunocompromised patients who are unlikely to maximally benefit from vaccines. The Mucorales spore coat (CotH) proteins have been identified as crucial fungal invasins that bind to glucose-regulated protein 78 (GRP78) and integrins of host barrier cells. Previously, we described a murine monoclonal antibody, anti-CotH C2, which protected diabetic ketoacidosis (DKA) and neutropenic mice from mucormycosis. Here, we advanced the development of the C2 immunoglobulin G1 (IgG1) by humanizing it, establishing a stable Chinese hamster ovary cell line producing the antibody at commercial yields, and carried out optimization of the upstream and downstream manufacturing processes. The resultant humanized IgG1 (VX-01) exhibited a 10-fold increase in binding affinity to CotH proteins and conferred comparable in vitro and in vivo efficacy when compared to C2 antibody. The mechanism of protection was reliant on prevention of angioinvasion and enhancing opsonophagocytic killing. VX-01 demonstrated acceptable safety profiles with no detectable damage to host cells in vitro and weak or moderate binding to only cytoplasmic proteins in ex vivo good laboratory practice–human tissue cross-reactivity studies. Our studies warrant continued development of VX-01 as a promising adjunctive immunotherapy.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"22 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-12DOI: 10.1126/scitranslmed.adp9957
Deshka S. Foster, Jason L. Guo, Emily Meany, Charlotte E. Berry, Mahsa Fallah, Maria Korah, Michael Januszyk, Khristian Erich Bauer-Rowe, David M. Lopez, Christian M. Williams, Rachel Song, Michelle Griffin, Alexia Kim, Malini S. Chinta, Clement D. Marshall, Derrick C. Wan, Jeong S. Hyun, Gerlinde Wernig, Jeffrey A. Norton, Eric A. Appel, Daniel Delitto, Michael T. Longaker
Postoperative abdominal adhesions are the leading cause of bowel obstruction and a cause of chronic pain and infertility. Adhesion formation occurs after 50 to 90% of abdominal operations and has no proven preventative or treatment strategy. Abdominal adhesions derive primarily from the visceral peritoneum and are composed of polyclonally proliferating tissue-resident fibroblasts. We have previously shown that signaling of the transcription factor JUN regulates adhesiogenesis and that a small-molecule JUN inhibitor (T-5224) decreases adhesion formation. Here, we encapsulated T-5224 in a shear-thinning hydrogel with antiadhesion properties for intraperitoneal postoperative delivery and sustained release of a JUN inhibitor for adhesion prevention. The material properties of the T-5224–hydrogel support its use for open or minimally invasive surgical application. We found this therapeutic system to be safe, well tolerated, and efficacious in murine and porcine preclinical models. T-5224–hydrogel minimized adhesion quantity and also diminished adhesion fibrosis at an ultrastructural level. Moving toward clinical translation, we developed a large mammal adhesion model in pigs with bowel resection. Single-cell transcriptomic analysis showed that JUN and associated pathway signaling were diminished in adhesion-derived fibroblasts treated with T-5224–hydrogel. The JUN-inhibiting T-5224–hydrogel provided robust prevention of adhesion without deleterious effects on bowel anastomosis or abdominal wall healing. Adhesion biology is similar across surgical sites, and, therefore, this formulation has potential for applicability across the body. The development of therapeutics to prevent adhesions is of paramount importance with potential for high-impact translation to patient care to address a common, unmet clinical need.
{"title":"Postoperative adhesions are abrogated by a sustained-release anti-JUN therapeutic in preclinical models","authors":"Deshka S. Foster, Jason L. Guo, Emily Meany, Charlotte E. Berry, Mahsa Fallah, Maria Korah, Michael Januszyk, Khristian Erich Bauer-Rowe, David M. Lopez, Christian M. Williams, Rachel Song, Michelle Griffin, Alexia Kim, Malini S. Chinta, Clement D. Marshall, Derrick C. Wan, Jeong S. Hyun, Gerlinde Wernig, Jeffrey A. Norton, Eric A. Appel, Daniel Delitto, Michael T. Longaker","doi":"10.1126/scitranslmed.adp9957","DOIUrl":"https://doi.org/10.1126/scitranslmed.adp9957","url":null,"abstract":"Postoperative abdominal adhesions are the leading cause of bowel obstruction and a cause of chronic pain and infertility. Adhesion formation occurs after 50 to 90% of abdominal operations and has no proven preventative or treatment strategy. Abdominal adhesions derive primarily from the visceral peritoneum and are composed of polyclonally proliferating tissue-resident fibroblasts. We have previously shown that signaling of the transcription factor JUN regulates adhesiogenesis and that a small-molecule JUN inhibitor (T-5224) decreases adhesion formation. Here, we encapsulated T-5224 in a shear-thinning hydrogel with antiadhesion properties for intraperitoneal postoperative delivery and sustained release of a JUN inhibitor for adhesion prevention. The material properties of the T-5224–hydrogel support its use for open or minimally invasive surgical application. We found this therapeutic system to be safe, well tolerated, and efficacious in murine and porcine preclinical models. T-5224–hydrogel minimized adhesion quantity and also diminished adhesion fibrosis at an ultrastructural level. Moving toward clinical translation, we developed a large mammal adhesion model in pigs with bowel resection. Single-cell transcriptomic analysis showed that <jats:italic>JUN</jats:italic> and associated pathway signaling were diminished in adhesion-derived fibroblasts treated with T-5224–hydrogel. The JUN-inhibiting T-5224–hydrogel provided robust prevention of adhesion without deleterious effects on bowel anastomosis or abdominal wall healing. Adhesion biology is similar across surgical sites, and, therefore, this formulation has potential for applicability across the body. The development of therapeutics to prevent adhesions is of paramount importance with potential for high-impact translation to patient care to address a common, unmet clinical need.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-05DOI: 10.1126/scitranslmed.ads8214
Juyeon Park, Lisa C. Lindesmith, Adam S. Olia, Veronica P. Costantini, Paul D. Brewer-Jensen, Michael L. Mallory, Cynthia E. Kelley, Ed Satterwhite, Victoria Longo, Yaroslav Tsybovsky, Tyler Stephens, Jeffrey Marchioni, Christina A. Martins, Yimin Huang, Ridhi Chaudhary, Mark Zweigart, Samantha R. May, Yaoska Reyes, Becca Flitter, Jan Vinjé, Sean N. Tucker, Gregory C. Ippolito, Jason J. Lavinder, Joost Snijder, Peter D. Kwong, George Georgiou, Ralph S. Baric
Human norovirus causes more than 700 million illnesses annually. Extensive genetic diversity and a paucity of information on conserved neutralizing epitopes pose major obstacles to the design of broadly protective norovirus immunogens. Here, we used high-resolution liquid chromatography–tandem mass spectrometry (LC-MS/MS)–driven proteomics to quantitatively characterize the circulating serum IgG repertoire before and after immunization with an experimental monovalent norovirus GII.4 VP1 capsid–encoding adenoviral vaccine. Two participants were specifically selected on the basis of the breadth of serum neutralization responses either across GII.4 variants (participant A) or across GII genotypes (participant B). In participant A, vaccination back-boosted highly abundant serum antibody clonotypes targeting epitopes conserved among rapidly evolving GII.4 variants spanning from a strain identified in 1987 to a strain identified in 2019. In participant B, we identified a recall response consisting of broadly neutralizing monoclonal antibodies with remarkable cross-GII ligand-binding blockade (blocking ≥ seven GII genotypes) and virus neutralization breadth. The cocrystal structure of one of these antibodies, VX22, in complex with the VP1 capsid protruding (P) domain revealed a highly conserved epitope (residues 479 to 484 and 509 to 513) within two lateral loops of the P1 subdomain. Antibody evolutionary trajectory analysis further revealed that VX22 had originally evolved from an early heterologous infection, likely by a GII.12 strain. Together, our study demonstrates that norovirus human monoclonal antibodies with broad GII.4 potency and cross-GII breadth can be boosted in serum after immunization with an adenoviral vector–based vaccine, findings that may guide the design of immunogens for broadly protective norovirus vaccines.
{"title":"Broadly neutralizing antibodies targeting pandemic GII.4 variants or seven GII genotypes of human norovirus","authors":"Juyeon Park, Lisa C. Lindesmith, Adam S. Olia, Veronica P. Costantini, Paul D. Brewer-Jensen, Michael L. Mallory, Cynthia E. Kelley, Ed Satterwhite, Victoria Longo, Yaroslav Tsybovsky, Tyler Stephens, Jeffrey Marchioni, Christina A. Martins, Yimin Huang, Ridhi Chaudhary, Mark Zweigart, Samantha R. May, Yaoska Reyes, Becca Flitter, Jan Vinjé, Sean N. Tucker, Gregory C. Ippolito, Jason J. Lavinder, Joost Snijder, Peter D. Kwong, George Georgiou, Ralph S. Baric","doi":"10.1126/scitranslmed.ads8214","DOIUrl":"https://doi.org/10.1126/scitranslmed.ads8214","url":null,"abstract":"Human norovirus causes more than 700 million illnesses annually. Extensive genetic diversity and a paucity of information on conserved neutralizing epitopes pose major obstacles to the design of broadly protective norovirus immunogens. Here, we used high-resolution liquid chromatography–tandem mass spectrometry (LC-MS/MS)–driven proteomics to quantitatively characterize the circulating serum IgG repertoire before and after immunization with an experimental monovalent norovirus GII.4 VP1 capsid–encoding adenoviral vaccine. Two participants were specifically selected on the basis of the breadth of serum neutralization responses either across GII.4 variants (participant A) or across GII genotypes (participant B). In participant A, vaccination back-boosted highly abundant serum antibody clonotypes targeting epitopes conserved among rapidly evolving GII.4 variants spanning from a strain identified in 1987 to a strain identified in 2019. In participant B, we identified a recall response consisting of broadly neutralizing monoclonal antibodies with remarkable cross-GII ligand-binding blockade (blocking ≥ seven GII genotypes) and virus neutralization breadth. The cocrystal structure of one of these antibodies, VX22, in complex with the VP1 capsid protruding (P) domain revealed a highly conserved epitope (residues 479 to 484 and 509 to 513) within two lateral loops of the P1 subdomain. Antibody evolutionary trajectory analysis further revealed that VX22 had originally evolved from an early heterologous infection, likely by a GII.12 strain. Together, our study demonstrates that norovirus human monoclonal antibodies with broad GII.4 potency and cross-GII breadth can be boosted in serum after immunization with an adenoviral vector–based vaccine, findings that may guide the design of immunogens for broadly protective norovirus vaccines.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"24 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143561349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-05DOI: 10.1126/scitranslmed.ads0848
Marcus Mumme, Anke Wixmerten, Alan Ivkovic, Giuseppe M. Peretti, Tayfun Yilmaz, Stephan Reppenhagen, Oliver Pullig, Sylvie Miot, Kaywan Izadpanah, Marcel Jakob, Laura Mangiavini, Corrado Sosio, Filip Vuletić, Oliver Bieri, Stefano Biguzzi, Brigitta Gahl, Gyözö Lehoczky, Rudolf Vukojevic, Sebastian Häusner, Anna Gryadunova, Martin Haug, Andrea Barbero, Ivan Martin
Cartilage lesions do not heal spontaneously and predispose to osteoarthritis. Functional cartilage tissues, engineered using autologous chondrocytes, have a therapeutic advantage over conventional cellular therapies in preclinical studies. Here, we tested whether ex vivo maturation of engineered grafts for cartilage repair leads to improved patient benefit. Using autologous nasal chondrocytes (NCs), we tested whether implantation of in vitro–matured NC-tissue-engineered cartilage (N-TEC) versus undifferentiated NC-cell-activated matrices (N-CAM) in focal cartilage lesions would result in a superior clinical outcome. The prospective, randomized, parallel, open-label phase-2 trial ( ClinicalTrials.gov , NCT02673905) enrolled 108 patients in five hospitals from four countries. Patients ranging in age from 30 to 46 years with full-thickness knee cartilage defects (size, 2.7 to 6.0 square centimeters) were equally randomized and treated with N-TEC or N-CAM. The primary preregistered outcome was the overall Knee Injury Osteoarthritis Outcome Score (KOOS) at 24 months. N-TEC, which underwent a longer NC culture time, was phenotypically, structurally, and functionally more like hyaline cartilage than N-CAM. The overall KOOS increased with clinical relevance in both groups compared with preoperative values. KOOS was higher at 24 months for N-TEC [85; interquartile range (IQR), 74 to 91] than for N-CAM (79; IQR, 65 to 85). N-TEC, but not N-CAM, was similarly effective in patients with larger defects or revision surgery. Radiologically, N-TEC resulted in a superior composition of both repair tissue and surrounding cartilage, whereas structural scores were similar. This trial validates the clinical efficacy of NC-based grafts for articular cartilage repair and supports the clinical relevance of engineering mature tissues, even for patients with more challenging cartilage defects.
{"title":"Clinical relevance of engineered cartilage maturation in a randomized multicenter trial for articular cartilage repair","authors":"Marcus Mumme, Anke Wixmerten, Alan Ivkovic, Giuseppe M. Peretti, Tayfun Yilmaz, Stephan Reppenhagen, Oliver Pullig, Sylvie Miot, Kaywan Izadpanah, Marcel Jakob, Laura Mangiavini, Corrado Sosio, Filip Vuletić, Oliver Bieri, Stefano Biguzzi, Brigitta Gahl, Gyözö Lehoczky, Rudolf Vukojevic, Sebastian Häusner, Anna Gryadunova, Martin Haug, Andrea Barbero, Ivan Martin","doi":"10.1126/scitranslmed.ads0848","DOIUrl":"https://doi.org/10.1126/scitranslmed.ads0848","url":null,"abstract":"Cartilage lesions do not heal spontaneously and predispose to osteoarthritis. Functional cartilage tissues, engineered using autologous chondrocytes, have a therapeutic advantage over conventional cellular therapies in preclinical studies. Here, we tested whether ex vivo maturation of engineered grafts for cartilage repair leads to improved patient benefit. Using autologous nasal chondrocytes (NCs), we tested whether implantation of in vitro–matured NC-tissue-engineered cartilage (N-TEC) versus undifferentiated NC-cell-activated matrices (N-CAM) in focal cartilage lesions would result in a superior clinical outcome. The prospective, randomized, parallel, open-label phase-2 trial ( <jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"uri\" xlink:href=\"https://clinicaltrials.gov/search?term=NCT02673905\">ClinicalTrials.gov</jats:ext-link> , NCT02673905) enrolled 108 patients in five hospitals from four countries. Patients ranging in age from 30 to 46 years with full-thickness knee cartilage defects (size, 2.7 to 6.0 square centimeters) were equally randomized and treated with N-TEC or N-CAM. The primary preregistered outcome was the overall Knee Injury Osteoarthritis Outcome Score (KOOS) at 24 months. N-TEC, which underwent a longer NC culture time, was phenotypically, structurally, and functionally more like hyaline cartilage than N-CAM. The overall KOOS increased with clinical relevance in both groups compared with preoperative values. KOOS was higher at 24 months for N-TEC [85; interquartile range (IQR), 74 to 91] than for N-CAM (79; IQR, 65 to 85). N-TEC, but not N-CAM, was similarly effective in patients with larger defects or revision surgery. Radiologically, N-TEC resulted in a superior composition of both repair tissue and surrounding cartilage, whereas structural scores were similar. This trial validates the clinical efficacy of NC-based grafts for articular cartilage repair and supports the clinical relevance of engineering mature tissues, even for patients with more challenging cartilage defects.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"36 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143561351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Adonis A. Rubio, Viren A. Baharani, Bernadeta Dadonaite, Megan Parada, Morgan E. Abernathy, Zijun Wang, Yu E. Lee, Michael R. Eso, Jennie Phung, Israel Ramos, Teresia Chen, Gina El Nesr, Jesse D. Bloom, Paul D. Bieniasz, Michel C. Nussenzweig, Christopher O. Barnes
The ongoing emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized amino-terminal domain (NTD)– and receptor binding domain (RBD)–specific monoclonal antibodies previously isolated from coronavirus disease 2019 (COVID-19) convalescent donors for their activity against emergent SARS-CoV-2 VOCs. Among these, the NTD-specific antibody C1596 displayed the greatest breadth of binding to VOCs, with cryo–electron microscopy structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596’s favorable binding profile, we designed a series of bispecific antibodies (bsAbs), termed CoV2-biRNs, that featured both NTD and RBD specificities. Two of the C1596-inclusive bsAbs, CoV2-biRN5 and CoV2-biRN7, retained potent in vitro neutralization activity against all Omicron variants tested, including XBB.1.5, BA.2.86, and JN.1, contrasting the diminished potency of parental antibodies delivered as monotherapies or as a cocktail. Furthermore, prophylactic delivery of CoV2-biRN5 reduced the viral load within the lungs of K18-hACE2 mice after challenge with SARS-CoV-2 XBB.1.5. In conclusion, NTD-RBD bsAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs.
{"title":"Bispecific antibodies targeting the N-terminal and receptor binding domains potently neutralize SARS-CoV-2 variants of concern","authors":"Adonis A. Rubio, Viren A. Baharani, Bernadeta Dadonaite, Megan Parada, Morgan E. Abernathy, Zijun Wang, Yu E. Lee, Michael R. Eso, Jennie Phung, Israel Ramos, Teresia Chen, Gina El Nesr, Jesse D. Bloom, Paul D. Bieniasz, Michel C. Nussenzweig, Christopher O. Barnes","doi":"","DOIUrl":"","url":null,"abstract":"<div >The ongoing emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized amino-terminal domain (NTD)– and receptor binding domain (RBD)–specific monoclonal antibodies previously isolated from coronavirus disease 2019 (COVID-19) convalescent donors for their activity against emergent SARS-CoV-2 VOCs. Among these, the NTD-specific antibody C1596 displayed the greatest breadth of binding to VOCs, with cryo–electron microscopy structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596’s favorable binding profile, we designed a series of bispecific antibodies (bsAbs), termed CoV2-biRNs, that featured both NTD and RBD specificities. Two of the C1596-inclusive bsAbs, CoV2-biRN5 and CoV2-biRN7, retained potent in vitro neutralization activity against all Omicron variants tested, including XBB.1.5, BA.2.86, and JN.1, contrasting the diminished potency of parental antibodies delivered as monotherapies or as a cocktail. Furthermore, prophylactic delivery of CoV2-biRN5 reduced the viral load within the lungs of K18-hACE2 mice after challenge with SARS-CoV-2 XBB.1.5. In conclusion, NTD-RBD bsAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 788","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adq5720","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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