Molecular Therapy最新文献_第2页

Unveiling New Insights into Extracellular Vesicles in Metastatic Cancer: A Journey from Mechanisms to Diagnostics and Targeted Therapies. 揭示转移性癌症细胞外囊泡的新见解：从机制到诊断和靶向治疗的旅程。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-07-17 DOI: 10.1016/j.ymthe.2025.07.016

Yaoqi Gui,Meixi Peng,Yongxiu Huang,Zhengyu Chen,Jianfeng Chen,Jianwen Xiao,Dan Liu,Yu Hou

引用次数: 0

Pluripotent Stem Cell-Based Approaches for Heart Repair and the Potential of Genetic Modifications. 基于多能干细胞的心脏修复方法和基因修饰的潜力。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-07-17 DOI: 10.1016/j.ymthe.2025.07.009

Józef Dulak,Tomasz Zieliński,Alicja Józkowicz,Agnieszka Łoboda

{"title":"Pluripotent Stem Cell-Based Approaches for Heart Repair and the Potential of Genetic Modifications.","authors":"Józef Dulak,Tomasz Zieliński,Alicja Józkowicz,Agnieszka Łoboda","doi":"10.1016/j.ymthe.2025.07.009","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.07.009","url":null,"abstract":"The limited regenerative capacity of the heart contributes to the pathology of heart failure, a growing global challenge in aging societies, particularly in the absence of effective treatments for advanced stages of the disease. With heart transplants constrained by donor shortages, alternative therapies are needed. Cellular therapies, particularly using induced pluripotent stem cells (iPSCs), show promise in producing functional cardiomyocytes and other cardiac cell types, driving preclinical and clinical studies. This review addresses the challenges inherent in using pluripotent stem cell-based approaches for heart repair. Key issues include developing efficient methods for the large-scale production of mature cardiomyocytes, particularly those with properties that minimize the risk of engraftment arrhythmias, and enhancing the proliferation and engraftment efficacy of transplanted cells while mitigating the risk of overproliferation. The review highlights how genetic modifications of pluripotent stem cell-derived cardiomyocytes can improve transplantation outcomes. Additionally, it examines the potential of pluripotent stem cell-derived progenitors and the co-delivery of cardiomyocytes with endothelial cells to overcome inadequate engraftment, vascularization, and arrhythmias observed when cardiomyocytes are delivered alone.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"109 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664212","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}

引用次数: 0

Intra-arterial transplantation of autologous mesoangioblasts in m.3243A>G mutation carriers is safe – first phase I/II human clinical study m.3243A>G突变携带者动脉内移植自体间血管母细胞是安全的- I/II期人类临床研究

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-07-17 DOI: 10.1016/j.ymthe.2025.07.005

Florence H.J. van Tienen, Janneke G.J. Hoeijmakers, Christiaan van der Leij, Erika Timmer, Nikki Wanders, Patrick J. Lindsey, Fangzheng Yi, Fong Lin, Susanne P.M. Kortekaas, Helene Roelofs, Inge M. Westra, Pauline Meij, Lambert A.C.M. Wijnen, Irenaeus F.M. de Coo, Hubert J.M. Smeets

{"title":"Intra-arterial transplantation of autologous mesoangioblasts in m.3243A>G mutation carriers is safe – first phase I/II human clinical study","authors":"Florence H.J. van Tienen, Janneke G.J. Hoeijmakers, Christiaan van der Leij, Erika Timmer, Nikki Wanders, Patrick J. Lindsey, Fangzheng Yi, Fong Lin, Susanne P.M. Kortekaas, Helene Roelofs, Inge M. Westra, Pauline Meij, Lambert A.C.M. Wijnen, Irenaeus F.M. de Coo, Hubert J.M. Smeets","doi":"10.1016/j.ymthe.2025.07.005","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.07.005","url":null,"abstract":"Progressive myopathy and exercise intolerance significantly impair quality of life in over 50% of m.3243A>G mutation carriers, with no curative therapy currently available. We hypothesize that intra-arterial administration of autologous, mtDNA mutation-free myogenic stem cells, mesoangioblasts, can reduce mutation load, enhance oxidative phosphorylation, and improve muscle function. To test this, the tibialis anterior muscles of three m.3243A>G mutation carriers were damaged by eccentric exercise before infusion of 50 million /kg autologous mesoangioblasts into the left anterior tibial artery. The right tibialis anterior muscle served as control. Expanded mesoangioblasts had a mutation load of <15%, though culturing increased this by 7–15%. Infusion caused mild, transient discomfort without serious adverse events or vascular obstructions, as confirmed by angiography. Blood and muscle biopsies revealed no systemic or local inflammation at 24 hours and 4 weeks post-transplantation. Biopsies of the treated muscle suggested mesoangioblast migration and early signs of regeneration. This first-in-human study demonstrates that intra-arterial administration of autologous mesoangioblasts is safe, with promising, though inconclusive, evidence for muscle regeneration and mesoangioblast homing. These findings support further investigation into the therapeutic potential of mesoangioblasts for treating myopathy in m.3243A>G mutation carriers.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"35 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664775","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}

引用次数: 0

Efficient in vivo generation of CAR T cells using a retargeted 4th generation lentiviral vector. 利用重定向的第四代慢病毒载体高效地在体内生成CAR - T细胞。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-07-16 DOI: 10.1016/j.ymthe.2025.07.006

Tiziana Coradin,Amy L Keating,Alun R Barnard,Lynsey Whilding,Diana Pombal,Zara Hannoun,Jack Lewis,Gayathri Devarajan,Sharifah Iqball,Emma Burton,Sara Ferluga,Daniel M Jones,Ben M Alberts,Jordan Wright,Daniel C Farley,Deirdre M O'Connor,Ravi M Rao,Kyriacos A Mitrophanous,Yatish Lad,Rachael Nimmo

{"title":"Efficient in vivo generation of CAR T cells using a retargeted 4th generation lentiviral vector.","authors":"Tiziana Coradin,Amy L Keating,Alun R Barnard,Lynsey Whilding,Diana Pombal,Zara Hannoun,Jack Lewis,Gayathri Devarajan,Sharifah Iqball,Emma Burton,Sara Ferluga,Daniel M Jones,Ben M Alberts,Jordan Wright,Daniel C Farley,Deirdre M O'Connor,Ravi M Rao,Kyriacos A Mitrophanous,Yatish Lad,Rachael Nimmo","doi":"10.1016/j.ymthe.2025.07.006","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.07.006","url":null,"abstract":"CAR T cell therapy has proven remarkably successful for the treatment of haematological malignancies. However, the bespoke manufacturing of autologous CAR T cells is complex and expensive. The development of methods for in vivo engineering of T cells will enable generation of CAR T cells directly within the patient, bypassing the need for ex vivo manufacturing thereby enabling greater access for patients. Here we describe development of an improved retargeted Nipah envelope system paired with a 4th generation lentiviral vector capable of specifically targeting T cells with increased efficiency, which generates high levels of functional CAR T cells in vivo. The retargeted vectors exhibited greater specificity to T cells compared to the VSV-G-pseudotyped vector. Vectors targeted to either CD3 or CD8 similarly generated high levels of CAR T cells which rapidly eradicated B cells suggesting that TCR engagement is not required for lentiviral vectors to efficiently transduce T cells in vivo. Furthermore, the 4th generation lentiviral vector platform (referred to as TetraVecta™ system) employs the TRiP system™ to prevent incorporation of CAR protein into the vector particles, minimizing the risk of inadvertent transduction of tumour cells.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"2 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652733","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}

引用次数: 0

HSC Engraftment is Enhanced by Combining Mobilization with Anti-C-Kit and Anti-CD47 Based Conditioning in Hematopoietic Stem Cell Transplantation. 造血干细胞移植中联合动员、抗c - kit和抗cd47调节促进造血干细胞植入

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-07-16 DOI: 10.1016/j.ymthe.2025.07.012

Isabel Ojeda-Perez,Omaira Alberquilla-Fernandez,Aida García-Torralba,Mercedes Lopez-Santalla,Rebeca Sánchez-Domínguez,Jose-Carlos Segovia

{"title":"HSC Engraftment is Enhanced by Combining Mobilization with Anti-C-Kit and Anti-CD47 Based Conditioning in Hematopoietic Stem Cell Transplantation.","authors":"Isabel Ojeda-Perez,Omaira Alberquilla-Fernandez,Aida García-Torralba,Mercedes Lopez-Santalla,Rebeca Sánchez-Domínguez,Jose-Carlos Segovia","doi":"10.1016/j.ymthe.2025.07.012","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.07.012","url":null,"abstract":"A significant limitation of hematopoietic stem cell transplantation (HSCT) that reduces its application across more disease areas and more geographically diverse populations is the toxicity from chemotherapy-based conditioning. A potential solution is to replace chemotherapy with monoclonal antibodies, but the replacement must result in therapeutically relevant levels of engraftment. In some cases, this level of engraftment can be quite low (<10%) but in others situations must be significantly higher. Naked monoclonal antibody therapy (without using a potentially toxic drug conjugate) alone has been inconsistent in generating high levels of engraftment. Agents that mobilize hematopoietic stem and progenitor cells (HSPCs) out of the bone marrow niche are safely used as a method to harvest HSPCs as a source of cells for HSCT. We hypothesized that mobilization might sensitize HSPCs to monoclonal antibody depletion to facilitate high levels of donor cell engraftment. We provide evidence to support this hypothesis by showing in different mouse models of HSCT that mobilization consistently, safely and reproducibly generates higher levels of engraftment when combined with a specific monoclonal antibody conditioning cocktail compared to monoclonal antibody therapy alone. This combination therapy is a promising approach to allowing HSCT to be applied to more diseases and broader populations than current chemotherapy-based conditioning permits.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"7 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652732","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}

引用次数: 0

Exendin-4 enhances insulin-positive phenotype of human pluripotent stem cell-derived β cells during transplantation. Exendin-4增强人多能干细胞来源的β细胞在移植过程中的胰岛素阳性表型。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-07-16 DOI: 10.1016/j.ymthe.2025.07.015

Kelly M Crumley,Elizabeth J Bealer,Anne C Lietzke,Scott A Soleimanpour,Lonnie D Shea

{"title":"Exendin-4 enhances insulin-positive phenotype of human pluripotent stem cell-derived β cells during transplantation.","authors":"Kelly M Crumley,Elizabeth J Bealer,Anne C Lietzke,Scott A Soleimanpour,Lonnie D Shea","doi":"10.1016/j.ymthe.2025.07.015","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.07.015","url":null,"abstract":"An emerging technique for the treatment of type 1 diabetes, which is characterized by hyperglycemia resulting from the loss of insulin-secreting β cells, involves transplantation of human pluripotent stem cell (hPSC)-derived β cells. This transplantation procedure can induce normoglycemia, yet the efficiency of cell survival and function post transplantation remain opportunities for improvement. Here, we investigated treatment with Exendin-4, a GLP-1 receptor agonist, throughout the post-transplantation period to improve the survival and function of transplanted cells. hPSC-derived β cell clusters were transplanted on microporous PLG scaffolds into the peritoneal fat, with Exendin-4 delivery resulting in a more rapid restoration of normoglycemia relative to control. We interrogated multiple avenues by which Exendin-4 enhanced transplantation, and observed a higher rate of cell survival, increased expression of maturation markers and greater metabolic outputs than untreated cells. Collectively, Exendin-4 delivered alongside hPSC-derived β cell transplantation decreased time to improved blood glucose levels and enhanced β cell number, differentiation, and maturation.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"33 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652800","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}

引用次数: 0

GDF11 secreting cell transplant efficiently ameliorates age-related pulmonary fibrosis. GDF11分泌细胞移植可有效改善年龄相关性肺纤维化。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-07-16 DOI: 10.1016/j.ymthe.2025.07.003

Li Guo, Pascal Duchesneau, Eric D Jong, Evan Sawula, Chengjin Li, Thomas K Waddell, Andras Nagy

{"title":"GDF11 secreting cell transplant efficiently ameliorates age-related pulmonary fibrosis.","authors":"Li Guo, Pascal Duchesneau, Eric D Jong, Evan Sawula, Chengjin Li, Thomas K Waddell, Andras Nagy","doi":"10.1016/j.ymthe.2025.07.003","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.07.003","url":null,"abstract":"<p><p>Here, we present a combination of cell and gene therapy that harnesses the regenerative properties of GDF11 in age-related pulmonary fibrosis. Our genome-edited SafeCell-GDF11 mouse ESC line provides controlled proliferation and efficient derivation to lung progenitors while inducibly expressing GDF11. When these cells were transplanted into bleomycin-injured aged mice, they acted as a source of reparative cells, restoring the damaged alveolar epithelium. Furthermore, the transplanted cells acted as an \"in situ factory\", enabling the production of GDF11 in response to the inducer drug. This approach attenuated age-associated senescence and led to the successful resolution of fibrosis. Our study presents a GDF11-expressing cell-based strategy that demonstrates the feasibility of promoting alveolar regeneration in a mouse model of age-related pulmonary fibrosis. Additionally, this approach offers a versatile tool that can be expanded to incorporate other regenerative and anti-aging factors. This helps overcome limitations such as high production costs and a short half-life of therapeutic factors. One of the strengths of our system is its ability to allow precise regulation of factor-expression when needed to address specific aging phenotypes.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659681","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}

引用次数: 0

A BACH1 Inhibitor Ameliorates Myocardial Infarction and Limb Ischemia in Mice. 一种BACH1抑制剂改善小鼠心肌梗死和肢体缺血。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-07-16 DOI: 10.1016/j.ymthe.2025.07.008

Jiayi Lin,Xin Liu,Qinhan Li,Fei Ge,Jinghua Ma,Xianlong Ng,Qi Pan,Xiangxiang Wei,Qingjun Jiang,Jiayu Jin,Siyu Ma,Yunquan He,Yongbo Li,Nan Jiang,Yannan Hou,Yueyang Yu,Xiaoke Lin,Quanshan Jin,Chengguo Xu,Xinhong Wang,Xiuling Zhi,Qianqian Liang,Lindi Jiang,Elena Osto,Jieyu Guo,Xiu-Jie Wang,Dan Meng

{"title":"A BACH1 Inhibitor Ameliorates Myocardial Infarction and Limb Ischemia in Mice.","authors":"Jiayi Lin,Xin Liu,Qinhan Li,Fei Ge,Jinghua Ma,Xianlong Ng,Qi Pan,Xiangxiang Wei,Qingjun Jiang,Jiayu Jin,Siyu Ma,Yunquan He,Yongbo Li,Nan Jiang,Yannan Hou,Yueyang Yu,Xiaoke Lin,Quanshan Jin,Chengguo Xu,Xinhong Wang,Xiuling Zhi,Qianqian Liang,Lindi Jiang,Elena Osto,Jieyu Guo,Xiu-Jie Wang,Dan Meng","doi":"10.1016/j.ymthe.2025.07.008","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.07.008","url":null,"abstract":"The transcription factor BTB and CNC homology 1 (BACH1) is linked to coronary artery disease risk and impairs angiogenesis after ischemic injury. However, there is a scarcity of specific BACH1 inhibitors. This study identifies BI033 as a selective BACH1 inhibitor, confirming its binding to the 91st alanine in BACH1's N-terminal. BI033 shows lower toxicity in human umbilical vein endothelial cells (HUVECs) than the BACH1 inhibitor, HPPE. Intraperitoneal BI033 injections in mice enhance vascular density in the infarct border zone, reduce scar size, and ameliorate contractile dysfunction post-myocardial infarction (MI). Intramuscular injections of BI033 in the ischemic hindlimbs of mice also enhance perfusion and vascular density in the ischemic tissue. Mechanistically, BI033 decreases BACH1's nuclear localization and the enrichment of its target genes like heme oxygenase-1 (HO-1) and vascular endothelial growth factor A (VEGFA), while enhancing Nuclear Factor Erythroid 2-Related Factor 2 (NRF2)'s nuclear accumulation and its enrichment of target genes in HUVECs. Additionally, BI033 reduces BACH1-Histone Deacetylase 1 (HDAC1) interaction, elevating the enrichment of the histone 3 lysine 27 acetylation (H3K27ac) at BACH1 target genes, leading to increased expression of angiogenic-related genes. Thus, the BACH1 inhibitor BI033 could serve as a therapy for MI and peripheral ischemic vascular disease.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"24 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652836","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}

引用次数: 0

Neo-antigen tumor vaccination depends on CD4-licensing conveyed by adeno-associated virus like particles. 新抗原肿瘤疫苗接种依赖于由腺相关病毒样颗粒传递的cd4许可。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-07-16 DOI: 10.1016/j.ymthe.2025.07.014

Lasse Neukirch,Silke Uhrig-Schmidt,Katharina von Werthern,Alexandra Tuch,Joscha A Kraske,Yanhong Lyu,Benedicte Lenoir,Stefan B Eichmüller,Marten Meyer,Inka Zörnig,Dirk Jäger,Patrick Schmidt

{"title":"Neo-antigen tumor vaccination depends on CD4-licensing conveyed by adeno-associated virus like particles.","authors":"Lasse Neukirch,Silke Uhrig-Schmidt,Katharina von Werthern,Alexandra Tuch,Joscha A Kraske,Yanhong Lyu,Benedicte Lenoir,Stefan B Eichmüller,Marten Meyer,Inka Zörnig,Dirk Jäger,Patrick Schmidt","doi":"10.1016/j.ymthe.2025.07.014","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.07.014","url":null,"abstract":"Personalized treatment has become a realistic option for tumor patients, accelerated by significantly reduced sequencing costs of tumor genomes and advances in vaccine formulations. The druggability of cancer neo-antigens caused by individual mutations is centered in this effort. We here use an AAV-based VLP platform to compose a neo-antigen specific protein vaccine that is effective in a murine prevention and treatment setting. Furthermore, we show that CD4+ T cell responses that are provided by the AAV capsid are crucial for an effective murine melanoma treatment. To uncover the optimal composition of a peptide vaccine we de-linked MHC-II helper peptides from the capsid and formulated an efficient neo-antigen specific vaccine, which showed the independence of CD4+ T cell response from tumor sequences. The findings are supported by clinical data of neo-antigen vaccinated tumor patients. Our results punctuate on the significance of MHC-II epitopes for CD8+ T cell responses and suggest a future use of AAVLPs as neo-epitope vaccines in personalized cancer treatments.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"52 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645838","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}

引用次数: 0

Nanobody-Engineered Bispecific IL-18 Mimetics Drive Antitumor Immunity by Engaging CD8+ T Cells and Evading IL-18BP in Preclinical Models. 纳米体工程双特异性IL-18模拟物通过参与CD8+ T细胞和逃避IL-18BP在临床前模型中驱动抗肿瘤免疫

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-07-16 DOI: 10.1016/j.ymthe.2025.07.004

Yanyang Nan,Min Zhu,Qian Wang,Xiaoxue Du,Caili Xu,Yuping Huang,Yujie Liu,Shaoyuan Zhou,Yuluoyan Qiu,Xiao Chu,Dianwen Ju,Yakun Wan,Xuyao Zhang

{"title":"Nanobody-Engineered Bispecific IL-18 Mimetics Drive Antitumor Immunity by Engaging CD8+ T Cells and Evading IL-18BP in Preclinical Models.","authors":"Yanyang Nan,Min Zhu,Qian Wang,Xiaoxue Du,Caili Xu,Yuping Huang,Yujie Liu,Shaoyuan Zhou,Yuluoyan Qiu,Xiao Chu,Dianwen Ju,Yakun Wan,Xuyao Zhang","doi":"10.1016/j.ymthe.2025.07.004","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.07.004","url":null,"abstract":"Cytokines are promising in cancer immunotherapy, but their pleiotropic effects limit specificity and clinical utility. Through binding to IL-18Rα and IL-18Rβ, interleukin-18 (IL-18) stimulates innate lymphocytes and effector T cells for antitumor immunity. However, clinical trials of recombinant IL-18 have been hampered by IL-18 binding protein (IL-18BP), a secreted high-affinity decoy receptor. Here, we developed decoy-resistant bispecific nanobodies that maintain IL-18 signaling potential. Based on agonistic nanobodies targeting IL-18Rα and IL-18Rβ, bispecific nanobody A4B2-mdFc effectively enhanced CD8+ T cells responses with distinct transcriptomic profiles. Systemic delivery of A4B2-mdFc boosted CD8+ T cells infiltration and activation, demonstrating dose-dependent antitumor efficacy in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Interestingly, PDCD1 and CTLA-4 expressions were drastically increased on CD8+ T cells when treated with A4B2-mdFc. Injection of A4B2-mdFc significantly improved the antitumor efficacy of immune checkpoint inhibitors (ICIs) targeting both PD-1 and CTLA-4. Our findings demonstrated that nanobody-based bispecific IL-18 mimetics elicited superior antitumor activity via CD8+ T cells activation and IL-18BP resistance, providing the potential application of cytokine-targeting bispecific nanobody monotherapy or in combination with ICIs for cancer immunotherapy.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"97 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652731","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}

引用次数: 0