更新于：2024-11-01

CD45

更新于：2024-11-01

基本信息

别名

白细胞共同抗原、CD45、GP180

+ [7]

简介

Protein tyrosine-protein phosphatase required for T-cell activation through the antigen receptor. Acts as a positive regulator of T-cell coactivation upon binding to DPP4. The first PTPase domain has enzymatic activity, while the second one seems to affect the substrate specificity of the first one. Upon T-cell activation, recruits and dephosphorylates SKAP1 and FYN. Dephosphorylates LYN, and thereby modulates LYN activity (By similarity). (Microbial infection) Acts as a receptor for human cytomegalovirus protein UL11 and mediates binding of UL11 to T-cells, leading to reduced induction of tyrosine phosphorylation of multiple signaling proteins upon T-cell receptor stimulation and impaired T-cell proliferation.

关联

项与 CD45 相关的药物

I-131-Apamistamab

靶点

CD45

作用机制

CD45抑制剂

在研机构

Actinium Pharmaceuticals, Inc.

原研机构

Fred Hutchinson Cancer Research Center

在研适应症

难治性急性髓细胞白血病 [+1]

非在研适应症-

最高研发阶段临床3期

首次获批国家/地区-

首次获批日期1800-01-20

At 211 MAb BC8-B10

靶点

CD45

作用机制

CD45抑制剂 [+1]

在研机构

Fred Hutchinson Cancer Research Center

原研机构

Fred Hutchinson Cancer Research Center

在研适应症

肿瘤

非在研适应症

复发性急性淋巴细胞白血病 [+7]

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

Lomab-ACT

靶点

CD45

作用机制

CD45抑制剂

在研机构

Actinium Pharmaceuticals, Inc.

原研机构

Actinium Pharmaceuticals, Inc.

在研适应症-

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

项与 CD45 相关的临床试验

NCT04512716 / Recruiting早期临床1期IIT

Iomab-ACT: a Pilot Study of 131-I Apamistamab Followed by CD19-Targeted CAR T-Cell Therapy for Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia or Diffuse Large B-Cell Lymphoma

This is a pilot study; patients will receive 131-I apamistamab prior to CAR T-cell infusion in order to determine the maximum tolerated dose of 131-I apamistamab is exceeded at 75 mCi, and if so, to assess the safety of a step-down dose of 50 mCi.

开始日期2021-02-02

申办/合作机构

Memorial Sloan Kettering Cancer Center

NCT04083183 / Suspended临床1/2期IIT

Targeted Astatine-211-Labeled BC8-B10 Monoclonal Antibody as Reduced Intensity Conditioning for Nonmalignant Diseases

This phase I/II trial studies the best dose of total body irradiation with astatine-211 BC8-B10 monoclonal antibody for the treatment of patients with nonmalignant diseases undergoing hematopoietic cell transplant. Radiation therapy uses high energy gamma rays to kill cancer cells and shrink tumors. Astatine-211-labeled BC8-B10 monoclonal antibody is a monoclonal antibody, called anti-CD45 monoclonal antibody BC8-B10, linked to a radioactive/toxic agent called astatine 211. Anti-CD45 monoclonal antibody BC8-B10 is attached to CD45 antigen positive cancer cells in a targeted way and delivers astatine 211 to kill them. Giving astatine-211 BC8-B10 monoclonal antibody and total-body irradiation before a donor stem cell transplant may help stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells.

开始日期2020-06-16

申办/合作机构

Fred Hutchinson Cancer Research Center

[+1]

NCT03670966 / Suspended临床1/2期IIT

A Phase I/II Study Evaluating Escalating Doses of 211At-Labeled Anti-CD45 MAb BC8-B10 (211At-BC8-B10) Followed by Related Haplo-Identical Allogeneic Hematopoietic Cell Transplantation for High-Risk Acute Leukemia or Myelodysplastic Syndrome (MDS)

This phase I/II trial studies the side effects and best dose of a radioactive agent linked to an antibody (211At-BC8-B10) followed by donor stem cell transplant in treating patients with high-risk acute leukemia or myelodysplastic syndrome that has come back (recurrent) or isn't responding to treatment (refractory). 211At-BC8-B10 is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Giving chemotherapy and total body irradiation before a stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can attack the body's normal cells, called graft versus host disease. Giving cyclophosphamide, mycophenolate mofetil, and tacrolimus after a transplant may stop this from happening.

开始日期2019-07-10

申办/合作机构

Fred Hutchinson Cancer Research Center

[+1]

100 项与 CD45 相关的临床结果

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100 项与 CD45 相关的转化医学

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0 项与 CD45 相关的专利（医药）

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15,765

项与 CD45 相关的文献（医药）

2025-03-01·Biomaterials

Reprogramming tumor microenvironment with precise photothermal therapy by calreticulin nanobody-engineered probiotics

Article

作者: Jiang, Yuke ; Long, Ying ; Shi, Guangwei ; Li, Zhijie ; Zhong, Xiaoru ; Huang, Zhenhui ; Yang, Runwei ; Dong, Zhiyu ; Li, Jiexuan ; Wang, Jigang ; Bai, Chongzhi ; Jia, Lin ; Chen, Chunbo ; Wang, Huifang ; Zheng, Liuhai ; Wei, Jinxi ; Dai, Lingyun

Targeted therapies have revolutionized traditional cancer treatments by precisely targeting tumor cells, enhancing efficacy and safety. Despite this advancement, the proportion of cancer patients eligible for such therapies remains low due to the absence of suitable targets. Here, we investigate whether the translocation of the immunogenic cell death (ICD) marker calreticulin (CALR) from the endoplasmic reticulum (ER) to the cell surface following ICD induction can serve as a target for targeted therapies. To target CALR, a nanobody Nb215 identified from a naïve VHH phage library with high binding affinity to both human and mouse CALR was employed to engineer probiotic EcN 1917. Our results demonstrated that CALR nanobody-modified EcN-215 coupled with the photothermal dye indocyanine green (ICG) was able to exert NIR-II imaging-guide photothermal therapy (PTT). Moreover, PTT with EcN-215/ICG can reshape the tumor microenvironment by enhancing the infiltration of CD45⁺CD3⁺ T cells and CD11b⁺F4/80⁺ macrophages. Furthermore, the antitumor activity of CALR-targeted EcN-215/ICG is synergistically enhanced by blocking CD47-SIRPα axis. Collectively, our study provides a proof of concept for CALR-targeted therapy. Given that CALR translocation can be induced by various anticancer therapies across numerous tumor cell lines, CALR-targeted therapies hold promise as a novel approach for treating multiple types of cancers.

2025-01-01·Journal of Affective Disorders

Causal effects of gut microbiota, metabolites, immune cells, liposomes, and inflammatory proteins on anorexia nervosa: A mediation joint multi-omics Mendelian randomization analysis

Article

作者: Bi, Tianyu ; Li, Zeyang

BACKGROUNDAnorexia nervosa (AN) is a significant psychological disorder influenced by environmental and genetic elements. Emerging research highlights the pivotal role of the gut microbiome in the development of diverse mental health conditions. This study aims to explore the causal effects and interactions of the gut microbiome, metabolites, immune cells, lipids, and inflammatory proteins on the risk of anorexia nervosa through mediation and multi-omics Mendelian Randomization (MR) analysis.METHODSThis study used data from the FinnGen genome-wide association study (GWAS) of AN (N = 402,625), integrated with GWAS data on 473 of gut microbiota (N = 5959), 233 metabolites (N = 136,016), 731 immune cells (N = 3757), 179 lipids (N = 7174), and 91 inflammatory proteins (N = 14,824). This study used the univariate MR (UVMR), mediation MR analysis, and sensitivity analysis to assess the potential causal associations between these biomarkers and AN.RESULTSThe inverse variance weighted (IVW) results suggest that 25 gut microbiota have causal effects on AN. Firmicutes E (OR: 0.294, 95 % CI: 0.107-0.806, P = 0.017), RUG147 (OR: 0.386, 95 % CI: 0.151-0.990, P = 0.048), CAG-977 (OR: 0.562, 95 % CI: 0.378-0.837, P = 0.005), Desulfobacterota A (OR: 0.651, 95 % CI: 0.466-0.909, P = 0.012), CAG-269 sp002372935 (OR: 0.673, 95 % CI: 0.483-0.937, P = 0.019), Klebsiella (OR: 0.684, 95 % CI: 0.566-0.827, P = 0.00009), Desulfovibrionia (OR: 0.706, 95 % CI: 0.538-0.926, P = 0.012), Klebsiella pneumoniae (OR: 0.737, 95 % CI: 0.600-0.906, P = 0.004), Desulfovibrionales (OR: 0.786, 95 % CI: 0.631-0.979, P = 0.031), CAG-776 (OR: 0.787, 95 % CI: 0.632-0.980, P = 0.032), Desulfovibrionaceae (OR: 0.788, 95 % CI: 0.635-0.978, P = 0.030). 13 gut microbiota were risk factors for AN, including Parachlamydiales (OR: 3.134，95%CI: 1.185-8.287, P = 0.021), Paenibacillus J (OR: 2.366，95%CI: 1.305-4.29, P = 0.005), Gillisia (OR: 1.947，95%CI: 1.135-3.339, P = 0.016), UBA1191 (OR: 1.856，95%CI: 1.221-2.822, P = 0.004), UBA7703 (OR: 1.843，95%CI: 1.032-3.289, P = 0.039), Faecalicatena sp002161355 (OR: 1.788，95%CI: 1.114-2.870, P = 0.016), Johnsonella ignava (OR: 1.742，95%CI: 1.031-2.944, P = 0.038), Staphylococcus aureus (OR: 1.614, 95%CI: 1.007-2.588, P = 0.047), Comamonas (OR: 1.522，95%CI: 1.004-2.307, P = 0.048), Ruminococcus D (OR: 1.24，95%CI: 1.050-1.464, P = 0.011), CAG-349 (OR: 1.198，95%CI: 1.048-1.370, P = 0.008), Ruminococcus D bicirculans (OR: 1.175，95%CI: 1.001-1.379, P = 0.048), CAG-177 (OR: 1.272，95%CI: 1.077-1.503, P = 0.005). Reverse MR analysis showed that causal effect of AN on 18 gut microbiota, but to a lesser extent. 12 metabolites have causal effects on AN. There are 7 protective factors, including glucose levels (OR: 0.700, 95%CI: 0.550-0.893, P = 0.004), isoleucine levels (OR: 0.769, 95%CI: 0.602-0.983, P = 0.036), phospholipids in large VLDL (OR: 0.856, 95%CI: 0.736-0.996, P = 0.044), total lipids in large VLDL (OR: 0.860, 95%CI: 0.740-0.999, P = 0.049), total lipids in small VLDL (OR: 0.863, 95%CI: 0.751-0.992, P = 0.038), free cholesterol in small VLDL (OR: 0.86, 95%CI: 0.752-0.996, P = 0.044), and free cholesterol in medium VLDL (OR: 0.866, 95%CI: 0.752-0.998, P = 0.047). There are 5 risk factors, including estimated degree of unsaturation (OR: 1.174, 95%CI: 1.009-1.367, P = 0.039), free cholesterol to total lipids ratio in small VLDL (OR: 1.199, 95%CI: 1.017-1.414, P = 0.031), phospholipids to total lipids ratio in small VLDL (OR: 1.216, 95%CI: 1.008-1.467, P = 0.041), total cholesterol levels in small HDL (OR: 1.241, 95%CI: 1.008-1.530, P = 0.042), and phospholipids to total lipids ratio in medium VLDL (OR: 1.280, 95%CI: 1.055-1.553, P = 0.012). Reverse MR analysis showed that AN had a causal effect on 15 metabolites. Mediation analysis reveals that the estimated degree of unsaturation mediates 0.69 % of the effect of Klebsiella pneumoniae on AN. Total lipids in small VLDL mediate 0.358 % of the effect of CAG-177 on AN, with a mediated proportion of 1.490 %. The mediation proportions for Estimated degree of unsaturation and Total lipids in small VLDL are relatively small. 36 immune cells have causal effects on AN. There are 7 protective factors, including Switched memory B cells %B cell (OR: 0.892，95%CI: 0.801-0.994, P = 0.038), CD127-CD8+ T cell absolute count (OR: 0.888，95%CI: 0.789-1.000, P = 0.049), IgD + CD24- B cell (OR: 0.917，95%CI: 0.862-0.975, P = 0.006), HVEM+ T cell (OR: 0.945，95%CI: 0.894-0.999, P = 0.045), CD40 + CD14 + CD16- monocyte (OR: 0.937，95%CI: 0.882-0.996, P = 0.038), CD64 + CD14 + CD16- monocyte (OR: 0.966，95%CI: 0.939-0.993, P = 0.016), CD8+ natural killer T cells (OR: 0.911，95%CI: 0.836-0.992, P = 0.032), HLA-DR+ T cells (OR: 0.921，95%CI: 0.866-0.980, P = 0.010), CD28-CD8+ T cells (OR: 0.886，95%CI: 0.792-0.991, P = 0.034). There are 26 risk factors. Reverse MR analysis showed that AN had a causal effect on 31 immune cells. AN increases the expression levels of five types of immune cells, including CD40 + CD14-CD16+ monocytes (OR: 1.087，95%CI: 1.004-1.177, P = 0.041), PDL-1+ CD14-CD16+ monocytes (OR: 1.082，95%CI: 1.002-1.168, P = 0.046), CD45+ CD33dim HLA-DR+ cells (OR: 1.145，95%CI: 1.019-1.287, P = 0.023), CD45+ basophils (OR: 1.164，95%CI: 1.036-1.307, P = 0.011), CD8+ natural killer T cells (OR: 1.102, 95%CI: 1.015-1.196, P = 0.020), and also decreases the expression levels of 26 immune cells. 6 liposomes showed exhibit protective effects against AN, including phosphatidylcholine (18:0_20:3) levels (OR: 0.852, 95%CI: 0.740-0.981, P = 0.026), phosphatidylcholine (O-18:2_18:1) levels (OR: 0.800, 95%CI: 0.672-0.952, P = 0.012), phosphatidylinositol (18:0_18:1) levels (OR: 0.873, 95%CI: 0.773-0.986, P = 0.029), phosphatidylinositol (18:1_18:2) levels (OR: 0.844, 95%CI: 0.734-0.971, P = 0.018), sphingomyelin (d38:1) levels (OR: 0.903，95%CI: 0.820-0.995, P = 0.039), and triacylglycerol (56:4) levels (OR: 0.786, 95%CI: 0.660-0.936, P = 0.007). There are 3 risk factors, including diacylglycerol (16:1_18:1) levels (OR: 1.208, 95%CI: 1.040-1.404, P = 0.014), phosphatidylcholine (18:1_18:3) levels (OR: 1.237, 95%CI: 1.003-1.526, P = 0.047), and phosphatidylinositol (16:0_20:4) levels (OR: 1.148, 95%CI: 1.003-1.314, P = 0.045). Reverse MR analysis showed that AN had a causal effect on 3 phosphatidylcholine (15:0_18:2) levels (OR: 1.075, 95%CI: 1.001-1.154, P = 0.048), phosphatidylcholine (O-16:2_18:0) levels (OR: 1.078, 95%CI: 1.002-1.159, P = 0.043), and triacylglycerol (51:1) levels (OR: 0.919, 95%CI: 0.850-0.994, P = 0.035). 6 inflammatory proteins have causal effects on AN, with protective factors including Glial cell line-derived neurotrophic factor levels (OR: 0.822，95%CI: 0.692-0.978, P = 0.027) and Interleukin-15 receptor subunit alpha levels (OR: 0.886, 95%CI: 0.789-0.995, P = 0.041) and risk factors including CC motif chemokine 4 levels (OR: 1.126, 95%CI: 1.011-1.254, P = 0.031), Interleukin-12 subunit beta levels (OR: 1.135, 95%CI: 1.033-1.248, P = 0.008), Monocyte chemoattractant protein-1 levels (OR: 1.152, 95%CI: 1.010-1.314, P = 0.035), and Sulfotransferase 1A1 levels (OR: 1.166, 95%CI: 1.006-1.351, P = 0.042). Reverse MR analysis showed that AN had a causal effect on Transforming growth factor-alpha (OR: 1.054，95%CI: 1.010-1.101, P = 0.016).CONCLUSIONSThis study used large-scale and novel GWAS data, for the first time reveals through mediation analysis and multi-omics MR analysis the roles of gut microbiota, metabolites, immune cells, lipids, and inflammatory proteins in the pathogenesis of AN. These findings provide new biomarkers and targets for further prevention and treatment strategies.

2025-01-01·Brain, Behavior, and Immunity

Skull bone marrow-derived immune cells infiltrate the injured cerebral cortex and exhibit anti-inflammatory properties

Article

作者: Ju, Jing ; Theus, Michelle H. ; Soliman, Eman ; Willison, Andrew ; Theus, Michelle H ; Gudenschwager Basso, Erwin Kristobal

Identifying the origins and contributions of peripheral-derived immune cell populations following brain injury is crucial for understanding their roles in neuroinflammation and tissue repair. This study investigated the infiltration and phenotypic characteristics of skull bone marrow-derived immune cells in the murine brain after traumatic brain injury (TBI). We performed calvarium transplantation from GFP donor mice and subjected the recipients to controlled cortical impact (CCI) injury 14 days post-transplant. Confocal imaging at 3 days post-CCI revealed GFP+ calvarium-derived cells were present in the ipsilateral injured cortex, expressing CD45 and CD11b immune markers. These cells included Ly6G-positive neutrophil or Ccr2-positive monocyte identities. Calvarium-derived GFP+/Iba1+ monocyte/macrophages expressed the efferocytosis receptor MERTK and displayed engulfment of NeuN+ and cleaved caspase 3+ apoptotic cells. Phenotypic analysis showed that greater calvarium-derived monocytes/macrophages disproportionately express the anti-inflammatory arginase-1 marker than pro-inflammatory CD86. To differentiate the responses of blood- and calvarium-derived macrophages, we transplanted GFP calvarium skull bone into tdTomato bone marrow chimeric mice, then performed CCI injury 14 days post-transplant. Calvarium-derived GFP+cells predominantly infiltrated the lesion boundary, while blood-derived tdTomato+ cells dispersed throughout the lesion and peri-lesion. Compared to calvarium-derived cells, more blood-derived cells expressed pro-inflammatory CD86 and displayed altered 3D morphologic traits. These findings uniquely demonstrate that skull bone marrow-derived immune cells infiltrate the brain after injury and contribute to the neuroinflammatory milieu, representing a novel immune cell source that may be further investigated for their causal role in functional outcomes.

213

项与 CD45 相关的新闻（医药）

2024-10-29

·GlobeNewswire-Health Care

Tonix Pharmaceuticals to Present at BIO-Europe® 2024

CHATHAM, N.J., Oct. 29, 2024 (GLOBE NEWSWIRE) -- Tonix Pharmaceuticals Holding Corp. (Nasdaq: TNXP) (Tonix or the Company), a fully-integrated biopharmaceutical company with marketed products and a pipeline of development candidates, announced today that Seth Lederman, M.D., Chief Executive Officer of Tonix Pharmaceuticals, will present at BIO-Europe®, being held November 4-6, 2024, in Stockholm, Sweden. The presentation will take place on Monday, November 4, 2024, at 1:00 p.m. CET. To schedule a meeting with the Company’s management at the conference, please submit a meeting request through the partneringOne system or contact brandon.weiner@westwicke.com. Tonix Pharmaceuticals Holding Corp.*Tonix is a fully integrated biopharmaceutical company focused on transforming therapies for pain management and modernizing solutions for public health challenges. Tonix’s development portfolio is focused on central nervous system (CNS) disorders, and its priority is to progress TNX-102 SL, a product candidate for which an NDA was submitted based on two statistically significant Phase 3 studies for the management of fibromyalgia. The FDA has granted Fast Track designation to TNX-102 SL for the management of fibromyalgia. TNX-102 SL is also being developed to treat acute stress reaction and acute stress disorder under a Physician-Initiated IND at the University of North Carolina in the OASIS study funded by the U.S. Department of Defense (DoD). Tonix’s CNS portfolio includes TNX-1300 (cocaine esterase), a biologic in Phase 2 development designed to treat cocaine intoxication that has FDA Breakthrough Therapy designation and its development is supported by a grant from the U.S. National Institute of Drug Abuse and Addiction. Tonix’s immunology development portfolio consists of biologics to address organ transplant rejection, autoimmunity and cancer, including TNX-1500, which is an Fc-modified humanized monoclonal antibody targeting CD40-ligand (CD40L or CD154) being developed for the prevention of allograft rejection and for the treatment of autoimmune diseases. Tonix also has product candidates in development in the areas of rare disease, including TNX-2900 for Prader-Willi syndrome, and infectious disease, including a vaccine for mpox, TNX-801. Tonix recently announced a contract with the U.S. DoD’s Defense Threat Reduction Agency (DTRA) for up to $34 million over five years to develop TNX-4200, small molecule broad-spectrum antiviral agents targeting CD45 for the prevention or treatment of infections to improve the medical readiness of military personnel in biological threat environments. Tonix owns and operates a state-of-the art infectious disease research facility in Frederick, MD. Tonix Medicines, our commercial subsidiary, markets Zembrace® SymTouch® (sumatriptan injection) 3 mg and Tosymra® (sumatriptan nasal spray) 10 mg for the treatment of acute migraine with or without aura in adults. * Tonix’s product development candidates are investigational new drugs or biologics; their efficacy and safety have not been established and have not been approved for any indication. Zembrace SymTouch and Tosymra are registered trademarks of Tonix Medicines. All other marks are property of their respective owners. This press release and further information about Tonix can be found at www.tonixpharma.com. Forward Looking StatementsCertain statements in this press release are forward-looking within the meaning of the Private Securities Litigation Reform Act of 1995. These statements may be identified by the use of forward-looking words such as “anticipate,” “believe,” “forecast,” “estimate,” “expect,” and “intend,” among others. These forward-looking statements are based on Tonix's current expectations and actual results could differ materially. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements. These factors include, but are not limited to, risks related to the failure to obtain FDA clearances or approvals and noncompliance with FDA regulations; risks related to the failure to successfully market any of our products; risks related to the timing and progress of clinical development of our product candidates; our need for additional financing; uncertainties of patent protection and litigation; uncertainties of government or third party payor reimbursement; limited research and development efforts and dependence upon third parties; and substantial competition. As with any pharmaceutical under development, there are significant risks in the development, regulatory approval and commercialization of new products. Tonix does not undertake an obligation to update or revise any forward-looking statement. Investors should read the risk factors set forth in the Annual Report on Form 10-K for the year ended December 31, 2023, as filed with the Securities and Exchange Commission (the “SEC”) on April 1, 2024, and periodic reports filed with the SEC on or after the date thereof. All of Tonix's forward-looking statements are expressly qualified by all such risk factors and other cautionary statements. The information set forth herein speaks only as of the date thereof. Investor ContactJessica MorrisTonix Pharmaceuticalsinvestor.relations@tonixpharma.com(862) 904-8182 Peter VozzoICR Westwickepeter.vozzo@westwicke.com (443) 213-0505 Media ContactRay JordanPutnam Insightsray@putnaminsights.com(949) 245-5432

快速通道临床3期临床2期疫苗突破性疗法

2024-10-29

·今日头条

【Nature子刊】同济大学蔡振宇团队：揭示化疗毒副作用的关键机制

【导读】过度的DNA损伤，会触发各种类型的程序性细胞死亡（PCD），但DNA损伤诱导细胞死亡的调节机制尚不完全清楚。在这项研究中，团队报道了PANoptosis，一种协调的PCD通路，包括细胞焦亡、细胞凋亡和坏死性凋亡，被DNA损伤激活。 2024年10月27日，同济大学医学院蔡振宇团队在期刊《Cell Death & Disease》上发表了题为“Sensing of endogenous retroviruses-derived RNA by ZBP1 triggers PANoptosis in DNA damage and contributes to toxic side effects of chemotherapy”的研究论文。研究结果表明，ZBP1介导的PANoptosis被DNA损伤激活，并导致基于DNA损伤的化疗的毒副作用。 ZBP1可能是一个有前途的治疗靶点，可以减轻化疗相关的副作用。 https://www-nature-com.libproxy1.nus.edu.sg/articles/s41419-024-07175-7 关于DNA损伤 01 触发DNA损伤诱导的细胞死亡，被认为是癌症治疗（如化疗或放疗）中的重要机制。然而，DNA损伤诱导的细胞死亡的许多方面，尚不完全清楚。 PANoptosis是一种协调的细胞死亡通路，整合了焦亡、细胞凋亡和坏死性凋亡的关键成分。ZBP1介导的PANoptisis，已被证明在感染性和炎症性疾病中起关键作用，例如，病毒和真菌感染以及感染性炎症。 ZBP1是一种胞质核酸传感器，在细胞死亡和炎症的调节中起着至关重要的作用，特别是在病毒感染和免疫应答的情况下。在无菌条件下，ZBP1已被证明可以识别ERV来源的dsRNA，以诱导坏死性凋亡和炎症。在这项研究中，团队发现ZBP1介导的PANoptosis，被DNA损伤化合物激活。从机制上讲，ERV被DNA损伤重新激活，并作为ZBP1的配体触发PANoptosis。ZBP1介导的PANoptosis有助于化疗药物的毒性作用。这些数据表明， ZBP1可能是减轻化疗引起的副作用的潜在治疗靶点。 ZBP1介导的PANoptisis，导致小鼠化疗诱导的毒性 02 包括ETO、CDDP和5-FU在内的DNA损伤剂是癌症治疗中最有效的化疗药物之一，然而，这些有效化疗药物的临床效用，受到其毒性不良反应的剂量限制。团队发现ETO严重破坏了小肠中的隐窝和绒毛，导致WT小鼠肺中严重的血管损伤、中性粒细胞浸润和IL-6表达增加，而这些影响在ZBP1中显著减弱。与ZBP1相比，WT小鼠的ETO处理，使脾脏重量和脾脏淋巴细胞的数量显著降低。腹膜注射CDDP，还导致WT小鼠小肠隐窝丢失，肺血管损伤和中性粒细胞浸润增加，脾脏淋巴细胞数量减少，所有这些影响在ZBP1中均得到缓解。此外，与载体对照治疗相比，ETO或CDDP治疗在小鼠小肠中PLA的红色荧光信号显著增加，这表明化疗诱导的dsRNA可以在体内被ZBP1识别。这些数据表明， ZBP1驱动的PANoptosis会导致化疗诱导的小鼠毒性和炎症。 ZBP1介导的PANoptis，导致小鼠化疗诱导的毒性。结直肠癌（CRC）患者非癌组织中的ZBP1，可感应化疗诱导的dsRNA 03 ZBP1的表达在肿瘤组织中下调。ZBP1表达在所有患者的癌细胞系中都不存在。与匹配的非癌性结肠组织相比，ZBP1在肿瘤中的表达显著降低或不存在，而Casp-6、RIPK3和MLKL的表达，在正常组织和肿瘤组织中通常相当。这些数据表明，肿瘤可能通过下调ZBP1表达，来逃避ZBP1介导的细胞死亡，并且，ZBP1驱动的PANoptisis很可能在非癌组织中被化疗激活。一些dsRNA阳性细胞是CD45阳性，表明dsRNA是由免疫前哨细胞中的化疗诱导的。在这些化疗正常的结肠组织中，通过PLA检测到dsRNA和ZBP1之间的关联，表明化疗中的ZBP1可以感应dsRNA。团队在化疗的正常结肠组织中检测到红色荧光PLA信号，但是，在没有化疗的正常结肠组织中不存在PLA信号。这些数据表明， ZBP1可以感应化疗诱导的dsRNA，并触发CRC患者非癌组织中的PANoptosis。 ZBP1在CRC患者的非癌组织中，感应化疗诱导的dsRNA。总结 04 1. PANoptosis与DNA损伤诱导的细胞死亡之间的关系尚未被研究，本研究发现ZBP1衍生的PANoptosis可被DNA损伤激活。 2. ZBP1通过其Zα结构域结合病毒来源的Z-RNA，触发PANoptosome复合物的组装，该复合物包含RIPK、NLRP3、ASC、Casp-6和Casp-8等关键组分。 3. ZBP1的Zα结构域能够结合左旋Z构象的核酸，对于触发炎性细胞死亡至关重要。研究提出dsRNA由DNA损伤诱导，并通过ZBP1的Zα结构域结合，对PANoptosis至关重要。 4. ZBP1介导的PANoptosis会导致化疗诱导的毒性和炎症，化疗药物如ETO、CDDP和5-FU的最佳使用受到剂量限制性副作用的限制。 5. ZBP1在肿瘤组织中的表达较低或不存在，表明ZBP1衍生的PANoptosis可能在非癌组织中被化疗激活。 6. 研究结果表明，抑制ZBP1衍生的PANoptosis可能是一种潜在的治疗方法，可以减轻化疗引起的副作用并改善癌症患者的生活质量。参考资料： 1. Goldstein M, Kastan MB. The DNA damage response: implications for tumor responses to radiation and chemotherapy. Annu Rev Med. 2015;66:129–43. 2. Cheung-Ong K, Giaever G, Nislow C. DNA-damaging agents in cancer chemotherapy: serendipity and chemical biology. Chem Biol. 2013;20:648–59. 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门推荐活动点击免费报名 🕓 上海｜11月15日-16日 ▶ 2024第一届中国类器官转化医学大会 🕓 上海｜11月21日-24日 ▶ 第七届上海国际肿瘤内科学论坛 🕓 全国｜2024年12月-2025年03月 ▶ 中国转化医学产业大会 🕓 上海｜2025年02月28日-03月01日 ▶ 第四届长三角单细胞组学技术应用论坛暨空间组学前沿论坛点击对应文字查看详情

2024-10-25

·今日头条

【Cell子刊】肠道战士：台湾中央研究院的益生菌革命，为抗癌免疫注入新活力

【导读】联合疗法为实体瘤的免疫抑制和异质性微环境，提供了一种令人信服的治疗方案。然而，在方案设计中纳入单独的治疗方式，可能会受到复杂的物流、制造和药代动力学考虑的阻碍。在这项研究中，团队展示了一种使用lpp基因敲除的渗漏益生菌且同步分泌免疫治疗和溶瘤效应分子的单载体联合抗癌疗法。 2024年10月22日，台湾中央研究院Kurt Yun Mou团队在期刊《Cell Reports Medicine》上发表了题为“Combinatorial leaky probiotic for anticancer immunopotentiation and tumor eradication”的研究论文。多功能渗漏益生菌可实现同步免疫激活和肿瘤靶向溶细胞活性，从而有效抑制肿瘤、提高肿瘤免疫细胞浸润和建立抗癌免疫记忆。LPP基因敲除可以提高益生菌耐受性和静脉适用性，为联合方案开发，提供了一种治疗可行的方法。 https://www-cell-com.libproxy1.nus.edu.sg/cell-reports-medicine/fulltext/S2666-3791(24)00540-8#sec-3 关于溶瘤益生菌 01 最近，细菌和益生菌作为治疗媒介的出现，为治疗开发提供了新的机会。重组克隆技术中的多样化工具集，为生成表达多种生物制剂的载体，提供了合成灵活性。此外，细菌的肿瘤嗜性及其在缺氧肿瘤微环境中增殖的能力，促进了肿瘤靶向生物制剂的递送。为了实现工程化单载体组合益生菌，团队在这项研究中采用了一种功能丧失策略，通过缺失lpp基因（Δlpp）来松动细菌的外膜，该基因编码共价吸附细菌外膜的脂蛋白。团队表明Δlpp细菌具有渗漏表型，能够直接释放表达的生物制剂，为联合治疗设计提供了一个灵活的平台。此外，由于Lpp脂蛋白与免疫刺激和反应原反应相关，因此，功能丧失Δlpp设计具有增强载体耐受性的额外好处。通过插入带有单个启动子的质粒，团队展示了多功能渗漏细菌的制备，这些细菌将免疫刺激、免疫检查点抑制剂和肿瘤靶向溶瘤成分结合在单个载体中，用于抗癌治疗。为了证明用于抗癌治疗的组合渗漏益生菌的制备，团队整合了免疫刺激和溶瘤嵌合蛋白，以诱导杀瘤活性、调节肿瘤微环境和促进抗癌适应性免疫反应。团队表明，渗漏的细菌能够筛选成分设计，并且在载体工程过程中，验证了每个治疗成分的功能。优化的渗漏益生菌，表示为组合免疫治疗-溶瘤益生菌（CIOP），展示了不同效应器功能的直接和同步释放，从而实现协同抗肿瘤活性。功能丧失Δlpp策略可以提高益生菌耐受性，而不影响其肿瘤嗜性，这使得CIOP适合静脉内给药。 CIOP在治疗侵袭性肿瘤类型方面优于单模式益生菌，它为肿瘤遏制提供了有利的抗癌免疫反应。多功能载体为单载体组合治疗开发，提供了一种通用方法。用于单载体联合抗癌治疗的组合免疫治疗-溶瘤益生菌示意图 CIOP的组合免疫治疗和溶瘤功能，发挥协同抗癌活性 02 大的MC38肿瘤在OP和CIOP之间显示出明显的差异，因为OP显示出可以忽略不计的抑制作用，而CIOP有效地控制了原发性肿瘤。CIOP治疗在抑制远端肿瘤生长方面比OP更有效，表明CIOP载体在诱导抗癌免疫反应方面具有优势。CIOP的组合功能赋予的治疗益处在快速生长、表达间皮素的CT26肿瘤模型中也很明显，这表明双重抗癌功能增强了益生菌治疗的肿瘤抑制作用。在携带高度侵袭性B16F10黑色素瘤的小鼠中，团队进一步证明， CIOP可以实现显著的肿瘤抑制，使肿瘤无法检测，并在单剂量治疗后诱导持久的抗癌适应性免疫。这些结果突出了CIOP在诱导杀瘤和免疫刺激活性，以实现稳健和持久的肿瘤遏制方面的协同作用。使用表达免疫治疗、溶瘤或组合抗癌功能的益生菌进行抗癌治疗静脉注射CIOP治疗，可实现肿瘤抑制并增加肿瘤微环境中的免疫细胞浸润 03 对免疫细胞组成的深入分析显示，在CIOP治疗的肿瘤中，CD8和CD4 T淋巴细胞的存在更高。除了T淋巴细胞外，CIOP还增加了MHCII阳性免疫细胞的数量，表明存在抗原呈递细胞，如CD19 B细胞、CD11c+树突状细胞和F4/80+ M1巨噬细胞。团队还观察到，CIOP治疗的肿瘤具有升高的CD45肿瘤浸润白细胞水平。这些发现证实了， CIOP中免疫调节剂成分介导的免疫刺激功能，它可以改变免疫抑制性肿瘤微环境，以改善疾病预后。渗漏益生菌提供的高剂量静脉注射治疗，进一步增强了抗癌细菌治疗的转化前景。 CIOP静脉治疗，抑制肿瘤生长并增加免疫细胞浸润总结 04 1. lpp基因敲除方法：通过敲除lpp基因，可以产生渗漏膜，这种方法适用于不同的细菌载体，为细菌疗法开发提供了一个多功能的平台。 2. 增强载体耐受性和安全性：敲除lpp基因不仅产生渗漏膜，还能增强载体的耐受性和安全性，这与荚膜多糖含量的减少有关，后者是病原菌的主要毒力因子。 3. 在肿瘤微环境中的增殖：尽管在血液中的活力降低，但这些渗漏的益生菌在肿瘤中仍然可以被检测到，表明它们能在缺氧和免疫抑制的肿瘤微环境中增殖，用于嗜瘤治疗递送。 4. 细菌疗法的广泛应用：细菌疗法在肿瘤学领域的应用日益普及，并且也适用于其他疾病，如代谢疾病、传染病和炎症性疾病。 5. 组合抗癌成分：文章还展示了通过整合细菌载体工程和嵌合融合蛋白设计，将多种抗癌成分组合成单个载体的可行性。这种设计可以导致协同抗肿瘤作用，增强免疫细胞扩增，同时抑制癌细胞生长。 6. 组合益生菌的优势：与传统的联合抗癌疗法相比，组合益生菌具有简化生产和简化给药方案的优势，解决了联合疗法背后的生产、物流和药理复杂性。参考资料： 1.Jin, H. ∙ Wang, L. ∙ Bernards, R. Rational combinations of targeted cancer therapies: background, advances and challenges Nat. Rev. Drug Discov. 2023; 22:213-234 2.Lu, X. ∙ Horner, J.W. ∙ Paul, E. ... Effective combinatorial immunotherapy for castration-resistant prostate cancer Nature. 2017; 543:728-732 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门推荐活动点击免费报名 🕓 上海｜11月15日-16日 ▶ 2024第一届中国类器官转化医学大会 🕓 上海｜11月21日-24日 ▶ 第七届上海国际肿瘤内科学论坛 🕓 全国｜2024年12月-2025年03月 ▶ 中国转化医学产业大会 🕓 上海｜2025年02月28日-03月01日 ▶ 第四届长三角单细胞组学技术应用论坛暨空间组学前沿论坛点击对应文字查看详情

免疫疗法微生物疗法临床研究