更新于：2024-11-01

toxB

更新于：2024-11-01

基本信息

别名

toxB、Toxin B

简介

Precursor of a cytotoxin that targets and disrupts the colonic epithelium, inducing the host inflammatory and innate immune responses and resulting in diarrhea and pseudomembranous colitis (PubMed:20844489, PubMed:24919149). TcdB constitutes the main toxin that mediates the pathology of C.difficile infection, an opportunistic pathogen that colonizes the colon when the normal gut microbiome is disrupted (PubMed:19252482, PubMed:20844489). Compared to TcdA, TcdB is more virulent and more important for inducing the host inflammatory and innate immune responses (PubMed:19252482, PubMed:24919149). This form constitutes the precursor of the toxin: it enters into host cells and mediates autoprocessing to release the active toxin (Glucosyltransferase TcdB) into the host cytosol (PubMed:10768933, PubMed:11152463, PubMed:12941936, PubMed:17334356, PubMed:20498856). Targets colonic epithelia by binding to the frizzled receptors FZD1, FZD2 and FZD7, and enters host cells via clathrin-mediated endocytosis (PubMed:27680706). Frizzled receptors constitute the major host receptors in the colonic epithelium, but other receptors, such as CSPG4 or NECTIN3/PVRL3, have been identified (PubMed:25547119, PubMed:26038560, PubMed:27680706). Binding to carbohydrates and sulfated glycosaminoglycans on host cell surface also contribute to entry into cells (By similarity). Once entered into host cells, acidification in the endosome promotes the membrane insertion of the translocation region and formation of a pore, leading to translocation of the GT44 and peptidase C80 domains across the endosomal membrane (PubMed:11152463, PubMed:12941936, PubMed:24567384). This activates the peptidase C80 domain and autocatalytic processing, releasing the N-terminal part (Glucosyltransferase TcdB), which constitutes the active part of the toxin, in the cytosol (PubMed:17334356, PubMed:27571750). Active form of the toxin, which is released into the host cytosol following autoprocessing and inactivates small GTPases (PubMed:8144660, PubMed:7777059, PubMed:16157585, PubMed:17901056, PubMed:24905543, PubMed:24919149). Acts by mediating monoglucosylation of small GTPases of the Rho family (Rac1, RhoA, RhoB, RhoC, RhoG and Cdc42) in host cells at the conserved threonine residue located in the switch I region ('Thr-37/35'), using UDP-alpha-D-glucose as the sugar donor (PubMed:7777059, PubMed:16157585, PubMed:17901056, PubMed:24905543, PubMed:24919149). Monoglucosylation of host small GTPases completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption and cell death, resulting in the loss of colonic epithelial barrier function (PubMed:7777059, PubMed:24919149).

关联

项与 toxB 相关的药物

Bezlotoxumab

靶点

toxB

作用机制

toxB抑制剂

在研机构

Merck Sharp & Dohme LLC [+2]

原研机构

Merck Sharp & Dohme Corp.

在研适应症

梭菌感染 [+2]

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2016-10-21

LMN-201

靶点

toxB

作用机制

toxB抑制剂

在研机构

Lumen Bioscience, Inc.初创企业

原研机构

Lumen Bioscience, Inc.初创企业

在研适应症

艰难梭菌感染

非在研适应症-

最高研发阶段临床2/3期

首次获批国家/地区-

首次获批日期1800-01-20

IMM-529

靶点

toxB

作用机制

toxB抑制剂

在研机构

原研机构

在研适应症

非在研适应症

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

项与 toxB 相关的临床试验

NCT06639997 / Not yet recruiting临床1期

A Phase I Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of AZD5148 in Healthy Japanese Adults

The purpose of this study is to measure safety, tolerability and PK of a single dose of AZD5148 administered via IV bolus or IM injection in healthy Japanese participants.

开始日期2024-10-30

申办/合作机构

AstraZeneca PLC

NCT05330182 / Recruiting临床2/3期

A Phase 2, Randomized, Double-blind, Placebo-controlled Study of LMN-201 for Prevention of C. Difficile Infection Recurrence

This is a multisite study to evaluate the safety, tolerability, and efficacy of LMN-201 in participants recently diagnosed with CDI who are scheduled to receive or are receiving SOC antibiotic therapy against C. difficile.

开始日期2024-08-29

申办/合作机构

Lumen Bioscience, Inc.初创企业

NCT06469151 / Recruiting临床1期

A Phase I Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of AZD5148 in Healthy Adults

The purpose of this study is to measure safety, tolerability, and pharmacokinetics (PK) of a single dose of AZD5148 administered via intravenous (IV) bolus or intramuscular (IM) injection in healthy participants.

开始日期2024-06-24

申办/合作机构

AstraZeneca PLC

100 项与 toxB 相关的临床结果

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100 项与 toxB 相关的转化医学

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0 项与 toxB 相关的专利（医药）

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1,484

项与 toxB 相关的文献（医药）

2024-12-31·Libyan Journal of Medicine

Prevalence of toxigenic Clostridium difficile in hospitalized patients in the southwestern province of Saudi Arabia: Confirmation using the GeneXpert analysis

Article

作者: Basode, Vinod Kumar ; Alamoudi, Mohammed Uthman A ; Zain, Khalid Amaash Mohammed ; Kameli, Nader ; Abdulhaq, Ahmed ; Ghzwani, Ahmad Hassn

Clostridium difficile (Clostridioides difficile) is a leading cause of nosocomial infections in hospitalized patients worldwide. Stool samples were collected from 112 inpatients admitted to different hospitals and were screened for C. difficile GDH + toxin A + B by immunoassay, and all positive samples by immunoassay were processed for molecular detection of C. difficile using the GeneXpert assay. C. difficile strains were detected in 12 (10.71%) out of 112 stool samples using the GDH + toxin A + B immunoassay method and toxigenic C. difficile was confirmed in 5 stool samples using the GeneXpert molecular assay. C. difficile strains were also detected in 7 (8.97%) out of 78 stool samples from intensive care unit patients, 3 (25%) out of 12 stool samples from internal medicine ward patients, 1 (11.11%) out of 9 stool samples from surgery ward patients, and 1 (10%) out of 10 stool samples from isolation ward patients using the GDH + toxin A + B immunoassay method and the toxigenic C. difficile strain was confirmed in 1, 2, 1, and 1 stool samples, respectively, using the GeneXpert molecular assay. Toxigenic C. difficile was confirmed in patients at 4 (51.14%) out of 7 hospitals. In the present study, we also analyzed the clinical information of patients with C. difficile-positive stool samples who were receiving one or more antibiotics during hospitalization. The binary toxin gene (cdt), the tcdC gene, and the C. difficile strain polymerase chain reaction (PCR) ribotype 027 were not detected using the GeneXpert molecular assay among 12 C. difficile-positive samples by immunoassay. This study should aid in the prevention of unnecessary empiric therapy and increase the understanding of the toxigenic C. difficile burden on the healthcare system in the southwestern province of Saudi Arabia.

2024-11-01·3 Biotech

Comparative genomics of zoonotic pathogen Clostridioides difficile of animal origin to understand its diversity

Article

作者: Sharma, Rajeev Kumar ; Priyadharshini, Murugaiyan Latha Mala ; Manoharan, Seeralan ; Karthik, Kumaragurubaran ; Anbazhagan, Subbaiyan

Clostridioides difficile, a zoonotic pathogen causing enteric diseases in different animals and humans. A comprehensive study on the presence of toxin genes and antimicrobial resistance genes based on genome data of C. difficile in animals is scanty. In the present study, a total of 15 C. difficile isolates were recovered from dogs and isolates with toxin genes (D1, CD15 and CD26) along with two other non-toxigenic strains (CD28, CD32) were used for whole genome sequencing and comparative genomics. Sequence type-based clustering was noted in the whole genome phylogeny with 4 known multi-locus sequence typing (MLST) clades namely I, II, IV, and V and a cryptic clade. ST11 and ST54 were reported for the 2^nd time worldwide in dogs. Out of 109 genomes used in the study, 29 genomes were predicted with all four toxin genes (toxA, toxB, cdtA, cdtB) while 22 did not have any of the toxin genes. ST11 of MLST clade V had the maximum number of 46 genomes predicted with at least one toxin gene. Among the genomes sequenced in this study, CD26 had a maximum of 5 AMR genes (aac(6')-aph(2″), ant(6)-Ia, catP, erm(B)_18, and tet(M)_11) and CD15 was predicted with 2 AMR genes (aac(6')-aph(2″), erm(B)_18). Tetracycline resistance genes were predicted most in the ST11 genome. Of the 22 non-toxigenic strains, 9 genomes (ST48 = 5, ST3 = 2, ST109 = 1, ST15 = 1) were predicted with a minimum of one AMR gene. Pangenome analysis indicated that the Bpan value is 0.12 showing that C. difficile has an open pangenome structure. This indicates that the organism can evolve by the addition of new genes. This study reports the circulation of clinically important ST11 and multidrug-resistant non-toxigenic strains among animals.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13205-024-04102-7.

2024-10-01·Gériatrie et Psychologie Neuropsychiatrie du Vieillissement

Clostridioides difficile infections: Update and therapeutic guidelines

Article

作者: Paccalin, Marc ; de Wazières, Benoit ; Gavazzi, Gaëtan ; Baudron, Claire Roubaud ; Berrut, Gilles

Clostridioides difficile infection (CDI) represents a significant challenge due to its increasing incidence, severity, and treatment difficulty. Effective management requires a multifactorial approach that includes preventive strategies, prudent antibiotic use, and adapted therapeutic options. Ongoing research and innovation offer promising prospects for improving ICD management, making vigilance and informed practices essential among healthcare professionals. Two main complications of ICD are pseudomembranous colitis (PMC) and toxic megacolon. PMC involves severe colonic inflammation due to C. difficile toxins, leading to pseudomembrane formation. Diagnosis relies on clinical criteria, microbiological tests, and endoscopy. Toxic Megacolon is characterized by severe colonic dilation and systemic toxicity, requiring immediate medical intervention. ICD diagnosis combines clinical signs and microbiological tests. These tests include toxin tests, GDH antigen detection, PCR for toxin genes, and stool culture. Imaging techniques assess colonic inflammation and complications. Combined diagnostic criteria from the American Gastroenterological Association (AGA) and European guidelines emphasize integrating clinical and laboratory findings for accurate diagnosis. ICD treatment involves stopping the implicated antibiotics and starting specific antimicrobial therapy. Common treatments include mainly fidaxomicin and oral vancomycin. Fecal microbiota transplantation (TMF) is recommended for recurrent cases unresponsive to standard treatments. Bezlotoxumab, an antibody targeting C. difficile toxin B, is used to prevent recurrence in high-risk adults. ICD poses a major challenge due to its increasing incidence, severity, and difficulty in treatment. A multifactorial approach involving rigorous preventive strategies, prudent antibiotic management, and adapted therapeutic options is essential for controlling the infection. Ongoing research and innovations in treatment offer promising prospects for improving patient management. Healthcare professionals must remain vigilant and informed to ensure effective practices in combating this infection and utilizing available resources optimally.

项与 toxB 相关的新闻（医药）

2024-03-21

·药明康德

生成式AI设计靶向任意蛋白的抗体！David Baker团队公布最新突破

▎药明康德内容团队编辑本月初，人工设计蛋白领域先驱David Baker教授团队发布了增强版的蛋白模拟工具RoseTTAFold All-Atom和蛋白设计工具RFdiffuion All-Atom。仅仅2周后，Baker教授团队在bioRxiv上发表另一项突破性进展：通过对其生成式AI系统RFdiffusion进行微调，他们成功得以针对任意选定的抗原表位从头设计基于重链可变区（VHH）的单域抗体，且该抗体与靶向抗原的有效结合经过具有原子级解析度的冷冻电镜（cryo-EM）结构所验证。这项进展有望加速未来更精准、靶向范围更广抗体疗法的开发，造福广大患者。目前开发治疗性抗体的过程仍然主要依赖于动物免疫或抗体库筛选，这不仅耗时，而且不一定能够产生与治疗关键表位产生相互作用的抗体。在抗体的计算设计领域，虽然已有研究团队尝试通过计算手段来优化抗体结构，但完全从头设计出结构准确的抗体仍然是一个巨大挑战。近期，尽管在设计能够与多种与疾病相关的蛋白质紧密结合的非抗体蛋白方面，RFdiffusion系统取得了一定的进展，但这种方法未能实现抗体的从头设计。这是因为该方法设计的蛋白与目标蛋白之间的结合主要是通过与目标表位的规则二级结构（比如螺旋或链结构）进行相互作用，因而不适用于抗体设计。根据David Baker教授实验室网站的介绍，RFdiffusion是一款结合了结构预测网络和生成式扩散模型的创新型生成式AI系统，它可以创造出与自然界中任何已知蛋白质不同的新蛋白。传统设计方法可能需测试成千上万个分子才能找到一个性能符合预期的分子。而采用RFdiffusion新方法，研究团队在每个设计挑战中只需测试少量分子即可。▲RFdiffusion系统可以产生与目标分子结合的新型蛋白质（视频来源：David Baker实验室网站）为了突破RFdiffusion在生成抗体分子方面的限制，研究人员利用已有抗体和抗原结合生成的复合体的结构数据库对RFdiffusion进行了训练，让RFdiffusion学习了抗体中抗体互补决定区域（CDR）与抗原之间相互作用的规律，从而设计出维持抗体重链可变区整体结构，但是可以靶向特定抗原表位的新抗体。在完成RFdiffusion的优化后，研究人员针对多个与疾病相关的靶标，包括艰难梭菌毒素B（TcdB）、流感病毒H1血凝素（HA）、呼吸道合胞病毒（RSV）F蛋白的I和III位点以及白介素-7受体α（IL-7Rɑ）等，设计了一系列抗体VHH结构。随后，再利用经过微调的RoseTTAFold2网络对所设计的抗体进行了筛选。▲利用RFdiffusion进行抗体设计的图示（图片来源：参考资料[1]）为了评估设计抗体的结合精度，研究团队通过cryo-EM结构测定，考察了所设计靶向流感病毒HA的VHH与天然糖基化的三聚体流感病毒HA糖蛋白复合物的相互作用。实验结果表明，具有原子级解析度的cryo-EM结构显示，其中一款所设计的VHH能够有效地与完全糖基化的HA三聚体结合，验证了通过计算方法所从头设计VHH的功能性，展示了RFdiffusion在抗体设计方面的高度精确性和创新潜力。▲从头设计的VHH与流感病毒HA结合的冷冻电镜结构（图片来源：参考资料[1]）这项研究结果显示，采用RFdiffusion及其相关方法，能够精确地针对特定的抗原表位进行抗体设计、优化抗体的关键药物属性、扩大靶向抗原范围，有望在未来大幅改善现有抗体疗法开发的效率与成本。然而，虽然本研究证明从头设计VHH是可行的，但这一领域仍有很大的改进空间。例如作者在文中提出，这些抗体虽然能够与抗原结合，但是亲和力却一般，仍有进一步改进的空间。让我们期待通过人工智能在医学上应用的技术不断往前，在不远的将来，我们能够针对各式疾病，快速、有效地设计出适用于临床治疗的抗体，实际上造福广大患者。大家都在看药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Nathaniel R. Bennett, Joseph L. Watson, Robert J. Ragotte, Andrew J. Borst, DeJenae L. See, Connor Weidle, Riti Biswas, Ellen L. Shrock, Philip J. Y. Leung, Buwei Huang, Inna Goreshnik, Russell Ault, Kenneth D. Carr, Benedikt Singer, Cameron Criswell, Dionne Vafeados, Mariana Garcia Sanchez, Ho Min Kim, Susana Vazquez Torres, Sidney Chan, David Baker，”Atomically accurate de novo design of single-domain antibodies.” bioRxiv 2024.03.14.585103; doi: https://doi.org/10.1101/2024.03.14.585103免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

临床3期

2023-02-24

·生物制药小编

诺贝尔奖得主之死

此前，根据法新社消息，经过再度开馆验尸后，在1973年死亡的智利诗人兼诺贝尔文学奖得主巴勃罗·聂鲁达被发现并不是像70年代皮诺切特官方声称的因前列腺癌去世，而是因为存在“大量与人体不相容的肉毒杆菌”，确系此前猜测的那样遭毒杀身亡。熟悉这段历史的读者可能知道整个历史事件的来龙去脉，这里就不详细赘述了，感兴趣的读者可以自行查阅。只是为何要选取肉毒杆菌作为生物武器？这可能是因为肉毒杆菌分泌的A型肉毒毒素是已知天然毒素和化学毒剂中毒性最强的毒性物质，因此成为了帮凶。虽然在上世纪80-90年代逐步出现了更多的用途，但其致命性仍然值得敬畏。而时至今日，虽然目前肉毒毒素已经在医美行业中得到了广泛的应用，但仍然具有潜在可能致死的副作用，解决这些存在的潜在问题是目前肉毒毒素的应用方向，本文将就肉毒毒素的作用机制，开发前景，防范措施进行简单介绍。肉毒毒素的作用机制肉毒杆菌是一种生长在缺氧环境下的细菌，在罐头食品及密封腌渍食物中具有极强的生存能力，该菌种在繁殖过程中分泌肉毒毒素（BoNT）。所有BoNT都由通过二硫键连接的两条肽链组成，但在BoNT的每个亚型中发现的各种肽链的氨基酸序列存在显著差异。重链的分子量为100 k道尔顿，轻链的分子量为50 k道尔顿。由于氨基酸序列存在差异而导致的七种毒素血清型(A-G)传统上是按其抗原性来区分的。它们具有不同的三级结构和层序差异。BoNT通过切割神经激活所需的关键蛋白质来发挥作用。骨骼肌收缩的功能单位包括运动终板，它是运动神经元和肌纤维之间的连接点。当中枢神经系统内运动神经元的初始段产生的动作电位到达末端时，乙酰胆碱(ACh)从运动轴突的末端释放。然后，当结合并打开肌纤维上特定离子型受体(烟碱胆碱能受体)的ACh使突触后膜去极化时，肌纤维收缩。BoNT基本上阻断了ACh从运动终末的释放，因此，即使动作电位继续到达运动终板，骨骼肌也不能收缩。首先，重链的受体结合域与细胞表面的多聚唾液酸神经节苷脂(PSGs)结合。随后，毒素通过与另一种表面受体(突触结合蛋白(Syt)或糖基化Sv2)结合而被内化。内化后，毒素会驻留在突触小泡内。然后，囊泡被H+离子酸化后通过囊泡质子泵，从而激活囊泡膜中的ACh转运蛋白，其输入并浓缩囊泡内的胞质ACh。在这个阶段，在没有BoNT的情况下，囊泡准备与突触前膜融合，并将ACh释放到突触间隙中。然而，BoNT会干扰其后的释放步骤。首先，轻链（LC）从囊泡内部“易位”到细胞质，这是由重链的N末端(易位结构域)促成的。轻链保持无活性，同时仍与毒素的其余部分结合。易位后，轻链通过裂解酶如热休克蛋白90 (hsp90)和硫氧还蛋白还原酶-硫氧还蛋白系统(TrxR-Trx)的作用被释放。游离且具有活性的轻链在此时能够切割和灭活各种蛋白质，如VAMP、SNAP25和突触融合蛋白，而这些蛋白质则是乙酰胆碱的释放是必要的。（如下图所示）一旦切割成功，这意味着乙酰胆碱囊泡不能与胞内细胞膜结合，阻止细胞释放神经递质囊泡。这会阻断神经信号，导致瘫痪。虽然不同的毒素类型都针对SNARE家族成员，但不同的毒素类型针对不同的SNARE家族成员。其中BoNT/A、BoNT/B、BoNT/E和BoNT/F会导致人类和动物肉毒中毒，而BoNT/C和BoNT/D只会导致家畜疾病。此外，现有的毒素类型可以重组，创造“杂交”(嵌合，嵌合)类型。例如BoNT/CD, BoNT/DC和BoNT/FA，第一个字母表示轻链类型，后者表示重链类型。图：A型肉毒杆菌毒素的示意图和晶体结构当人们食入和吸收这种毒素后，神经系统将遭到破坏，出现眼睑下垂、复视、斜视、吞咽困难、头晕、呼吸困难和肌肉乏力等症状，严重者可因呼吸麻痹而死亡。一般估计致死量为：静脉或肌肉注射的致死剂量0.09~0.15μg，吸入的致死剂量0.70~1.0μg，口服的致死剂量70μg。而除了历史上较为有名的暗杀行动之外，（例如CIA试图暗杀卡斯特罗的多次都用到了肉毒素）一些过期的罐头食品的食用也可能导致中毒。不过在进入19世纪末期后，除了生物武器这一罪恶的用途之外，BoNT在医学和美容上的应用得到了出乎意料的拓宽。医学上的适用范围在医学和美容方面，由于可以抑制胆碱能神经末梢释放乙酰胆碱，导致肌肉松弛型麻痹，因此一些神经相关疾病，是肉毒杆菌的适用范围。BoNT于1989年由美国FDA首次批准用于治疗斜视。自那以后，对肉毒杆菌毒素的研究激增，导致了适应症范围越来越广的新配方的增加。迄今为止，BoNT已被神经科医师和美容医师广泛使用。随着BoNT的治疗适应症数量的迅速增加，第一个商品名“oculinum”在进入市场的头两年内改名为“Botox ”。近年来，泌尿科医生和疼痛专家越来越多地将BoNT用于各种新的适应症。例如治疗膀胱过度活动（尿失禁等），偏头痛等疾病。而在过去的几年中，已经开发了许多创新的BoNT配方。除了自然衍生的产品，合成的、基因工程的产品现在也可以获得。但是可获得的制剂的药理学特征存在一些差异，这一点值得审查。总的来说，有超过六种不同的配方被批准用于临床，还有更多正在研发中。BoNT的开发前景由于BoNT本身具有强大的副作用（甚至可能致死），因此一些现有的开发手段将致力于解决BoNT的不足之处，并拓宽其用途。例如，有一种开发方法是从两种不同的BoNT血清型或亚型中设计嵌合蛋白，2008年发表的一篇文献开发了BoNT/EA和BoNT/AE，两种嵌合蛋白都保留了基本的BoNT功能，但瘫痪时间不同，并且效力低于任何一种亲本毒素。发现重组毒素切割SNAP-25，AE嵌合体的恢复需要37天。还发现BoNT/EA可阻断辣椒素诱发的促炎降钙素基因相关肽(CGRP)的释放，因此这种肉毒毒素可能还是治疗偏头痛型头痛的潜在方法。此外还有增强毒力方面的开发，例如2012年发表的一篇文献指出BoNT/BA嵌合体的毒性是BoNT/A的两倍，是BoNT/AB的20倍。发现BoNT/AB嵌合体比亲代BoNT/A显著切割更多的SNAP-25，并导致更持久的瘫痪。BoNT/AB嵌合体的效力是重组BoNT/A的8.4倍又例如使用重组DNA技术，也可以通过改变BoNT氨基酸序列来修饰BoNT的活性。根据临床需要，修饰的BoNT可能靶向其他受体蛋白。通过观察BoNTs中自然发生的点突变导致的结构和功能变化，说明了这种方法的可行性。在2011年，就有研究人员鉴定出一种具有LC突变的重组BoNT/C1，该株则不能切割SNAP-25。此前韩国成均馆大学的研究团队曾经开发过一种重组肽C肉毒杆菌神经毒素A-1型(BoNT/A1)可作为重组肽的阻断材料，用于标记神经系统或治疗各种神经元疾病。伊朗阿扎德大学的研究人员则致力于将其开发成一种无需注射的渗透型药物BoNT/A(1–448)，以此减少BoNT可能致死的副作用。预防措施考虑到肉毒素的致命性，一些可能的生物恐怖主义行为值得担忧，例如美国或英国确实在历史上使用过肉毒杆菌作为生物武器，并不能排除现在还在开发的可能，尤其是1973年至今技术可能有所迭代。此外，因为某些事故意外中毒也值得担忧，那么肉毒素的预防措施能够做到未雨绸缪吗？一般来说，接种疫苗是预防肉毒杆菌神经毒素中毒的有效方法。在以前的研究中，已知会导致人类肉毒中毒的BoNT血清型A、B、E和F的重组Hc抗原被证明是高度免疫原性和有效的，并且可以用作针对肉毒中毒的单价疫苗。2022年4月来自我国的研发团队发表的一篇文献指出，该研究团队在此基础上开发了一种四价肉毒杆菌疫苗(TBV)。TBV对小鼠各种BoNT均有较强的保护效力，并在4℃保存两年后仍保持有效，表明该制剂稳定高效。吸附实验还表明，铝佐剂能很好地吸附储存2年后的抗原。参考来源：Kim HR, Jung Y, Shin J, Park M, Kweon DH, Ban C. Neuron-recognizable characteristics of peptides recombined using a neuronal binding domain of botulinum neurotoxin. Sci Rep. 2022 Mar 23;12(1):4980. doi: 10.1038/s41598-022-09145-5. PMID: 35322139; PMCID: PMC8943039.Saffarian P, Peerayeh SN, Amani J, Ebrahimi F, Sedighianrad H, Halabian R, Imani Fooladi AA. Expression and purification of recombinant TAT-BoNT/A(1-448) under denaturing and native conditions. Bioengineered. 2016 Nov;7(6):478-483. doi: 10.1080/21655979.2016.1201252. Epub 2016 Aug 26. Erratum for: Addendum to: Saffarian P., Peerayeh S. N., Amani J., Ebrahimi F., Sedighian H., Halabian R., Fooladi A. A., TAT-BoNT/A(1–448), a novel fusion protein as a therapeutic agent: analysis of transcutaneous delivery and enzyme activity. Applied Microbiology and Biotechnology, 2016. 100(6): p. 2785-95. doi: 10.1007/s00253-015-7240-7. PMID: 27566060; PMCID: PMC5241812.Choudhury S, Baker MR, Chatterjee S, Kumar H. Botulinum Toxin: An Update on Pharmacology and Newer Products in Development. Toxins (Basel). 2021 Jan 14;13(1):58. doi: 10.3390/toxins13010058. PMID: 33466571; PMCID: PMC7828686.Shi DY, Liu FJ, Li ZY, Mao YY, Lu JS, Wang R, Pang XB, Yu YZ, Yang ZX. Development and evaluation of a tetravalent botulinum vaccine. Hum Vaccin Immunother. 2022 Nov 30;18(5):2048621. doi: 10.1080/21645515.2022.2048621. Epub 2022 Apr 18. PMID: 35435814; PMCID: PMC9196761.

2023-01-17

·BioSpace

Immuron Receives European Patent on Drug Composition to Treat Clostridioides difficile Associated Disease

MELBOURNE, Australia, Jan. 17, 2023 (GLOBE NEWSWIRE) -- Immuron Limited (ASX: IMC; NASDAQ: IMRN), an Australian based and globally integrated biopharmaceutical company that has developed two commercially available oral immunotherapeutic products for the treatment of gut mediated diseases, is pleased to announce that has been granted a European Patent for compositions and methods for the treatment and/or prophylaxis of Clostridioides difficile associated disease. Notification of the decision to grant European Patent 14784945.9, entitled “Methods and Compositions for the treatment and/or prophylaxis of Clostridium difficile associated disease,” was formally received yesterday, and grant of this application will be published in the European Patent Bulletin on 25 January 2023 under European Patent No. 2986316. The company previously reported it had received notification from the European Patent Office of the intent to grant in July last year (ASX announcement July 7, 2022). The European registration adds to Immuron's patent position for compositions and methods for the treatment and/or prophylaxis of Clostridioides difficile associated disease in Australia, New Zealand and the United States. Clostridioides difficile (previously known as Clostridium difficile) infection (CDI) is a disease of the large intestine caused by toxins produced by the spore forming bacterium Clostridioides difficile. CDI can also result in serious disease complications including bowel perforation, toxic megacolon and sepsis, and it can prove fatal in the most severe cases. In recent years, increases in the frequency and severity of CDI have been observed worldwide, as well as an increased risk of community-associated CDI, and CDI in persons previously thought to be low risk. It is estimated that CDI affects up to 1.2% of hospitalized patients in the United States, representing an estimated cost of USD 4.8 billion per year (source: CDC). In Europe, the estimated cost is approximately 3 billion per year, which is likely to increase concomitantly with a more elderly society; more than 134 million Europeans will be >65 years by 2050. This release has been authorised by the directors of Immuron Limited. COMPANY CONTACT: Steven Lydeamore Chief Executive Officer Ph: +61 (0)3 9824 5254 info@immuron.com About Immuron Immuron Limited (ASX: IMC, NASDAQ: IMRN), is an Australian biopharmaceutical company focused on developing and commercializing orally delivered targeted polyclonal antibodies for the treatment of infectious diseases. About IMM-529 IMM-529 is a polyclonal antibody biological product intended to prevent and treat Clostridioides difficile(C.difficile) infections and has been developed to spare the gut microbiome from the effects of "classic" antibiotic treatments. The delivery of IMM-529 results in localized toxin B neutralization at the site of infection and prevents severe damage occurring to the gut while also binding to C.difficile spores and vegetative cells preventing further colonization. In addition, the antibodies in IMM-529 have demonstrated cross-reactions with a variety of human and animal C.difficile isolates and their associated Toxin B, vegetative cell and spore components. The antibodies in IMM-529 have also been shown to neutralize Toxin B from a historical C. difficile strain (630) and from a hypervirulent (HV) strain which caused a worldwide outbreak of the disease. For more information visit:

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