A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Immunogenicity of G03-52-01 in Adult Subjects

A Phase 2, randomized, double-blind, placebo-controlled single or repeat dose trial

开始日期2022-06-29

申办/合作机构

Resilience Government Services, Inc.

[+1]

NCT04171115 / Completed临床1期

A Phase 1, Randomized, Double-Blind, Dose Escalation Study to Evaluate the Safety and Pharmacokinetics of a Single IM Dose of G03-52-01 vs Placebo in Adult Subjects

A Phase 1, randomized, double-blind, placebo-controlled dose escalation trial of four dose cohorts of 10 subjects (1: 10mg, 2: 25mg, 3: 50mg, 4: 100mg).

开始日期2020-06-01

申办/合作机构

Resilience Government Services, Inc.

[+1]

EUCTR2011-004994-94-CZ / Not yet recruitingN/A

A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Safety and Tolerability of a Single Infusion of MK-6072 (Human Monoclonal Antibody to C. difficile toxin B), and MK-3415A (Human Monoclonal Antibodies to C. difficile toxin A and B) in Patients Receiving Antibiotic Therapy for C. difficile Infection (MODIFY II) - MODIFY II

开始日期2012-03-06

申办/合作机构

Merck & Co., Inc.

100 项与 toxB x toxA 相关的临床结果

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100 项与 toxB x toxA 相关的转化医学

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0 项与 toxB x toxA 相关的专利（医药）

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项与 toxB x toxA 相关的文献（医药）

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.

2024-08-01·Anaerobe

Monoclonal antibody-mediated neutralization of Clostridioides difficile toxin does not diminish induction of the protective innate immune response to infection

Article

作者: Alam, Md Zahidul ; Abt, Michael C ; Maslanka, Jeffrey R ; Mdluli, Nontokozo V ; Lieberman, Linda A ; Denny, Joshua E

Clostridioides difficile infection causes pathology that ranges in severity from diarrhea to pseudomembranous colitis. Toxin A and Toxin B are the two primary virulence factors secreted by C. difficile that drive disease severity. The toxins damage intestinal epithelial cells leading to a loss of barrier integrity and induction of a proinflammatory host response. Monoclonal antibodies (mAbs) that neutralize Toxin A and Toxin B, actoxumab and bezlotoxumab, respectively, significantly reduce disease severity in a murine model of C. difficile infection. However, the impact of toxin neutralization on the induction and quality of the innate immune response following infection is unknown. The goal of this study was to define the quality of the host innate immune response in the context of anti-toxin mAbs therapy. At day 2 post-infection, C. difficile-infected, mAbs-treated mice had significantly less disease compared to isotype-treated mice despite remaining colonized with C. difficile. C. difficile-infected mAbs-treated mice still exhibited marked neutrophil infiltration and induction of a subset of proinflammatory cytokines within the intestinal lamina propria following infection that is comparable to isotype-treated mice. Furthermore, both mAbs and isotype-treated mice had an increase in IL-22-producing ILCs in the intestine following infection. MAbs-treated mice exhibited increased infiltration of eosinophils in the intestinal lamina propria, which has been previously reported to promote a protective host response following C. difficile infection. These findings show that activation of host protective mechanisms remain intact in the context of monoclonal antibody-mediated toxin neutralization.

2024-07-01·Veterinary Microbiology

Molecular Characterization and Potential Host-switching of Swine Farm associated Clostridioides difficile ST11

Article

作者: Li, Qingtian ; Huang, Jiewen ; Ni, Peihua ; Guo, Xiaokui ; Dong, Ke ; Li, Tinghua ; Kuo, Chih-Jung ; Zhu, Yongzhang ; Wei, Beiwen

OBJECTIVETo conduct molecular prevalence and genetic polymorphism analysis of 24 Swine Farm associated C. difficile ST11 strains, in addition to other representative sequenced ST strains.METHODSThe collected C. difficile strains underwent whole genome sequencing and bioinformatic analysis using the illumina NovaSeq platform, SPAdes, Prokka, MOB-suite, and FastTree. Virulence and antibiotic resistance genes were identified through NCBI Pathogen Database. Cytotoxicity tests were conducted on HT-29 cells and Vero cells to verify the function of toxin A and toxin B.RESULTSThe most prevalent resistance genes in ST11 were found to be against β-lactamases, aminoglycosides, and tetracycline. A C. difficile isolate (strain 27) with tcdA deletion and high antibiotic resistance genes was far apart from other swine farm associated ST11 isolates in the phylogenetic branch. The remarkable genetic similarity between animal and human C. difficile strains suggests potential transmission of ST11 strains between animals and humans. The plasmid replicon sequences repUS43 were identified in all ST11 strains except one variant (strain 27), and 91.67% (22/24) of these were assessed by MOB-typer as having mobilizable plasmids.CONCLUSIONSwine farm associated C. difficile ST11 carried fewer virulence genes than ST11 strains collected from NCBI database. It is critical to monitor the evolution of C. difficile strains to understand their changing characteristics, host-switching, and develop effective control and prevention strategies.

项与 toxB x toxA 相关的新闻（医药）

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.