A Phase 4, Open Label Field Study to Evaluate the Clinical Benefit, Safety, and Pharmacokinetics of Anthim (Obiltoxaximab) When Used in the Treatment of Suspected, Probable, or Confirmed Cases of Inhalational Anthrax Due to B. Anthracis

This field study is a post-marketing requirement from the FDA to evaluate the clinical benefit (course of illness and survival), safety and pharmacokinetics of obiltoxaximab administered to patients as part of their medical care for treatment or prophylaxis of inhalational anthrax infection following exposure to Bacillus anthracis (B. anthracis). The protocol can be implemented for any individual who receives obiltoxaximab for a suspected, probable, or confirmed case of inhalational anthrax due to B. anthracis in the United States, including sporadic cases, small incidents and/or a mass event. In case of a small anthrax incident, to the extent possible, the information will be collected prospectively at prespecified time points, except where it would interfere with management of the subject's illness. However, because of the logistical complexities that would likely accompany a mass anthrax event, most data in this study are anticipated to be collected retrospectively. Both retrospective and prospective data collection are allowed to maximize information collection. This study will collect data on the use of obiltoxaximab in anthrax infected or exposed subjects and the data collected will inform the understanding of the clinical benefit and safety of obiltoxaximab.

开始日期2023-12-01

申办/合作机构

Elusys Therapeutics, Inc.

[+2]

NCT01952444

/ Completed临床1期

An Open-Label, Randomized, Parallel Group Study to Assess the Safety, Tolerability and Pharmacokinetics of ETI-204 Alone and in the Presence of Ciprofloxacin in Adult Volunteers

Evaluate the safety, tolerability and pharmacokinetics (PK) of intravenous (IV) ETI-204 alone and in the presence of IV and oral ciprofloxacin

开始日期2013-10-29

申办/合作机构

Elusys Therapeutics, Inc.

NCT01932437

/ Completed临床1期

A Randomized, Double-Blind, Single Ascending Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single Intramuscular Doses of ETI-204 in Adult Volunteers

This study is to evaluate the safety, local tolerability, pharmacokinetics (PK) and immunogenicity of escalating single intramuscular (IM) doses of ETI-204 in healthy volunteers

开始日期2013-07-26

申办/合作机构

Elusys Therapeutics, Inc.

100 项与奥托萨昔单抗相关的临床结果

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100 项与奥托萨昔单抗相关的转化医学

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100 项与奥托萨昔单抗相关的专利（医药）

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项与奥托萨昔单抗相关的文献（医药）

2023-09-02·Expert Opinion On Drug Safety

United States’ regulatory approved pharmacotherapies for nuclear reactor explosions and anthrax-associated bioterrorism

Review

作者: Armitage, James O. ; Georgantopoulos, Peter ; Hrushesky, William J ; Bennett, Charles L ; Armitage, James O ; Gale, Robert Peter ; Nabhan, Chadi ; Knopf, Kevin ; Bennett, Charles L.

INTRODUCTION:

Nuclear reactor incidents and bioterrorism outbreaks are concerning public health disasters. Little is known about US Food and Drug Administration (FDA)-approved agents that can mitigate consequences of these events. We review FDA data supporting regulatory approvals of these agents.

AREAS COVERED:

We reviewed pharmaceutical products approved to treat Hematopoietic Acute Radiation Syndrome (H-ARS) and to treat or prevent pulmonary infections following Bacillus anthracis (anthrax) exposure. Four drugs were approved for H-ARS: granulocyte-colony stimulating factor (G-CSF), granulocyte/macrophage colony stimulating factor, pegylated G-CSF, and romiplostim. For bioterrorism-associated anthrax, the FDA approved five antibiotics (doxycycline, penicillin-G, levofloxacin, moxifloxacin, and ciprofloxacin), two monoclonal antibodies (obiltoxaximab and raxibacumab), one polyclonal antitoxin (Anthrax Immune Globulin Intravenous) and two vaccines (Anthrax Vaccine Adsorbed and Anthrax Vaccine Adsorbed with an adjuvant). A national stockpile system ensures that communities have ready access to these agents. Our literature search was based on data included in drugs@FDA (2001-2023).

EXPERT OPINION:

Two potential mass public health disasters are aerosolized anthrax dissemination and radiological incidents. Five agents authorized for anthrax emergencies only have FDA approval for this indication, five antibiotics have FDA approvals as antibiotics for common infections and for bacillus anthrax, and four agents have regulatory approvals for supportive care for cancer and for radiological incidents.

2022-10-17·Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Pre- and Postlicensure Animal Efficacy Studies Comparing Anthrax Antitoxins

Article

作者: Boucher, David ; Cook, Rachel ; Slay, Raymond M ; Hendricks, Katherine ; Merchlinsky, Michael

Abstract:

Background:

The deliberate use of Bacillus anthracis spores is believed by the US government to be a high bioweapons threat. The first line of defense following potential exposure to B. anthracis spores would be postexposure prophylaxis with antimicrobials that have activity against B. anthracis. Additional therapies to address the effects of toxins may be needed in systemically ill individuals. Over the last 2 decades, the United States government (USG) collaborated with the private sector to develop, test, and stockpile 3 antitoxins: anthrax immunoglobulin intravenous (AIGIV), raxibacumab, and obiltoxaximab. All 3 products target protective antigen, a protein factor common to the 2 exotoxins released by B. anthracis, and hamper or block the toxins’ effects and prevent or reduce pathogenesis. These antitoxins were approved for licensure by the United States Food and Drug Administration based on animal efficacy studies compared to placebo.

Methods:

We describe USG-sponsored pre- and postlicensure studies that compared efficacy of 3 antitoxins in a New Zealand White rabbit model of inhalation anthrax; survival following a lethal aerosolized dose of B. anthracis spores was the key measure of effectiveness. To model therapeutic intervention, intravenous treatments were started following onset of antigenemia.

Results:

In pre- and postlicensure studies, all 3 antitoxins were superior to placebo; in the postlicensure study, raxibacumab and obiltoxaximab were superior to AIGIV, but neither was superior to the other.

Conclusions:

These data illustrate the relative therapeutic benefit of the 3 antitoxins and provide a rationale to prioritize their deployment.

2022-03-11·ACS infectious diseases2区 · 医学

Exotoxin-Targeted Drug Modalities as Antibiotic Alternatives

2区 · 医学

Review

作者: Laisi, Arttu ; Sakari, Moona ; Pulliainen, Arto T.

The paradigm of antivirulence therapy dictates that bacterial pathogens are specifically disarmed but not killed by neutralizing their virulence factors. Clearance of the invading pathogen by the immune system is promoted. As compared to antibiotics, the pathogen-selective antivirulence drugs hold promise to minimize collateral damage to the beneficial microbiome. Also, selective pressure for resistance is expected to be lower because bacterial viability is not directly affected. Antivirulence drugs are being developed for stand-alone prophylactic and therapeutic treatments but also for combinatorial use with antibiotics. This Review focuses on drug modalities that target bacterial exotoxins after the secretion or release-upon-lysis. Exotoxins have a significant and sometimes the primary role as the disease-causing virulence factor, and thereby they are attractive targets for drug development. We describe the key pre-clinical and clinical trial data that have led to the approval of currently used exotoxin-targeted drugs, namely the monoclonal antibodies bezlotoxumab (toxin B/TcdB, Clostridioides difficile), raxibacumab (anthrax toxin, Bacillus anthracis), and obiltoxaximab (anthrax toxin, Bacillus anthracis), but also to challenges with some of the promising leads. We also highlight the recent developments in pre-clinical research sector to develop exotoxin-targeted drug modalities, i.e., monoclonal antibodies, antibody fragments, antibody mimetics, receptor analogs, neutralizing scaffolds, dominant-negative mutants, and small molecules. We describe how these exotoxin-targeted drug modalities work with high-resolution structural knowledge and highlight their advantages and disadvantages as antibiotic alternatives.

项与奥托萨昔单抗相关的新闻（医药）

2025-12-31

·百度百家

抗体药物的崛起：改变感染性疾病的治疗格局

人们对抗体药物最初的认识源于机体对细菌感染后的自然免疫反应。在疫苗接种和抗生素疗法出现之前，血清疗法曾是抗某些细菌感染的主要治疗方法。血清疗法通过使用含有特定抗体的免疫血清来治疗白喉和破伤风，因其有效性在历史上得到广泛应用。自19世纪末起，Emil Behring实验室就已开始使用超免疫血清进行被动免疫，以治疗白喉和破伤风。这些经过白喉棒杆菌和破伤风梭菌类毒素免疫的马血清中富含相应抗体，这些高烈性毒素是白喉和破伤风的主要致病因素。尽管血清的安全性存在不足，但其高度有效性使得血清疗法在很长一段时间内仍被广泛应用于这两种疾病的治疗。同时，由于缺乏有效的破伤风疫苗和抗生素，抗血清疗法至今在破伤风暴露后的预防中仍占据重要地位。当然，血清疗法并非仅限于白喉和破伤风的治疗。它也曾被尝试用于肺炎链球菌和金黄色酿脓葡萄球菌等病菌感染的治疗。然而，血清疗法在面对其他细菌感染时效果有限，由于更复杂的疾病发病机理以及病原体的异质性，与白喉和破伤风相比，生效相对有限。随着20世纪40年代青霉素等抗生素的发现，抗菌血清疗法逐渐被淘汰。然而，随着时间的推移，人们逐渐认识到某些细菌感染可能对抗生素疗法产生抗性。同时，抗生素的滥用也导致了超级细菌的出现，这使得感染性疾病再次成为人们关注的焦点。在此背景下，抗血清疗法这一曾被废弃的治疗方法再次进入人们的视野。随着抗生素耐药问题的加剧，单克隆抗体药物重新成为研究热点，并显示出显著治疗优势。过去三十年来，全球制药行业经历了巨大的变革。以单克隆抗体为代表的大分子药物在癌症、自身免疫性疾病和心血管等多个领域得到了广泛的应用。如今，针对感染类疾病，抗体药物正以全新的方式回归。接下来，我们将探讨抗体药物在感染类疾病中的应用现状及未来发展趋势。抗体药物尤其在针对毒素类细菌感染时展现出明显优势。因为毒素类细菌的感染方式更为剧烈，抗体药物能彻底清除这些毒素，防止疾病恶化，而抗生素可能会加剧毒素介导的疾病。 2.1 【炭疽杆菌及抗体药物研发】炭疽杆菌（Bacillus anthracis），属于芽孢杆菌属，是导致某些家畜和人类患上炭疽病（一种人畜共患疾病）的元凶。这种病原菌的荚膜及其所产生的毒素是其主要的致病根源。炭疽杆菌主要通过其荚膜和毒素致病。多个针对其保护性抗原的单抗药物正在研发中，如Raxibacumab和Obiltoxaximab。 2.2 【难辨梭菌及治疗挑战】难辨梭菌（C.difficile）是一种革兰氏阳性菌，是临床期间抗生素相关性腹泻的主要病原体。难辨梭菌感染因高复发率和严重的健康威胁成为治疗难点，其高复发率和毒力成为临床治疗的巨大挑战。目前有两款针对它的单抗药物处于临床试验阶段。 2.3 【金黄色葡萄球菌及耐药性问题】金黄色葡萄球菌（S.aureus）是葡萄球菌属中的一种革兰氏阳性菌，以其高度抗药性著称。金黄色葡萄球菌因多重抗药性和复杂的致病机制构成巨大治疗挑战。近年来出现的耐甲氧西林金黄色葡萄球菌被称为“超级细菌”，能抵抗大多数药物。新型抗体药物正在开发，以应对这些挑战。 2.4 【绿脓杆菌及治疗进展】绿脓杆菌（P.aeruginosa），也被称为铜绿色假单胞菌，是一种具有低致病力却高度抗药性的杆菌。绿脓杆菌因其高度抗药性和多样的毒素结构使得治疗方法有限。针对该菌的单抗显示出潜在的治疗突破，例如Aridis Pharmaceuticals公司的Panobacumab展现了令人鼓舞的结果。自上世纪40年代抗生素问世以来，人类逐渐掌握了对抗感染性疾病的主动权。然而，随着耐药性“超级细菌”的相继涌现，部分疾病再次面临无药可治的困境，这促使人们重新关注抗菌类药物的研发。单克隆抗体药物在对抗菌感染的应用中展现出光明前景。尽管面临挑战，但其在特定领域的优势明显。目前，FDA已批准两款抗菌类抗体药物，并受理一款BLA申请。展望未来，随着更多此类药物的问世，抗菌类抗体药物有望获得更广泛的关注和应用，我们将持续追踪报道其最新进展。

微生物疗法疫苗信使RNA临床研究

2025-11-12

·中国抗生素杂志

噬菌体与抗体类非传统窄谱抗菌药物临床研发进展与挑战

点击蓝字关注我们当前，抗菌药物耐药性(antimicrobial resistance, AMR)问题日益严峻，为全球卫生和社会经济带来了重大挑战，而新型抗菌药物研发管线的不足更加剧了细菌等微生物耐药危机。2019年，全球204个国家或地区共计约127万人死于细菌耐药[1]，到2050年预计将飙升至1000万人，累计经济损失预计高达100万亿美元[2]，但在2017-2020年间，仅11款抗菌新药上市[3]，且没有一款药物为窄谱抗菌药物。广谱抗菌药物能够强效抑制大部分革兰阴性菌和革兰阳性菌，某些药物还能抑制支原体等其他病原微生物；窄谱抗菌药物则只能特异性杀灭某一种或一类细菌[4]。过去，临床和商业因素都极大地驱动了广谱抗菌药物的研发。虽然细菌培养与药敏试验有助于更好地选择敏感药物，但结果报告通常滞后于临床需求，因而临床医生常常倾向于经验性地选择广谱抗菌药物以尽可能覆盖病原菌[5]；广谱抗菌药物的选择偏好以及可用于肺炎、腹腔感染或尿路感染等广泛适应症所带来的巨大经济利益撬动了药企的资金投入，而窄谱抗菌药物在先导化合物发现与优化过程中却往往被放弃进一步研发[6]。然而，广谱抗菌药物往往会对肠道菌群带来附加伤害，从而可能导致二重感染[7]，最严重的不良反应之一为艰难梭菌过度生长引起的伪膜性肠炎，死亡率超40%[8]；此外，广谱抗菌药物的使用还会加剧AMR的产生，广谱抗菌药物对于致病菌以外的其他细菌可能具有较弱的活性，在长期的亚抑制暴露水平下，这些细菌可能产生耐药性[9]。有学者曾提出“STEDI”(谱/转移/支持/多样/保障，spectrum/transmission/enablement/diversity/insurance)原则[10]以全面评估抗菌药物的社会价值，指导新型抗菌药物的研发，其中“S”即代表开发窄谱抗菌药物，以降低对其他菌群的附加伤害和选择性压力。近年来，新型窄谱抗菌药物的研发正在逐渐增多，尤其是许多非传统产品[6]。本文对目前处于临床开发阶段的窄谱抗菌药物进行了梳理，尤其关注噬菌体、抗体药物等非传统产品的研发进展、目前面对的主要挑战和未来发展前景。1 临床研发中窄谱抗菌药物1.1 噬菌体疗法噬菌体(bacteriophage，简称phage)于1915年首次被发现[11]，可感染细菌、真菌、螺旋体和支原体等，具有病毒的生物学特征，即个体微小、结构简单，只含有一种核酸(DNA或RNA)，只能在活细胞中以复制的方式增殖。噬菌体由头部和尾部组成，头部衣壳内含有噬菌体的遗传物质DNA或RNA，尾部含能够特异性识别宿主细胞表面受体的受体结合蛋白(receptor binding protein, RBP)，与噬菌体黏附有关[12]。根据能否裂解细菌，噬菌体可分为烈性噬菌体(溶菌型噬菌体)和温和噬菌体(溶原型噬菌体)两大类，前者能够在侵入宿主菌后不断增殖并使细菌裂解死亡(图1)，所以一般采用烈性噬菌体治疗细菌感染[13]，而且由于其增殖特性，烈性噬菌体天然成为一种可自我扩增的“药物”，这是传统抗菌药物不可能做到的。此外，由于噬菌体与细菌表面受体的分子结构存在互补性，所以还具有窄谱抗菌特性，能够特异性感染宿主菌，进而使其裂解死亡[14]。①噬菌体可通过其尾部的RBP黏附于细菌表面受体(如λ噬菌体特异性结合大肠埃希菌LamB受体)，产生酶裂解局部细胞壁，并将自身核酸(DNA或RNA)注入细菌；②利用细菌的氨基酸、核苷酸、能量和细胞器进行病毒自身核酸的复制和蛋白质外壳的合成；③组装成完整的子代噬菌体；④释放内溶素等酶破坏宿主菌细胞壁，使其裂解死亡，子代噬菌体释放到外界，继续感染新的宿主。噬菌体疗法即为借助噬菌体裂解宿主菌的特性达到杀灭细菌的目的，从而治疗细菌感染。Félix d’Hérelle是开启噬菌体疗法的先驱，1919年，d’Hérelle从鸡粪中分离出噬菌体，成功治疗了一种鸡伤寒病[15]；之后，在自我给药证明口服噬菌体制剂的安全性后，他首次在人体使用噬菌体疗法成功治疗了3名志贺菌感染所致细菌性痢疾的患儿[16]。噬菌体疗法开始应用的时间远早于青霉素上市，但由于青霉素等药物的抗菌活性强，所以噬菌体疗法逐渐被放弃，仅在格鲁吉亚、波兰和俄罗斯等东欧国家继续使用。 21世纪以来，由于AMR日益泛滥和传统抗菌药物研发陷入困境，噬菌体疗法迎来新一轮临床关注，Petrovic Fabijan等详细梳理了噬菌体科学和噬菌体疗法发展的重要里程碑[17]，可供参考。此前许多同情用药的单一病例报告已证明了噬菌体疗法在广泛患者人群中的安全性[18]，如Maddocks等报道一位77岁女性在肺癌术后出现严重的呼吸机相关性肺炎，感染细菌为多重耐药铜绿假单胞菌，对包括美罗培南、亚胺培南、哌拉西林/他唑巴坦和环丙沙星等在内的多种抗菌药物产生耐药性，体外药敏实验结果显示AB-PA01(4种专性烈性噬菌体组成的混合物，每种噬菌体的浓度约为1×109，扩大使用计划经FDA批准)对该患者的分离株具有高度活性，在获得患者的知情同意后，于第23天开始为期7 d的噬菌体静脉注射和雾化吸入辅助治疗，在噬菌体治疗第4天，铜绿假单胞菌培养转阴，且在AB-PA01治疗完成后的6个月内一直保持阴性，此外，在治疗期间和随访过程中均未观察到不良事件[19]。目前正积极开展临床试验以评估噬菌体疗法的有效性和安全性疗效，但尚无FDA或EMA批准上市的噬菌体产品。根据ClinicalTrials检索结果，截至2024年10月，有12款噬菌体产品处于临床研发阶段(表1)，与2020年(仅4款噬菌体产品)相比明显增加[6]。大多数产品处于I/Ⅱ期和II期临床试验(10/12，83%)，只有1款噬菌体裂解酶CF-301推进到了Ⅲ期临床试验(本综述主要关注噬菌体疗法，有关CF-301及该类药物的介绍可参考McCarthy等[20]和Murray等[21]报道)。由于噬菌体的极端生物特异性，单一噬菌体难以解决临床实际中多种细菌感染的问题，故目前正在积极探索扩大噬菌体宿主谱的方法，根据研究进展，有以下4种方法：①将多种宿主范围不同的噬菌体组合成噬菌体“鸡尾酒”；②通过基因工程定向改造噬菌体宿主谱；③体外连续培养诱导噬菌体宿主范围发生改变；④从自然界中分离筛选宽谱噬菌体[22]。根据检索结果，目前临床管线中的噬菌体产品采用的是前两种方法：除YPT-01(单种噬菌体)和CF-301(噬菌体裂解酶)外，其余噬菌体产品均为噬菌体“鸡尾酒”。尤其值得注意的是，大多数产品使用的是野生型噬菌体，而LBP-EC01[23]和SNIPR001[24]均为基因工程噬菌体，均对噬菌体进行了CRISPR/Cas3增强。 CRISPR/Cas系统增强的基因工程噬菌体最早可追溯至2014年[25]，Bikard等将CRISPR/Cas9系统克隆至噬菌体ΦNM1z中，体外研究及小鼠皮肤感染模型中的研究发现，在特殊设计的CRISPR RNA(crRNA)引导下，Cas9能够特异性破坏金黄色葡萄菌中携带耐药基因的质粒，而对非靶向菌株的影响较小[25]。Choi等最近报告了一种高效的工程噬菌体改造工具，该团队通过将Cas9基因和λRed重组系统(包括Exo、Bet和Gam蛋白)整合到铜绿假单胞菌的染色体上，构建了生产者(producer, PD)细胞，当野生型噬菌体感染这些PD细胞后，Cas9会根据sgRNA的引导，靶向切割野生型噬菌体基因组中的特定序列，同时λRed系统利用同源重组机制，将编辑模板整合到切割位点，从而生成重组噬菌体，实现对噬菌体基因组的快速、精确编辑[26]。然而，目前处于临床试验阶段的工程噬菌体LBP-EC01和SNIPR001均使用的是CRISPR/Cas3(单链DNA核酸酶和解旋酶，属于I型CRISPR系统)系统，而非CRISPR/Cas9(双链DNA核酸酶，属于Ⅱ型CRISPR系统)系统，这是因为前者能够在特定位点产生单链缺口，并继续沿DNA链大片段剪切DNA序列，有利于彻底清除目标基因，因此多用于抗菌领域[27]。在SNIPR001的临床前研究中，Gencay等在8种野生型噬菌体(α15、α17、α20、α31、α33、α46、α48和α51)的基因组中引入CRISPR/Cas3系统后，CRISPR RNA(crRNA)能够引导Cas3蛋白结合并降解E. coli基因组中的目标DNA(包括毒力基因和必需基因)，使82株E. coli菌株的细菌计数均降至检测下限(200 CFU/mL)以下；在启动子PbolA的驱动下，这些噬菌体还能够显著降低大肠埃希菌生物膜的代谢活性，表明SNIPR001对于治疗生物膜相关感染具有潜在益处[24]。表2对比了传统抗菌药物与噬菌体疗法的特点[28]，相较于传统抗菌药物，噬菌体疗法天然具有窄谱抗菌特性并且可自我扩增，而且其杀菌效果已在广泛体内外研究中得到证实。尤其值得注意的是，病原菌对噬菌体抗性的产生可能反而会恢复其对抗菌药物的敏感性或降低毒力，噬菌体可以通过与外排泵或脂多糖(lipopolysaccharide, LPS)、荚膜抗原等毒力因子特异性结合而黏附于病原菌，若产生噬菌体抗性，则可能导致以上物质表达水平下调，前者能够恢复病原菌对抗菌药物的敏感性[29]，而后者能够使病原菌毒力下降(León等对毒力降低的噬菌体耐药菌株进行了总结[30])或更容易被巨噬细胞吞噬[31]。但噬菌体疗法也存在一些固有的局限性：噬菌体的极端生物特异性要求用药前检测病原菌对噬菌体的敏感性，否则可能导致治疗失败，也因此从诊断到开始治疗需要经过较长时间；噬菌体难以穿过真核细胞膜，故可能无法治疗胞内感染；细菌裂解后，可能会释放出抗原(如内毒素)，可能导致疾病恶化[28]；作为一种生物产品，噬菌体可能具有免疫原性[32]；噬菌体生产过程中容易掺入细菌抗原等。1.2 抗菌抗体抗体类药物包括单克隆抗体(monoclonal antibody, mAb，以下简称单抗)、双特异性抗体 (bispecific antibody, BsAb，以下简称双抗)和抗体-药物偶联物(antibody-drug conjugates, ADC)3种，目前研发中的窄谱抗菌药物包含以上全部类型，这是因为绝大多数细菌抗原与人类明显不同，所以存在许多单抗或双抗的理想靶标；此外，抗菌药物具有高度特异性且安全性较好，成为ADC的理想载体。根据ClinicalTrials检索结果，截至2024年10月，共有20款抗体药物处于临床研发阶段(表3)，与2020年(仅6款抗体药物)相比显著增加[6]。大多数产品处于I期临床试验(9/20，45%)，且绝大多数产品为单抗(18/20，90%)，其余为1款双抗MEDI-3902和1款ADC药物DSTA4637S；靶向的细菌主要为金黄色葡萄球菌(6/20，30%)，其次是肉毒杆菌(3/20，15%)和铜绿假单胞菌(3/20，15%)。抗菌抗体主要通过以下机制发挥功能：①阻断细菌毒素分泌[33]，如单抗KB001，靶向铜绿假单胞菌Ⅲ型分泌系统(type three secretion system, T3SS) 尖端蛋白PcrV，阻断毒素分泌，然而，KB001在II期临床试验中未能达到疗效终点，另一药物为双抗MEDI-3920，其靶点之一即为PcrV，目前正在进行II期临床试验；②阻断细菌毒素与宿主受体结合，如2016年获批的单抗bezlotoxumab，可通过与艰难梭菌毒素B(TcdB)的CROPS区域结合，阻断TcdB与宿主受体结合[34]，从而预防艰难梭菌感染的复发；③激活补体级联反应，从而导致溶菌作用，抗菌抗体通过Fab端识别并结合细菌抗原(如鞭毛、荚膜多糖、脂多糖等)，Fc端则与补体C1q结合，通过经典途径激活补体，最终形成攻膜复合物(membrane attack complex, MAC)，锚定在细菌细胞膜并破坏局部磷脂双层，形成跨膜通道，导致渗透压改变，最终发挥溶菌作用[35]；④通过抗体介导的吞噬调理作用，促进细菌吞噬和炎症因子分泌。抗菌抗体的Fc端与中性粒细胞或巨噬细胞表面的Fc受体(Fc receptors, FcRs)结合，从而导致抗体依赖性的细菌吞噬作用，并促进TNF-α和IL-1β等炎症因子的分泌[36]。目前约60%的抗体药物针对的靶点为细菌毒素，通过阻断细菌毒素与宿主受体的结合，从而发挥抗菌作用。对于此类药物，在选择靶标时需要特别考虑该靶标在细菌进化中是否保守。拟治疗金黄色葡萄球菌感染的MEDI-4893所针对的靶点为α毒素(AT，由hla基因编码)，它是一种溶细胞成孔毒素，是脓毒症、皮肤和软组织感染以及肺炎动物模型中的关键致病毒力因子，且在全球金黄色葡萄球菌，包括甲氧西林敏感的金黄色葡萄球菌(MSSA)和甲氧西林耐药的金黄色葡萄球菌(MRSA)等呼吸道分离株中高度保守[37-38]。与传统抗菌药物相比，抗菌抗体具有独特优势。①由于抗体药物与靶点存在特异性结合，所以天然成为一种窄谱抗菌药物，相较于广谱抗菌药物，有助于降低选择性压力、延缓AMR产生；②抗体与传统抗菌药物的作用机制不同[39]，因而不易产生交叉耐药，从而可为难治细菌感染提供新的治疗选择；③抗体药物是免疫系统的产物，能够与其他免疫活性分子(如补体和细胞因子等)相互协调介导免疫反应(如补体依赖的细胞毒作用和抗体依赖的细胞毒作用)，从而增强抗菌活性[40]。然而，该类药物仍有一定缺陷。①对病原体快速诊断方法提出更高要求，这是所有窄谱抗菌药物的共性，如果快速诊断方法无法在临床实践中广泛应用，那么窄谱抗菌药物的精准治疗无疑是天方夜谭；②抗体类药物大多需要注射给药，口服生物利用度较低，给药途径不便可能会影响患者依从性；③与其他治疗性蛋白产品类似，抗菌抗体也可能诱导人体产生抗药抗体(anti-drug antibody, ADA)， ADA可能会影响药物的药动学(pharmacokinetics, PK) 特征，还可能导致不良事件，部分具有中和作用的ADA还可能会降低疗效[41]；④相较于传统抗菌药物，抗体类药物的储存和运输条件更为严苛，而且还要持续监测生物或化学污染，从而进一步增加了其临床应用成本[32]。2 临床研发面临的挑战相较于广谱抗菌药物，窄谱抗菌药物的临床开发可能会面临一些额外的挑战。①具有特定耐药表型的患者数量较少，入组速度受限；②由于临床上快速诊断技术较为匮乏[42]，可能在初期需要进行经验性抗菌治疗，在临床试验方案设计时可以考虑将窄谱抗菌药物作为联合用药或降阶梯疗法用药[6]，但这种做法可能会干扰研究药物在非劣效试验中的有效性评价；③对于潜在的伴随多种细菌感染的患者，可能需要在试验期间持续使用其他广谱抗菌药物，如果广谱抗菌药物与研究药物的抗菌谱有所重合，则会在一定程度上混淆研究药物的有效性评价结果[43]。面对以上挑战和困难，监管机构可能也会适当放宽要求，依据单个临床试验的说服力、疾病严重程度和紧急程度，FDA可以考虑仅靠1项充分、对照组设置良好的确证性临床试验证据批准药物上市[44]，如注射用舒巴坦钠/度洛巴坦钠(XACDURO®)，其适应症为鲍曼-醋酸钙不动杆菌复合体(ABC)敏感分离株所致医院获得性肺炎(HAP)、呼吸机相关性肺炎(VAP)，仅依靠1项关键Ⅲ期临床试验(n=209，亚胺培南/西司他丁作为背景治疗，黏菌素作为对照组)成功上市[45]。2.1 噬菌体疗法对于噬菌体疗法这一非传统产品的临床开发还存在一些独特的难题。首先是监管障碍，目前中国仍缺乏相应监管法规，国际上噬菌体相关产品的监管文件也尚在酝酿阶段。FDA在2020年制定了eIND(Emergency Investigational New Drug, 紧急使用研究药物)程序[46]，目前的大多数经验都是在该监管框架下获得的。欧盟尚未批准任何用于人类治疗的噬菌体产品，但从2015年开始，EMA就在积极推动噬菌体产品的结构性和规范性监管法规制定[47]。第二个重要挑战为PK/PD研究困难。首先是噬菌体作为一种生物产品，其PK特征更为复杂，传统药物研发所积累的经验不再适用。噬菌体疗效很大程度上取决于给药途径，不同给药途径下生物利用度存在明显差异[48]；噬菌体的体内过程(吸收、分布、代谢和排泄，ADME)受噬菌体一般物理性质、细胞类型、微生物组和免疫反应等多种因素的影响(图2)；PK研究困难的最主要原因在于噬菌体自我扩增的独特性，这是以往药物研发中未曾遇到的挑战。噬菌体可以通过不同途径给药，如口服、吸入和静脉注射。静脉注射可实现噬菌体的完全吸收，而口服和吸入给药后噬菌体的吸收受噬菌体大小、形态及给药部位细胞类型的影响。噬菌体在组织器官的分布取决于噬菌体大小、形态、细胞类型以及微生物组。噬菌体代谢受pH、微生物组和免疫反应的影响。噬菌体的肾脏排泄速率与噬菌体大小呈负相关。由于噬菌体具有自我扩增(呈非线性且存在密度依赖性)特性，故其动力学特征远远不同于传统抗菌药物，理解噬菌体的动力学特征应从生态相互作用(ecological interaction)的角度出发，而不是采用传统化学反应动力学的视角[49]。噬菌体杀灭病原菌存在两种途径：第一种为“主动治疗”，即噬菌体经广泛扩增后释放至外界环境，对病原菌造成二次感染来杀灭细菌；第二种为“被动治疗”，即噬菌体初始给药剂量足够大，使其在初次感染时就能杀灭绝大多数病原菌[50]。 “主动治疗”更能体现噬菌体作为自我扩增药物的优势，而要实现“主动治疗”，前提条件为噬菌体成功增殖，这一过程可用基本再生数(R0)[51]来表征，可采用基本生活史参数(即细菌平均复制速率、正常细菌死亡速率和受噬菌体感染细菌的裂解速率等)预测R0，只有R0＞1时，噬菌体才能实现扩增。更进一步理解，R0取决于细菌密度，只有当细菌密度超过增殖阈值(Xp，R0=1时的细菌密度)时，噬菌体才能增殖；将细菌密度达到增殖阈值的时间定义为噬菌体的增殖开始时间(Tp)，只有Tp早于宿主发生有害反应(即病原菌造成的免疫或毒性反应)的时间，才能成功实现“主动治疗”；而在到达Tp之前，必须保证体内尚存噬菌体，若接种时间太早，噬菌体可能被机体清除，从而导致治疗失败，故接种时间必须晚于失败阈值时间(Tf)；与抗菌药物相似的是，噬菌体同样存在淹没阈值，即细菌载量开始下降所需的噬菌体密度，对于“主动治疗”，若增殖后噬菌体的密度始终无法超过淹没阈值，将导致治疗失败，对于“被动治疗”，只有初始给药的噬菌体密度超过淹没阈值，治疗才有可能成功。对于动力学的深入理解会为临床实践带来更加科学的指导：①虽然对于大多数疾病的大多数治疗，一般认为越早越好，而对于噬菌体疗法，过早接种对疾病治疗毫无益处；②噬菌体疗法与抗菌药物联合使用时，必须保证抗菌药物不会干扰噬菌体增殖，否则抗菌药物作用下细菌载量的减少，将导致噬菌体缺乏足够的宿主来实现广泛增殖，从而推迟Tf和Tp，可能导致噬菌体疗法失败、协同作用消失；③无论是“主动治疗”还是“被动治疗”，均需保证噬菌体密度在某一时刻能够超过淹没阈值，否则将导致治疗失败。其次，对噬菌体PD参数的选择缺乏标准化[52]，噬菌体敏感性检测方法有待进一步研究。通常采用双层或单层琼脂平板法以及浮游生物杀伤试验来评价噬菌体的抗菌活性[53]，目前正在积极探索建立统一方法[54]。综上所述，目前关于噬菌体疗法的PK/PD研究仍较为有限，Nang等[53]总结了目前已发表的有关PK/PD研究的文献，如Cairns等进行了空肠弯曲菌GIIC8与噬菌体CP8的体外PK/PD研究，并采用数学模型进行了拟合，强调了增殖阈值与淹没阈值在治疗成败中的重要作用[55]，但如何指导临床研究进行剂量设计与给药时间设计仍需进一步探索，成为阻碍噬菌体疗法临床转化的主要障碍(图3)。 2.2 抗体药物虽然抗体药物在肿瘤和自身免疫性疾病领域表现优异，但在抗感染领域，抗体药物从临床前向临床的转化却面临极大挑战，目前仅3种抗菌抗体被FDA批准，raxibacumab和obiltoxaximab用于治疗炭疽杆菌感染，bezlotoxumab用于治疗艰难梭菌感染[56]，部分抗体药物的临床试验因未达到预期疗效被迫终止。单克隆抗体MEDI-4893的I期临床试验和II期临床试验结果均已发表，I期临床试验结果表明MEDI4893给药后血清AT中和活性大幅增加，并且与药物暴露高度相关(R2=0.91)[57]；然而，Ⅱ期临床试验结果表明MEDI-4893与安慰剂相比30 d金黄色葡萄球菌肺炎发生率无显著差异[58]。双特异性抗体MEDI3902同样未能降低铜绿假单胞菌所致呼吸机相关性肺炎(VAP)的发生率[59]。抗体-抗菌药物偶联物(antibody-antibiotic conjugate, AAC)DSTA4637S的体外研究表明DSTA4637S能够根除人巨噬细胞、内皮细胞以及上皮细胞中的MRSA感染，并能够有效阻止细菌的细胞间转移；在小鼠菌血症模型中，在清除胞内细菌、减少播散性感染方面，DSTA4637S相较于万古霉素的优异疗效也得到了验证，相关工作已发表于Nature[60]；然而，在Ib期的探索性研究中，DSTA4637S治疗组未观察到细菌载量和炎症生物标志物改善趋势[61]。这些临床研究失败的原因仍在探索，可能为后续药物研发与临床试验设计提供前车之鉴。Centoxin是首个针对革兰阴性菌所致脓毒血症开发的抗体，然而由于抗体缺乏特异性、试验中未严格执行受试者入组标准等等原因，试验结果被FDA质疑，最终流产[62]；某些抗体药物发挥作用可能需依赖于免疫系统，如Pagibaximab可能是因为在免疫功能发育不成熟的新生儿中开展试验最终导致未获得预期疗效[63]；细菌在动物和人体中的免疫逃逸机制可能存在种属差异，尽管动物研究中取得了良好疗效，但在人体试验中有效性仍有可能无法证实[64]。3 未来展望临床偏好和商业利益所驱动的广谱抗菌药物滥用使AMR愈演愈烈，近年来，新型窄谱抗菌药物的研发逐渐吸引了人们的兴趣，尤其是对于噬菌体疗法和抗菌抗体等非传统产品，临床研发管线呈明显增加。然而，窄谱抗菌药物只有在预期靶点存在、可识别且为主要致病因素时才有效，未能准确理解临床前研究结果和药理规律使这些非传统产品的早期临床试验遭遇了一些失败；而且，相较于广谱抗菌药物，窄谱抗菌药物的临床试验可能将面临特定耐药表型患者入组缓慢、与广谱抗菌药物联用混淆有效性和安全性评价结果等新的挑战。虽然遇到了一些挫折，科学家仍在积极探索新的治疗手段，包括基于CRISPR-Cas3的工程化噬菌体[65]、开发无细胞方法扩增噬菌体[66]、使用脂质体包裹的噬菌体延长有效时间[67]以及噬菌体/抗体与传统抗菌药物联用[68-69]等。新型窄谱抗菌药物的研发有助于延缓耐药性产生、避免破坏有益菌群以及为死亡率高的严重感染提供有效治疗手段，具有巨大临床价值，伴随着快速诊断技术(如PCR、MALDI-TOF质谱和基因组测序[70])的应用以及严格的抗菌药物管理，有望减缓AMR所带来的全球健康威胁。利益冲突所有作者均声明不存在利益冲突参考文献（略）来源：齐春业, 冶会静, 武晓捷, 等. 噬菌体与抗体类非传统窄谱抗菌药物临床研发进展与挑战[J]. 中国抗生素杂志, 2025, 50(10): 1123-1134. 点击下方“阅读原文”下载全文 ↓↓↓

微生物疗法临床研究

2023-11-20

·GlobeNewswire-Health Care

NightHawk Biosciences Provides Q3 2023 Business Update

DURHAM, N.C., Nov. 20, 2023 (GLOBE NEWSWIRE) -- NightHawk Biosciences (NYSE American: NHWK), a fully integrated biopharmaceutical company specializing in the end-to-end development, manufacturing, and commercialization of innovative therapies, today provided strategic, financial, and operational updates for the quarter ended September 30, 2023. Jeff Wolf, Chief Executive Officer of NightHawk, commented, “We are very pleased with the progress of our Scorpius San Antonio facility where operations are advancing well and the feedback from our customers has been extremely positive. As a result, we are currently evaluating a variety of strategic options to maximize the potential of the business. We look forward to providing further updates on our efforts in the near future.” Third Quarter 2023 Financial Results In August, the Company determined to make available for sale the equity interests of Elusys Therapeutics, Inc. Therefore, the results of operations have been reclassified as discontinued operations on a retrospective basis for all periods presented.For the three months ended September 30, 2023 we recognized $6.7 million of revenue from product sales, which is included in discontinued operations, $0.6 million of revenue from process development and $0.1 million from service revenue. For the three months ended September 30, 2022 we recognized $5.98 million of product sales revenue, which is included in discontinued operations, and $0.5 million of grant revenue. The increase in product sales revenue is due to the completion of the manufacturing conversion of ANTHIM® and the increase in process development revenue is attributable to the operations of the San Antonio CDMO facility. No grant revenue was recognized in 2023 as the CPRIT grant has ended.Cost of revenues were $2.7 million for the three months ended September 30, 2023. $2.2 million of these expenses primarily reflect the manufacturing conversion costs from the sale of ANTHIM® which are included in discontinued operations. The remaining $0.5 million primarily consists of direct cost of labor, overhead and material costs at Scorpius. We recognized $6.4 million of product cost of revenues for the three months ended September 30, 2022, driven by the sale of ANTHIM® to Canada which is included in discontinued operations.Research and development expenses decreased approximately 3.7% to $5.2 million for the three months ended September 30, 2023, compared to $5.4 million for the three months ended September 30, 2022. The components of R&D expense are as, in millions: HS-110 expense decreased by $0.1 million primarily due to the discontinuation of the clinical trial in 2022; HS-130 expense decreased to $0.0 from $0.1 million due to the de-prioritization of our oncology assets; PTX-35 expense decreased by $0.5 million primarily due to the discontinued clinical trial and development of the product candidate in the third quarter of 2022; other programs expense stayed consistent at $0.3 million and primarily relate to close out costs of our R&D facility; and unallocated research expenses increased by $0.5 million primarily due to increased personnel costs, depreciation expense, amortization expense and scientific hardware and software.Selling, general and administrative expenses were $6.1 million and $4.8 million for the three months ended September 30, 2023 and 2022, respectively. The increase was primarily due to increases in marketing expense of $0.6 million, personnel expense of $0.4 million, depreciation and amortization of $0.2 million, and rent expense of $0.2 million, offset by a decrease in insurance expense of $0.1 million.As of September 30, 2023, the Company had approximately $9.5 million in cash, cash equivalents, and short-term investments of which $3.3 million is in current assets held for sale. NightHawk Biosciences, Inc.NightHawk Biosciences leverages its integrated ecosystem of subsidiaries to streamline the advancement of novel therapies, breaking through barriers that prolong traditional drug development. This empowers us to bring our ideas to life with efficient control, superior quality, and uncharacteristic agility. For more information on the Company and its subsidiaries, please visit: www.nighthawkbio.com, and also follow us on Twitter. Forward Looking StatementThis release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. In some cases forward-looking statements can be identified by terminology such as "may," "should," "potential," "continue," "expects," "anticipates," "intends," "plans," "believes," "estimates," and similar expressions, and include statements such as the evaluation of a variety of strategic options to maximize the potential of the Scorpius San Antonio operations and providing updates on the Company’s efforts in the near future. Important factors that could cause actual results to differ materially from current expectations include, among others, , NightHawk’s ability to successfully maximize the potential of its operations, NightHawk’s financing needs, its cash balance being sufficient to sustain operations and its ability to raise capital when needed, NightHawk’s ability to successfully operate as a CDMO, NightHawk’s and its subsidiaries’ ability to maintain license agreements, the continued maintenance and growth of NightHawk’s and its subsidiaries’ patent estates, , the ability to obtain required regulatory approval or to comply with ongoing regulatory requirements, regulatory limitations relating to NightHawk’s ability to promote or commercialize its product candidates for the specific indications, acceptance of product candidates and services in the marketplace and the successful development, marketing or sale of NightHawk’s services and products, developments by competitors that render such products or services obsolete or non-competitive, and other factors described in NightHawk’s annual report on Form 10-K for the year ended December 31, 2022, subsequent quarterly reports on Form 10-Qs and any other filings NightHawk makes with the SEC. The information in this presentation is provided only as of the date presented, and NightHawk undertakes no obligation to update any forward-looking statements contained in this presentation on account of new information, future events, or otherwise, except as required by law. Media and Investor Relations ContactDavid Waldman+1 919 289 4017investorrelations@heatbio.com

财报

100 项与奥托萨昔单抗相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10776	奥托萨昔单抗	J06BB22	DB05336

研发状态

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
炭疽	加拿大	Elusys Therapeutics, Inc.	2020-07-30
吸入炭疽	美国	Elusys Therapeutics, Inc.	2016-03-18

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01932437 (CTgov)	临床1期	吸入炭疽	36	Placebo+ETI-204 (Cohort 1)	膚鬱願齋醖憲壓選顧鹹 = 壓製簾餘網鬱襯繭憲齋顧鹹壓範鑰顧窪醖衊蓋 (鹽鏇觸憲齋鏇窪範鏇鬱, 蓋製構衊襯糧衊鹹膚糧 ~ 願範獵積積範淵齋糧鬱) 更多	-	2019-05-01
				Placebo+ETI-204 (Cohort 2)	膚鬱願齋醖憲壓選顧鹹 = 構鑰廠選選醖鏇窪廠艱顧鹹壓範鑰顧窪醖衊蓋 (鹽鏇觸憲齋鏇窪範鏇鬱, 膚淵網齋艱衊膚獵蓋繭 ~ 夢製艱鹽壓鹽範範願築) 更多
NCT01932242 (CTgov)	临床1期	吸入炭疽	70	Placebo+ETI-204 (Sequence A)	願淵艱夢觸憲衊鏇顧獵 = 艱艱蓋願範願艱遞簾製淵壓願淵積夢襯齋願獵 (網願鏇遞憲範鹽鏇鏇艱, 積築醖糧廠願遞簾網廠 ~ 願廠膚糧鹽衊製鹹膚範) 更多	-	2019-04-22
				Placebo+ETI-204 (Sequence B)	願淵艱夢觸憲衊鏇顧獵 = 獵遞觸製鬱齋衊構鏇廠淵壓願淵積夢襯齋願獵 (網願鏇遞憲範鹽鏇鏇艱, 襯衊築範製積廠網窪鹹 ~ 醖繭窪鬱夢構鹹餘觸網) 更多
NCT01929226 (CTgov)	临床1期	吸入炭疽	280	ETI-204	糧夢鹹糧糧壓衊築觸夢 = 繭鏇願蓋遞艱糧餘製鹹襯選鬱糧築簾蓋醖獵壓 (廠網繭齋鏇繭襯鹽齋鏇, 獵醖鏇餘壓網積醖壓鹹 ~ 觸糧築網廠齋築醖衊衊) 更多	-	2019-04-08
NCT01952444 (CTgov)	临床1期	吸入炭疽	40	Ciprofloxacin+ETI-204 (ETI-204 + Ciprofloxacin)	鏇鹹選積網製簾選繭膚 = 願窪選窪觸選齋餘夢淵觸淵糧壓積膚餘願憲糧 (繭膚顧廠糧憲餘遞鹹蓋, 襯築鹹鏇襯選網鏇淵選 ~ 膚願襯繭鹽夢選網製淵) 更多	-	2019-04-08
				diphenhydramine+ETI-204 (ETI-204)	鏇鹹選積網製簾選繭膚 = 鹹蓋膚鹽艱糧網壓廠廠觸淵糧壓積膚餘願憲糧 (繭膚顧廠糧憲餘遞鹹蓋, 鹹鹽醖積鹹築窪鬱構齋 ~ 願艱醖願鏇製醖壓顧願) 更多