Suvratoxumab

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 ↓↓↓

LOS GATOS, Calif., Dec. 20, 2024 (GLOBE NEWSWIRE) -- Aridis Pharmaceuticals, Inc. (OTC: ARDS) (“Aridis” or the “Company”), a biopharmaceutical company, today announced a corporate update on recent developments. Company update: The Company continues to diligently explore multiple paths to monetize its assets amidst a protracted challenging capital market and limited internal resources. During the second half of this year it has been in discussions with other pharmaceutical companies and investment firms on possible partnerships and investments in the clinical product candidates AR-301, AR-320, AR-501, and the APEX platform technology. The Company has substantially reduced its operational cash burn by delaying the expenses associated with SEC filings in favor of business development discussions with potential partners and investors. As a result of voluntary non-compliance, the Company was transitioned to and expects to continue to be listed on the OTC Expert Market until a positive outcome(s) from the business development effort on one or more of its programs. Importantly, two promising developments have been achieved involving the lead assets AR-301 and AR-501 that, if realized, are expected to generate near term revenues and shareholder value: Phase 2 product candidate AR-501 The Company recently executed an Asset Acquisition Terms Agreement with an undisclosed pharmaceutical company (Partner) to assign exclusive ownership of AR-501 upon receiving the Partner’s payments totaling $6,500,000. Two payments of $3,250,000 each are expected to be received in the first and second quarter of 2025, respectively. The Partner is further obligated to make annual royalty payments to Aridis of 12% to 15% of the net sales revenue for up to 10 years following the first commercial sale. Development status: AR-501 is being developed as a therapeutic treatment for chronic bacterial lung infections in cystic fibrosis (CF) patients. A Phase 1 trial in healthy adults and a Phase 2a trial in cystic fibrosis patients have been completed. The primary endpoint of safety was achieved in both studies, showing that AR-501 was well tolerated when administered as an inhaled dosage form over several weekly treatments. The pharmacokinetic data showed effective delivery of AR-501 into the lungs of CF patients and a fast clearance rate. The positive clinical trial data also facilitated the filing for non-dilutive grant funding support from governmental sources and non-governmental organizations (NGOs), which we intend to explore. Lead product candidate AR-301 The discussions with potential partners and investors to continue the development of AR-301 resulted in an investment proposal from a globally recognized private investment firm in an amount that the Company believes is sufficient to complete the second and final Phase 3 study and product approval. The Company is working closely with the investment firm to satisfy specific requirements for the closing of investment. Details of the investment proposal and the progress toward investment closing are expected to be disclosed in 1Q25. Development status: AR-301 is being evaluated for the adjunctive therapeutic treatment of Ventilator Associated Pneumonia (VAP). The first of two planned Phase 3 clinical trials saw significant reduction in patient enrollment that was brought about by the COVID-19 pandemic, resulting in an under-powered study. However, despite a small sample size, a positive efficacy trend in favor of AR-301 in VAP patients was observed (p=0.242 at day 21). Remarkably, in a prespecified subpopulation of adults 65 years and older, the efficacy signal was increased by approximately 300%, reaching statistical significance level (p=0.056 at day 21 and p=0.025 at day 28 post-treatment). Furthermore, AR-301 treated patients had a median reduction of length of stay in the intensive care unit (ICU) and hospital by 7 days and by 9 days in the over 65 subpopulation. The clinical data and the proposed design for the second and final Phase 3 study were presented to the FDA and the European Medicines Agency (EMA). Concurrence has been achieved with the regulators on a single, globally harmonized Phase 3 study for licensure. Moving the final Phase 3 study forward is predicated on finalizing the above proposed investment. Phase 3 product candidate AR-320 Following a lengthy effort to resolve the product licensing dispute with MedImmune Limited (“MedImmune”, a subsidiary of AstraZeneca), a mutually satisfactory resolution has not been reached. The Company is currently exploring its legal options for loss recovery. Development status: AR-320 is being developed for the prevention of Ventilator Associated Pneumonia (VAP) in a pivotal Phase 3 clinical trial. The AR-320-003 Phase 3 clinical study was initiated in 2022, with 24 patients enrolled. The study was placed on voluntary hold at the time that the product license dispute with MedImmune arose, and is now expected to be discontinued. Company operations and financials The Company’s primary focus in the past year has been on business development discussions related to its clinical product candidates, on laboratory activities to support two NIH active grant awards and on one funded external collaboration related to the APEX platform technology. Operating expenses, including clinical trial and clinical supplies manufacturing have been substantially lowered while all clinical trials have either been completed or terminated. The Company has been working with its lead lender Streeterville Capital, LLC to service the loan. The Company’s near-term goals will be to successfully complete the business objectives described above and to become current on its SEC filings in the first half of 2025. About Aridis Pharmaceuticals, Inc. Aridis Pharmaceuticals, Inc. discovers and develops anti-infectives to be used as add-on treatments to standard-of-care antibiotics. The Company is advancing multiple clinical stage monoclonal antibodies (mAbs) targeting bacteria that cause life-threatening infections such as ventilator associated pneumonia (VAP) and hospital acquired pneumonia (HAP), in addition to preclinical stage antiviral mAbs. The use of mAbs as anti-infective treatments represents an innovative therapeutic approach that harnesses the human immune system to fight infections and is designed to overcome the deficiencies associated with current standard-of-care broad spectrum antibiotics. Such deficiencies include, but are not limited to, increasing drug resistance, short duration of efficacy, disruption of the normal flora of the human microbiome and lack of differentiation among current treatments. The Company’s mAb portfolio is complemented by a novel non-antibiotic small molecule anti-infective candidate mechanism being developed to treat lung infections in cystic fibrosis patients. The Company’s pipeline is highlighted below: Aridis' Pipeline AR-301 (VAP). AR-301 is a fully human IgG1 mAb targeting gram-positive Staphylococcus aureus (S. aureus) alpha-toxin that has recently completed the first of two planned Phase 3 superiority clinical studies as an adjunctive treatment of S. aureus ventilator associated pneumonia (VAP).AR-320 (VAP). AR-320 is a fully human IgG1 mAb targeting S. aureus alpha-toxin that is being evaluated in a Phase 3 clinical study as a preventative treatment of S. aureus colonized mechanically ventilated patients who do not yet have VAP.AR-501 (cystic fibrosis). AR-501 is an inhaled formulation of gallium citrate with broad-spectrum anti-infective activity being developed to treat chronic lung infections in cystic fibrosis (CF) patients. This program has successfully completed Phase 2a clinical development in CF patients.AR-701 (COVID-19). AR-701 is a cocktail of fully human mAbs discovered from convalescent COVID-19 patients that are directed at multiple protein epitopes on the SARS-CoV-2 virus. It is formulated for delivery via intramuscular injection or inhalation using a nebulizer.AR-401 (blood stream infections). AR-401 is a fully human mAb preclinical program aimed at treating infections caused by gram-negative Acinetobacter baumannii.AR-101 (HAP). AR-101 is a fully human immunoglobulin M, or IgM, mAb in Phase 2 clinical development targeting Pseudomonas aeruginosa (P. aeruginosa) liposaccharides serotype O11, which accounts for approximately 22% of all P. aeruginosa hospital acquired pneumonia (HAP) cases worldwide.AR-201 (RSV infection). AR-201 is a fully human IgG1 mAb out-licensed preclinical program aimed at neutralizing diverse clinical isolates of respiratory syncytial virus (RSV). For additional information on Aridis Pharmaceuticals, please visit https://aridispharma.com/. [I haven’t reviewed the website, but you’ll want to be sure there are no inconsistencies with this release] Forward-Looking Statements Certain statements in this press release are forward-looking statements that involve a number of risks and uncertainties. These statements may be identified by the use of words such as "anticipate," "believe," "forecast," "estimated" and "intend" or other similar terms or expressions that concern Aridis' expectations, strategy, plans or intentions. These forward-looking statements are based on Aridis' 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, the need for additional financing, the timing of regulatory submissions, Aridis' ability to obtain and maintain regulatory approval of its existing product candidates and any other product candidates it may develop, approvals for clinical trials may be delayed or withheld by regulatory agencies, risks relating to the timing and costs of clinical trials, risks associated with obtaining funding from third parties, management and employee operations and execution risks, loss of key personnel, competition, risks related to market acceptance of products, intellectual property risks, risks related to business interruptions, including the outbreak of COVID-19 coronavirus, which could seriously harm our financial condition and increase our costs and expenses, risks associated with the uncertainty of future financial results, Aridis' ability to attract collaborators and partners and risks associated with Aridis' reliance on third party organizations. While the list of factors presented here is considered representative, no such list should be considered to be a complete statement of all potential risks and uncertainties. Unlisted factors may present significant additional obstacles to the realization of forward-looking statements. Actual results could differ materially from those described or implied by such forward-looking statements as a result of various important factors, including, without limitation, market conditions and the factors described under the caption "Risk Factors" in Aridis' 10-K for the year ended December 31, 2022 and Aridis' other filings made with the Securities and Exchange Commission. Forward-looking statements included herein are made as of the date hereof, and Aridis does not undertake any obligation to update publicly such statements to reflect subsequent events or circumstances. Contact:Rebecca EdwardsAdministratorAridis Pharmaceuticals, Inc.info@aridispharma.com408-385-1742 SOURCE Aridis Pharmaceuticals, Inc.