Bezlotoxumab

Key Points Immuron Engages Pullan Consulting to Advance IMM-529 Partnering Strategy Immuron is seeking a partner to support clinical development through regulatory approval and commercialization Immuron has U.S. Food and Drug administration (FDA) approval for IMM-529 Investigational New Drug (IND) application IND 32095 is Immuron’s Investigational new drug (IND) application for clinical development of IMM-529 as a product to specifically prevent or treat Clostridioides difficile infection (CDI) MELBOURNE, Australia, July 06, 2026 (GLOBE NEWSWIRE) -- Immuron Limited (ASX: IMC; NASDAQ: IMRN) is pleased to announce that it has engaged Pullan Consulting to provide business development services to assist in securing a strategic partnership for IMM-529. Pullan Consulting is a highly regarded life sciences advisory firm with a strong track record of executing between five and twelve partnering transactions annually over the past 20 years. The firm specializes in guiding biotechnology and pharmaceutical companies through the partnering process, from strategy development and partner identification to negotiation and transaction execution. Pullan Consulting's expertise is expected to support Immuron in maximizing the value of IMM-529 while advancing the program toward commercialization. Immuron has U.S. Food and Drug administration (FDA) approval for IMM-529 Investigational New Drug (IND) application (IND 32095) for clinical development of IMM-529 as a product to specifically prevent or treat Clostridioides difficile infection (CDI) in a Phase 2 clinical trial. IMM-529 has a validated biological target. FDA-approved monoclonal antibody Bezlotoxumab was developed as a first‑in‑class therapy designed to prevent recurrence of Clostridioides difficile infection (CDI) by neutralizing toxin B, the major driver of recurrent disease. IMM-529’s polyclonal antibodies offer multivalent defense compared with monoclonal single-epitope antibodies (Bezlotoxumab). IMM-529 also has an advantage over current standard of care antibiotic treatments that disrupt microbiota. IMM-529 decolonizes the gut facilitating clearance of the pathogen, recovery of the microbiome and prevention of recurrent infection. Immuron has completed an Investigational Brochure and clinical protocol and has secured a principal investigator and three Australian sites. This trial is eligible for Australia’s Clinical Trial Notification (CTN) scheme, a fast-track method for initiating trials. 1 Immuron has manufactured and released drug product for supply of a clinical trial. The trial protocol is for a randomized, double blind, placebo-controlled clinical study of IMM-529 with Standard of Care (SOC) for the treatment of CDI in subjects with first episode CDI or recurrent CDI. Up to 60 subjects will be enrolled in the study. Subjects would be randomly assigned to IMM-529 + SOC or placebo + SOC in a 2:1 ratio at multiple sites. The primary objective would be to evaluate the safety and tolerability of IMM-529 together with SOC in patients with CDI or recurrent CDI. Determination of efficacy would be assessed by the measurement and comparison of mortality rate, disease symptoms and recurrence rate for each treatment group. Opportunity assessment by Lumanity indicates that if efficacious, IMM-529 will be positioned as early in treatment algorithm as payers will allow. It is anticipated that first-episode and recurrent patients will be recruited in the IMM-529 Phase 2 clinical trial design. Up to ~98k patients would be eligible if IMM-529 is positioned at the first recurrence. Based on the estimated market size, anticipated payer restrictions, pricing, and competition, base case yearly revenue for IMM-529 is projected at US$400M. Oral dosing of IMM-529 was viewed as a positive by infectious disease experts. The Company is seeking partners to advance clinical development of IMM-529. Under a licensing model, the licensee typically funds development, registration, and commercialization costs. Common licensing agreements include upfront fees upon execution of the document, as well as developmental milestone payments and royalties on product sales. Terms from select historical CDI-focused deals that show a range of possible transaction structures are shown below. With upfront payments ranging from USD$1-$50 million, milestone payments ranging from USD$25-$570 million, and typical royalties on sales in the mid-to-high single digit percentage range, a successful development partnership for its IMM-529 asset could prove transformational for Immuron. Year Licensor / Asset Owner Licensee / Acquirer Licensed Asset Financial terms (public) Stage at deal Status 2023 Destiny Pharma Sebela Pharmaceuticals NTCD-M3 (nontoxigenic C. difficile strain, live biotherapeutic) Upfront $1M; up to $570M milestones (incl. $19M development and up to $550M sales) plus royalties. ( FT Markets ) Phase 3 ready Phase 3 preparation continues, including work on a more patient friendly capsule formulation and regulatory alignment on Phase 3 design. 2017 Summit Therapeutics Eurofarma Ridinilazole (small molecule antibiotic) $2.5M upfront; up to $25M milestones plus royalties. ( BioSpace ) Phase 2/3 Phase 3 program did not meet superiority vs vancomycin; Summit later focused its strategy on oncology (ivonescimab). ( Fierce Biotech ) 2017 Assembly Biosciences Allergan (later AbbVie) Microbiome GI programs (often cited as ABI-M201, ABI-M301; not CDI specific) $50M upfront plus milestones and royalties (per deal announcement coverage). ( BioSpace ) Preclinical Partnership was later unwound and the microbiome candidates returned; Assembly ultimately exited microbiome work. Note: public deal descriptions emphasize UC and Crohn’s, not CDI. ( Fierce Biotech ) The increased incidence of antibiotic resistant ‘superbugs’ has amplified the use of broad-spectrum antibiotics worldwide. An unintended consequence of antimicrobial treatment is disruption of the gastrointestinal microbiota, resulting in susceptibility to opportunistic pathogens, such as Clostridioides difficile (C. diff). Paradoxically, treatment of Clostridioides difficile infection (CDI) also involves antibiotic use, and the heavy reliance on antibiotics to control C. diff does not allow for the gut flora to regenerate and predisposes the patient to relapsing CDI. C. diff is currently the most common pathogen in healthcare-associated infections and was deemed an urgent threat in the Center for Disease Control and Prevention’s report on antibiotic resistance threats in the United States (CDC, 2019). CDI affects over 400,000 people in the US on a yearly basis, contributing to over 30,000 deaths in the US alone annually. This serious health threat has led to an urgent call for the development of new therapeutics to reduce or replace the use of antibiotics to treat bacterial infections. Immuron collaborated with Dr. Dena Lyras and her team at Monash University, Australia to develop vaccines to produce bovine colostrum-derived antibodies. Dairy cows were immunised to generate hyperimmune bovine colostrum (HBC) that contains antibodies targeting three essential C. diff virulence components. IMM-529 targets Toxin B (TcB), the spores, and the surface layer proteins of the vegetative cells (refer to MOA schematic - below). This unique 3-target approach has yielded promising results in pre-clinical infection and relapse models, including (1) Prevention of primary disease (80% P =0.0052); (2) Protection of disease recurrence (67%, P <0.01) and (3) Treatment of primary disease (78.6%, P<0.0001; TcB HBC). Importantly IMM-529 antibodies cross-react with whole cell lysates of many different human strains of C. diff including hypervirulent strains. To our knowledge, IMM-529 is, to date, the only investigational drug that has shown therapeutic potential in all three phases of the disease. This release has been authorized by the directors of Immuron Limited. COMPANY CONTACT: Steven Lydeamore Chief Executive Officer steve@immuron.com PULLAN CONSULTING CONTACT: Kristine Dorward kristine@pullanconsulting.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. Immuron Platform Technology Immuron’s proprietary technology is based on polyclonal immunoglobulins (IgG) derived from engineered hyper-immune bovine colostrum. Immuron has the capability of producing highly specific immunoglobulins to any enteric pathogen and our products are orally active. Bovine IgG can withstand the acidic environment of the stomach and is resistant to proteolysis by the digestive enzymes found in the Gastrointestinal (GI) tract. Bovine IgG also possesses this unique ability to remain active in the human GI tract delivering its full benefits directly to the bacteria found there. The underlying nature of Immuron’s platform technology enables the development of medicines across a large range of infectious diseases. The platform can be used to block viruses or bacteria at mucosal surfaces such as the Gastrointestinal tract and neutralize the toxins they produce. References 1. The Clinical Trial Notification (CTN) pathway is Australia’s primary, fast-track method for initiating trials with unapproved therapeutic goods. It involves HREC ethics approval and institutional governance review, followed by an online notification to the TGA (4-8 week process), rather than direct regulatory review, facilitating rapid start-up. Hutton, M.L., Cunningham, B.A., Mackin, K.E. et al. Bovine antibodies targeting primary and recurrent Clostridium difficile disease are a potent antibiotic alternative. Sci Rep 7, 3665 (2017). For more information visit: Subscribe to Immuron’s InvestorHub: Here FORWARD-LOOKING STATEMENTS: This press release may contain “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, each as amended. Such statements include, but are not limited to, any statements relating to our growth strategy and product development programs and any other statements that are not historical facts. Forward-looking statements are based on management’s current expectations and are subject to risks and uncertainties that could negatively affect our business, operating results, financial condition, and stock value. Factors that could cause actual results to differ materially from those currently anticipated include: risks relating to our growth strategy; our ability to obtain, perform under and maintain financing and strategic agreements and relationships; risks relating to the results of research and development activities; risks relating to the timing of starting and completing clinical trials; uncertainties relating to preclinical and clinical testing; our dependence on third-party suppliers; our ability to attract, integrate and retain key personnel; the early stage of products under development; our need for substantial additional funds; government regulation; patent and intellectual property matters; competition; as well as other risks described in our SEC filings. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions, or circumstances on which any such statement is based, except as required by law. A photo accompanying this announcement is available at

抗生素耐药性日益增长的趋势使得新的抗感染治疗策略成为必要。基于数十年的广泛研究和开发，单克隆抗体在治疗抗生素耐药性细菌感染方面具有巨大潜力。在这篇对该领域的全面综述中，研究人员总结了快速新兴的单克隆治疗领域，这些方法提供了针对对人类健康构成严重关切的细菌病原体的替代策略。研究人员按物种和分子靶点组织研究结果，讨论了已证明有治疗潜力的抗体以及未能提供疗效的抗体，为未来高疗效治疗药物的设计和发现提供了新见解。此外，研究人员讨论了分子生物学的最新进展，这些进展彻底改变了单克隆抗体作为治疗药物的实施、效力和实用性，并持续推动着抗菌单克隆抗体将迈入一个激动人心的时代。**1 引言**抗生素耐药性（AMR）正日益成为人类健康和福祉的严重威胁。小分子药物表现出强烈的选择压力，导致逃逸突变，引发AMR并消除药物的效用。单克隆抗体（mAbs）提供了一种替代方法，通过多种宿主介导的保护机制（如血清杀菌活性和调理吞噬活性）间接杀死细菌。尽管逃逸突变也可能因mAb治疗而发生，但其选择压力与小分子不同，使治疗性mAb成为减少耐药性发生的有价值的策略。数十年的抗细菌mAb研究和开发已产生了大量用于预防和治疗多种病原体感染候选药物。尽管取得了这些进展，但仅有少数抗细菌mAb获批临床使用，包括obiltoxaximab和raxibacumab用于治疗炭疽杆菌毒素暴露，以及bezlotoxumab用于治疗艰难梭菌胃肠道感染。在这篇广泛的综述中，研究人员总结了抗细菌mAb发现和开发的大部分历程，重点关注关键细菌病原体以及针对其特定表位的众多mAb。**2 艰难梭菌**艰难梭菌是一种革兰氏阳性厌氧胃肠道细菌，通过孢子形式经粪-口途径传播。毒素A（TcdA）和毒素B（TcdB）被认为是艰难梭菌发病机制中的主要毒力因子。它们通过多步骤过程使宿主细胞中毒，包括结合特异性受体、内吞、在酸化内体中形成孔道、易位和葡萄糖基化宿主GTPases。艰难梭菌感染（CDI）每年在美国估计导致462,100例病例，12,800例死亡和10亿美元医疗费用。早期尝试使用高免疫牛初乳进行口服治疗，显示出治疗潜力，但因制造复杂性而未能进一步开发。**2.1 艰难梭菌：抗毒素mAbs**Medarex首次报告了抗毒素mAbs，后授权给默克。两种全人源IgG1κ mAbs，抗TcdA（CDA1/actoxumab）和抗TcdB（CDB1/bezlotoxumab）被选出。Bezlotoxumab通过识别TcdB CROPs结构域上的两个不同位点，阻止TcdB与宿主细胞表面受体CSPG4结合。两项全球III期研究（MODIFY I和MODIFY II）显示，与安慰剂相比，bezlotoxumab显著降低了rCDI。Bezlotoxumab已获批用于预防高风险CDI患者复发。不幸的是，Zinplava?于2025年1月停产。阿斯利康正在开发另一种抗TcdB mAb，AZD5148，该抗体通过YTE替换（Fc区M252Y/S254T/T256E三重突变）延长半衰期。AZD5148结合TcdB的GTD结构域，阻止TcdB酶活性递送进入宿主细胞。该抗体表位高度保守，正在PRISM研究（NCT07285213）中评估其预防CDI复发的有效性和安全性。**3 金黄色葡萄球菌**金黄色葡萄球菌是一种革兰氏阳性菌，是医院获得性感染的主要原因，2019年全球约导致100万人死亡。该菌依靠大量分泌和表面表达的毒力因子来穿透组织、促进粘附和损害宿主免疫反应。毒力基因表达在感染过程中受时间和空间调控，且许多毒力因子功能冗余。尽管已有几种抗毒力mAbs在临床前模型中产生并验证，但只有少数进入临床试验。**3.1 金黄色葡萄球菌：针对成孔毒素的mAbs**金黄色葡萄球菌拥有六种溶细胞性成孔毒素，包括α毒素（Hla）和双组分杀白细胞素。Hla通过与受体ADAM10相互作用表现出广泛的细胞向性。人源抗Hla mAb LC10经YTE替换工程改造后产生suvratoxumab（MEDI4893），在II期SAATELLITE研究中与安慰剂相比使呼吸机相关性肺炎相对减少31.8%。Tosatoxumab（AR-301）在重症监护室患者严重金黄色葡萄球菌肺炎的随机I/II期研究中显示缩短了通气持续时间。ASN100（ASN1和ASN2组合）在非人灵长类模型中显示出保护作用，但在II期研究中因无效而终止。**3.2 金黄色葡萄球菌：针对其他分泌蛋白的mAbs**金黄色葡萄球菌的补体抑制剂和趋化抑制蛋白通过干扰补体激活级联来促进免疫逃逸。人源mAb 6D4在体外抑制金黄色葡萄球菌补体抑制剂活性。针对金黄色葡萄球菌超抗原（SAgs），特别是葡萄球菌肠毒素B（SEB），已开发出人源化IgG2抗SEB mAbs，在金黄色葡萄球菌诱导的败血症模型中保护小鼠免受致死性SEB中毒。此外，针对中毒性休克综合征毒素-1的几种有效中和mAbs已在临床前模型中显示出疗效。**3.3 金黄色葡萄球菌：针对表面蛋白的mAbs**金黄色葡萄球菌表达大量细胞壁锚定蛋白，其中MSCRAMM（识别粘附基质分子的分子表面组分）数量最多。凝集因子A（ClfA）存在于所有分离株中，结合纤维蛋白原促进凝集和粘附。小鼠mAb Aurexis及其人源化版本tefibazumab在II期临床试验中显示出潜在益处，但未进一步进行更大统计学效力的试验。AZD7745是另一种人源IgG1抗ClfA mAb，结合高度保守的表位，在体外介导调理吞噬杀伤（OPK）活性，并在小鼠致死性菌血症模型中提供保护。AZD7760是suvratoxumab和AZD7745的多机制mAb组合，正在I/IIa期临床研究中评估。金黄色葡萄球菌蛋白A（SpA）通过其Fcγ和Fab结合能力损害IgG效应功能。抗SpA mAb 3F6的人源化版本抑制人IgG与SpA结合，并表现出更好的稳定性。脂磷壁酸是另一种主要细胞壁成分，抗脂磷壁酸的pagibaximab在III期研究中未能在早产儿中显著降低迟发性败血症。**3.4 金黄色葡萄球菌：针对营养和铁摄取的mAbs**金黄色葡萄球菌表达参与营养摄取的表面暴露脂蛋白。铁调节表面决定簇（Isd）系统从宿主中清除血红素铁。抗IsdA和抗IsdH mAbs在小鼠败血症模型中提供保护。最近描述了一种骆驼科纳米抗体，能交叉反应结合IsdH和IsdB的血红素结合口袋，降低三种致病性MRSA菌株的体外生长。几种抗锰转运蛋白C（MntC）mAbs在体外诱导中性粒细胞呼吸爆发，减少小鼠菌血症中的细菌负荷，并在幼年大鼠模型中提供保护。**4 铜绿假单胞菌**铜绿假单胞菌是一种革兰氏阴性杆菌，是机会性病原体，因其耐药性和显著毒力而成为新药开发的长期目标。**4.1 铜绿假单胞菌：靶向PcrV的mAbs**III型分泌系统的针尖蛋白PcrV是理想的mAb靶点。2002年开发的小鼠mAb结合PcrV C末端，阻断细胞毒素易位。该mAb成为KB001的基础，这是一种人源化聚乙二醇化Fab抗体。在II期研究中，KB001降低了囊性纤维化患者的气道炎症标志物，但未能减少需要抗生素治疗的时间。随后使用多种方法开发了其他抗PcrV mAbs，包括从恢复期或慢性感染患者血浆B细胞分离的全人源mAbs。**4.2 铜绿假单胞菌：靶向Psl外多糖的mAbs**通过使用目标非依赖性筛选策略，研究人员鉴定了靶向Psl外多糖的mAbs。最有效的抗体Cam003对表型和地理多样的铜绿假单胞菌菌株表现出显著广度和效力。Cam003介导浓度依赖性OPK活性，并阻断铜绿假单胞菌粘附于培养的上皮细胞。在临床前模型中，Cam003对致死性肺炎、热损伤和角膜感染提供剂量依赖性预防保护。**4.3 铜绿假单胞菌：靶向Psl和PcrV的双特异性mAb Gremubamab**Gremubamab（MEDI3902）是一种首创的二价双特异性人源IgG1κ mAb，同时靶向Psl外多糖和PcrV。与任一亲本抗体或其组合相比，该抗体表现出更优效力。在临床前模型中，MEDI3902对急性肺炎、呼吸机相关性肺炎等多种模型提供剂量依赖性保护。I期研究证实参与者耐受性良好。II期研究（EVADE）在整体人群中未达到减少院内肺炎发病率的主要终点，但事后分析提示在基线炎症标志物较低的患者亚组中可能存在获益。在GREAT-2试验中，针对慢性定植铜绿假单胞菌的支气管扩张症患者，500 mg剂量显著降低肺部细菌水平，1500 mg剂量显著减少急性加重频率。**4.4 铜绿假单胞菌：靶向脂多糖的mAbs**脂多糖（LPS）是革兰氏阴性菌的关键毒力因子。人源IgM mAb panobacumab针对铜绿假单胞菌血清型O11 LPS，在II期研究中作为医院获得性肺炎的辅助治疗，与安慰剂相比显著缩短临床缓解时间。另一种研究小组开发了针对血清型O5 LPS的IgG2b mAbs混合物，在小鼠肺炎模型中减轻炎症和气道菌落形成单位（CFUs）。LPS血清型的多样性对所有靶向LPS的mAbs的广度构成挑战。**4.5 铜绿假单胞菌：靶向其他结构的mAbs**Aridis Pharmaceuticals开发的AR-105靶向藻酸盐，但在II期研究中未减少感染患者达到临床治愈的时间。另一个小组开发了靶向IV型菌毛PilQ-PilA二硫键（QA）区域的mAb，与抗生素联用时显示出辅助疗效。靶向铁载体FpvA的mAb和靶向鞭毛主要蛋白亚基FliC的mAb均显示出一定的体内保护效力。靶向外膜蛋白OprF的IgG2a mAb在体外减少生物被膜形成，但在小鼠急性肺炎模型中未提供保护。**5 鲍曼不动杆菌**鲍曼不动杆菌是一种广泛耐药革兰氏阴性杆菌，世界卫生组织宣布其对新疗法开发构成严重关切。**5.1 鲍曼不动杆菌：靶向外膜蛋白的mAbs**外膜蛋白A（OmpA）是潜在的疫苗候选物。Russo小组的研究表明，OmpA仅能在无荚膜的突变菌株中被mAb结合，而在具有完整荚膜的临床分离株中则不能。遗传性消除荚膜可恢复抗OmpA mAbs的活性。针对OmpA的小鼠IgG2a mAbs在小鼠致死性肺炎模型中提供保护，但样本量小且生存跟踪时间短。**5.2 鲍曼不动杆菌：靶向荚膜的mAbs**由于荚膜可能屏蔽关键抗原，多个研究小组将重点转向靶向荚膜本身。Spellberg实验室通过使用活细菌免疫小鼠开发了多种mAbs，事后确定这些mAbs靶向荚膜多糖。人源化IgG1 mAbs在血液和肺部感染小鼠模型中表现出高效保护效力，与粘菌素联用显示协同作用，且连续传代后未检测到逃逸突变。这些mAbs后来被用于产生人源化双特异性mAb，靶向多种荚膜类型。第三种抗荚膜mAb靶向伪氨基糖，在鲍曼不动杆菌的血液和软组织感染模型中展示出广泛体外结合和强效体内活性。**6 肺炎克雷伯菌**肺炎克雷伯菌是一种普遍存在的高度耐药革兰氏阴性病原体。**6.1 肺炎克雷伯菌：靶向LPS O抗原的mAbs**O抗原的靶向在早期工作中显示可穿透荚膜。Arsanis Biosciences生产的IgG1κ mAb显示，结合和中和LPS能在兔菌血症模型中提供保护，且其保护机制可独立于补体沉积和调理吞噬作用。阿斯利康开发了靶向O1型LPS的mAb KPE33，但在另一常见血清型O2上无活性。随后通过使用目标非依赖性筛选方法，他们发现了人源化IgG1 mAb B39，该抗体结合O1和O2型LPS共有的表位，显著提高了结合广度，并在体内模型中对有荚膜的野生型O1和O2菌株表现出强大效力。**6.2 肺炎克雷伯菌：靶向表面蛋白的mAbs**阿斯利康通过目标非依赖性发现，确定了3型菌毛主要亚基MrkA是一个有效靶点，该靶点不被荚膜排除且独立于O血清型。靶向MrkA的mAbs在体内肺炎模型中有效。另一个研究小组最近发现了人源化IgG mAbs，能交叉反应大肠杆菌和肺炎克雷伯菌的FimH抗原，有效抑制菌毛介导的粘附，在UTI小鼠模型中对两种病原体均提供保护。**6.3 肺炎克雷伯菌：靶向荚膜的mAbs**Fries实验室开发了靶向K1荚膜的mAbs，以及靶向ST258菌株荚膜的IgG3 mAbs，后者能促进调理吞噬、中性粒细胞介导的杀伤和小鼠肺炎模型中肺部CFUs减少。他们还开发了具有交叉枝系活性的IgG2b mAb。另一个研究小组最近发现了靶向常见于高毒力肺炎克雷伯菌的K64型荚膜的mAb，在菌血症模型中具有预防效力。由于存在超过140种基因预测的荚膜类型，靶向荚膜多糖在临床上仍具有挑战性。**7 结核分枝杆菌**结核分枝杆菌是一种专性人类病原体，是结核病的病原体。**7.1 围绕结核分枝杆菌抗体的教条转变**过去认为抗体无效，因为M. tuberculosis居于细胞内。但研究表明，抗体通过Fc介导机制对其他胞内病原体如沙门氏菌提供保护。系统水平分析显示，抗体质量（包括Fc受体结合、糖基化和效应功能）而非数量决定感染控制。在非人灵长类中，静脉注射BCG后鉴定出抗原特异性IgM抗体是保护的最强相关因素之一。**7.2 结核分枝杆菌：靶向表面抗原的mAbs**针对肝素结合血凝素粘附素的抗体4057 D2在小鼠模型中降低致死率和脾脏播散。α-晶体蛋白特异性IgA也通过限制肺部M. tuberculosis生长提供保护。针对脂阿拉伯甘露聚糖的mAb SMITB在致死性攻击中强效保护动物。这些LAM特异性抗体通过调理吞噬作用驱动抗菌控制。**7.3 多种靶点mAbs以Fc依赖性方式限制结核分枝杆菌**一项跨比较研究测试了24种M. tuberculosis特异性mAbs，强调了针对多种分泌毒素、表面蛋白和多糖的抗体能在体内控制细菌。保护性M. tuberculosis特异性mAbs通过Fc依赖性方式，要求与肺部免疫细胞交叉通讯，挑战了胞内定位排除抗体功效的观点。**8 生物被膜**微生物生物被膜保护微生物免受抗菌药物和免疫活性攻击。**8.1 生物被膜：靶向DNABII的mAbs**DNABII蛋白家族在真细菌中普遍存在，在生物被膜中协调胞外DNA。靶向胞外DNABII的抗体导致DNABII解离，引起生物被膜结构崩塌。Bakaletz小组开发的DNABII结合尖端mAbs混合物在体外崩溃四种病原体的胞外DNA基质，并在动物模型中改善感染结果。这项技术正在由Clarametyx Biosciences临床开发为CMTX-101。Trellis Biosciences开发的TRL1068能破坏MRSA和铜绿假单胞菌的生物被膜，在植入物感染模型中增强达托霉素治疗，I期临床研究显示消除3/11患者假体污染。**8.2 生物被膜：靶向其他结构的mAbs**聚-N-乙酰葡糖胺（PNAG）是生物被膜的结构成分。两种靶向乙酰化和去乙酰化PNAG的人源IgG1 mAbs在小鼠金黄色葡萄球菌感染模型中协同拯救90%小鼠。靶向Curli淀粉样纤维的mAbs抑制鼠伤寒沙门氏菌生物被膜形成，与氨苄西林协同消除CFU负担，并在小鼠植入模型中促进吞噬反应。针对金黄色葡萄球菌生物被膜的人源IgG1 mAbs可同时靶向浮游细胞和生物被膜结构。**9 单域抗体**骆驼科单域抗体（VHH）大小12-15 kDa，具有出色稳定性，可进入隐藏的保守表位。针对艰难梭菌毒素的VHH，如VNA2（四价VHH四聚体），在小鼠、仓鼠和悉生仔猪模型中提供保护。其他VHH已成功针对金黄色葡萄球菌IsdH/IsdB和ClfA开发。靶向脂质A的VHH能结合天然细菌并促进膜不稳定性。**10 抗体-抗生素偶联物**抗体-抗生素偶联物（AACs）通过可裂解连接子将抗生素连接到mAb，仅在吞噬溶酶体中释放抗生素。首个AAC是靶向细胞壁磷壁酸的THIOMAB，连接新型利福平类抗生素，在小鼠菌血症模型中优于万古霉素。I期研究显示DFA曲线类似传统mAb。另一项研究将万古霉素偶联到抗SpA mAb，在假体关节感染模型中需与游离万古霉素联用才有效。针对铜绿假单胞菌LPS O抗原的AAC使用G2637，能在吞噬后使巨噬细胞内抗生素浓度提高约26倍。**11 体内表达生物制剂**治疗性mAb生产费时且昂贵。体内表达生物制剂平台使用核酸编码的mAb序列，将身体作为自身的生物反应器。**12 基于AAV的mAb递送**腺相关病毒（AAV）可维持长期表达，但只能包裹<3.3 kb DNA，限制了可递送的mAb形式。AAV递送的抗毒素mAbs在炭疽和艰难梭菌毒素疾病模型中提供保护。但AAV平台存在免疫原性问题，且大多数人对某些AAV血清型有抗体滴度。**13 基于DNA质粒的mAb递送**非病毒DNA质粒通过电穿孔递送，可递送大段DNA序列，不引发病载体免疫。DNA-based mAb（DmAb）递送在临床前模型中显示血清表达治疗性mAb水平。Weiner实验室在I期试验中验证了DmAb平台的临床可行性，峰值浓度达1.61 μg/mL，持续表达超过72周。但峰值表达通常延迟14-21天，且需要电穿孔设备。**14 基于mRNA的mAb递送**mRNA/LNP递送在约24小时内达到峰值表达，适合需要即时保护的被动免疫。通过mRNA优化策略可延长表达时间。临床前研究显示静脉注射后功能性IgG表达达170 μg/mL。mRNA-1944（抗基孔肯雅IgG）在I期研究中显示24小时内血清水平>1 μg/mL，持续长达16周。但静脉给药不便。冻干技术使mAb编码的mRNA/LNP可在室温下储存一个月。**15 其他新兴技术****15.1 Fc工程**Fc工程包括Fc“沉默”和半衰期延长策略。YTE平台（M252Y/S254T/T256E）和LS平台（M428L/N434S）用于半衰期延长。点突变可调整Fcγ受体和补体接合以增强调理吞噬等效应功能。对于金黄色葡萄球菌SpA逃逸问题，Fc修饰可能有益。**15.2 计算发现与设计**计算设计可优化mAb结合域，且最近已能完全在计算机内从头设计mAb候选物，包括靶向艰难梭菌TcdB的ScFv和VHH。该领域虽仍处于初期，但潜力巨大。**16 结论**靶向细菌病原体的mAb开发是抗击AMR的一个有前景但复杂的领域。抗毒素mAb的成功以及多特异性方法的进展验证了mAb疗法的潜力。挑战包括细菌表面抗原结构多样性、毒力因子差异调控、表位屏蔽和广菌株覆盖需求。未来抗体工程进步，包括半衰期延长、合理Fab和Fc设计、多特异性格式和新型递送方法，正在扩大其效用。mAbs将在AMR时代对致命性细菌感染的治疗库中发挥日益重要的作用。