Brilacidin

金黄色葡萄球菌耐药机制与新型治疗策略研究进展王羽何昀珈 殷海欣 马悦 郭海勇DOI:10.13560/j.cnki.biotech.bull.1985.2025-1032摘 要金黄色葡萄球菌（Staphylococcus aureus, S. aureus）及其耐甲氧西林金黄色葡萄球菌（Methicillin-Resistant Staphylococcus aureus, MRSA）因强耐药性和高致病性，已成为全球抗生素耐药领域的核心问题之一。其耐药性由多重机制共同介导，包括mecA/mecC基因介导的PBP2a异常表达、耐药基因水平传播、生物膜形成以及持留细胞的产生。由于传统抗生素对耐药菌株的疗效受限，开发新型抗 S. aureus 感染策略已成为临床及科研领域的重要方向。纳米抗菌疗法通过靶向递送和多靶点杀菌机制，在克服细菌耐药性方面显示出潜力；抗菌肽因广谱抗菌活性和低耐药诱导风险而备受关注；噬菌体疗法、噬菌体裂解酶及免疫疗法等替代方案也取得了重要的研究进展。然而，这些新策略在走向临床应用时，仍面临毒性、稳定性及潜在耐药传播风险等挑战。未来研究需聚焦于递药系统优化、靶向精确性提升与毒副作用控制，进一步解析耐药动态演化机制，推动安全有效的抗感染策略的临床转化，最终实现对S. aureus感染的有效控制。关键词金黄色葡萄球菌；耐甲氧西林金黄色葡萄球；耐药机制；新型治疗策略引用本文：王羽,何昀珈,殷海欣等.金黄色葡萄球菌耐药机制与新型治疗策略研究进展[J].生物技术通报,2025. DOI:10.13560/j.cnki.biotech.bull.1985.2025-1032.金黄色葡萄球菌（Staphylococcus aureus, S. aureus）是一种广泛存在于自然环境和宿主皮肤表面的革兰氏阳性球菌，可引发从皮肤软组织感染到败血症、心内膜炎等一系列严重侵袭性疾病。自青霉素问世以来，抗生素便成为治疗该菌感染的主要手段。但由于S. aureus强大的遗传可塑性和与环境适应能力，使其迅速对各类抗菌药物产生耐药性。1961年，MRSA的出现标志着S. aureus进入多重耐药时代［1］。此后，MRSA在全球范围内迅速传播，不仅在医院环境中造成严重的院内感染，也逐渐在社区中流行，成为公共卫生的重大威胁。随着临床抗生素的长期使用，耐药问题不断加剧。万古霉素作为治疗MRSA感染的最后一道防线，其疗效正面临异质性万古霉素中介金黄色葡萄球菌（heterogeneous vancomycin-intermediateS. aureus, hVISA）和万古霉素耐药金黄色葡萄球菌（vancomycin-resistant S. aureus, VRSA）出现的挑战。此外，S. aureus对利奈唑胺、达托霉素等新型抗菌药物的敏感性下降也有报道［2-3］。传统基于小分子化合物筛选的抗生素研发模式进展缓慢，难以应对耐药菌快速演变的速度，导致抗感染治疗逐渐陷入药物匮乏的局面。面对日益严峻的耐药形势，突破传统抗生素研发的局限，探索更具创新性和协同性的治疗路径已成当务之急。近年来，一系列新型治疗策略展现出巨大潜力。例如，纳米材料因其独特的理化性质，在药物靶向递送、细胞膜破坏与多靶点杀菌方面展现出明显优势，降低因单一靶点突变所导致耐药风险［4-6］。抗菌肽是固有免疫系统的关键效应分子，具有广谱抗菌活性和较低的耐药诱导风险，已成为抗耐药病原体药物研发的重要方向［7］。不同作用机制的抗生素联合应用可通过协同效应扩大抗菌谱，并显著延缓耐药性的产生［8］。同时，噬菌体疗法、裂解酶、毒力因子抑制剂及免疫调节等新兴方法逐步形成了多元化的治疗体系，为抗多重耐药感染提供了新的方向［9-12］。本文阐述了S. aureus的主要耐药机制，重点综述了抗S. aureus 感染新兴治疗策略的研究进展，分析了各策略的优势与局限性，最后对未来发展方向进行了展望，以期为开发更有效、更安全的抗S. aureus 感染治疗方案提供科学参考。1S. aureus的致病机制与耐药机制1.1S. aureus的致病机制S. aureus的致病过程具有复杂的层级结构，涉及毒力因子表达调控、宿主免疫逃逸及组织侵袭等复杂环节。其致病过程通常经历黏附定植、免疫逃逸、组织侵袭与毒素介导损伤等主要阶段。在完成定植并逃避宿主免疫后，S. aureus可通过分泌多种胞外水解酶和毒素破坏宿主组织屏障，促进细菌扩散。分泌的胞外毒素不仅可直接破坏宿主细胞，还可通过异常激活免疫系统引发过度炎症反应，从而介导组织损伤与系统性病理效应。α-溶血素（α-hemolysin, Hla）能在宿主细胞膜上形成孔道，引起细胞裂解。杀白细胞素主要靶向攻击中性粒细胞，通过诱导细胞裂解释放大量炎症介质，间接引发局部过度炎症反应，进而促发组织损伤与坏死。中毒性休克综合征毒素-1是一种超抗原，能够以不依赖主要组织相容性复合体的方式激活大量T细胞，引发过度的免疫反应，导致细胞因子风暴，进而诱发中毒性休克综合征。除细菌毒素的直接作用外，宿主细胞在感染过程中的异常应答也可加剧组织损伤。近期研究表明，干扰素诱导蛋白IFP35可通过促进核因子E2相关因子2的泛素化降解，介导铁死亡，从而加重S. aureus感染［17］。1.2S. aureus的主要耐药机制S. aureus因其复杂的耐药机制（图1）和广泛的抗药谱，成为临床多重耐药细菌的典型代表。S. aureus最具典型耐药机制是获得外源性耐药基因mecA或mecC，它们编码青霉素结合蛋白2a（penicillin-binding protein 2a, PBP2a）。PBP2a 对β-内酰胺类抗生素亲和力极低，即使在高浓度抗生素存在下，仍能维持肽聚糖交联所需的转肽酶活性，从而赋予细菌对大多数β-内酰胺类药物产生耐药性，形成MRSA［18］。染色体突变也是S. aureus产生耐药的重要途径，如rpoB基因突变可导致其编码的RNA聚合酶β亚基结构改变，而grlA和gyrA基因突变可降低氟喹诺酮类药物的抑制效果［19-20］。此外，耐药基因通过质粒、转座子及噬菌体等可移动遗传元件在不同菌株间传播，促进了多重耐药性的快速扩散。图1S. aureus的主要耐药机制（由Biorender创建：JF28YTYA8N）Fig. 1Main drug resistance mechanisms of S. aureus (created by Biorender:JF28YTYA8N)生物膜的形成不仅是S. aureus致病机制的关键环节，也是其重要的耐药屏障。生物膜内的细菌处于代谢缓慢的持留细胞状态，这种状态使其对临床常用抗生素表现出高度耐受性，这也是S. aureus感染复发的重要原因。S. aureus还可以通过NorA主动外排泵将胞内抗生素排出，降低胞内药物浓度［20-22］。S. aureus对万古霉素敏感性下降的机制则更为复杂，万古霉素中介金黄色葡萄球菌（vancomycin-intermediateS. aureus, VISA）和hVISA涉及细胞壁增厚、肽聚糖交联度降低，而VRSA通过合成D-Ala-D-Lac替代肽聚糖前体，降低万古霉素与靶点的结合亲和力［23-24］。S. aureus的致病过程与耐药机制相互影响，共同促成感染持续与耐药加剧的恶性循环。生物膜既通过促进定植与免疫逃逸参与致病过程，又通过物理屏障作用与持留细胞特性增强耐药能力［25-27］。PBP2a的表达不仅介导S. aureus对β-内酰胺类抗生素的耐药，其引发的细胞壁结构的改变可能间接影响毒力因子的表达，进一步强化细菌致病能力［28］。此外，S. aureus的外排泵系统不仅通过主动外排抗生素降低其胞内浓度，还参与调控生物膜形成及毒力因子表达，反映出耐药性与致病性之间的紧密关联［29］。S. aureus通过多层次、多途径的致病与耐药机制协同作用，使其成为临床抗感染治疗中极具挑战性的病原体。2抗菌剂的现状与局限性2.1主要抗S. aureus药物的应用局限虽然过去几十年在S. aureus抗菌治疗方面取得了重要进展，但其临床疗效正面临日益严峻的耐药挑战。目前，治疗耐药性S. aureus感染尤其是MRSA感染，主要依赖于糖肽类（如万古霉素、替考拉宁）、脂肽类（如达托霉素）、噁唑烷酮类（如利奈唑胺）、截短侧耳素类（如来法莫林）以及新型β-内酰胺类药物（如第五代头孢菌素头孢洛林）等。这些药物虽然是当前对抗耐药S. aureus的重要手段，但耐药菌株的持续演化仍不断削弱其长期有效性。万古霉素作为治疗MRSA感染的经典药物已逾半个世纪，目前仍是复杂性菌血症等中重度MRSA感染的初始经验性治疗选择之一。其疗效与AUC/MIC比值相关，但治疗窗窄且存在肾毒性风险。在临床实践中，为平衡疗效与安全性，需通过治疗药物监测实施AUC导向的给药方案，将AUC/MIC比值维持在400-600的范围内［30］。在长期抗生素选择压力下，hVISA和VISA的检出率持续上升，已成为万古霉素治疗失败的重要原因，在复杂性菌血症和感染性心内膜炎中更为常见［31］。更需警惕的是，完全耐药的VRSA虽仍属罕见，但其出现证实vanA耐药基因已成功从粪肠球菌转移至S. aureus，提示耐药基因可跨物种传播，凸显了潜在的公共卫生风险［32］。利奈唑胺作为首个上市的噁唑烷酮类抗生素，通过抑制细菌蛋白质合成起始阶段发挥抗菌作用，对MRSA、VISA和VRSA均具有良好的抗菌活性。该药口服生物利用度高且组织分布广泛，在皮肤软组织及骨关节等感染部位达到有效治疗浓度。然而，长期使用可能导致骨髓抑制、血小板减少、肝胆系统损害，并伴随贫血、周围神经病变和视神经病变［35-36］。尽管S. aureus对利奈唑胺的耐药相对少见，但携带23S rRNA突变基因或可移动cfr基因的耐药菌株已在全球多地被检出。此类耐药基因可通过质粒介导的水平基因转移传播，导致噁唑烷酮类、截短侧耳素类及林可酰胺类抗生素间的交叉耐药，已在部分区域引起临床疗效下降的警惕［37-38］。头孢洛林可与PBP2a结合，从而恢复对MRSA的抗菌活性［39］。尽管头孢洛林对MRSA具有较强抗菌活性，但其对生物膜内持留细胞的杀菌作用较弱，且可能引起过敏反应。截短侧耳素类药物如来法莫林已在社区获得性肺炎中显示出良好疗效和口服短期安全性，但在败血症和感染性心内膜炎等重症感染中的长期疗效及耐药风险仍需进一步研究。2.2现行抗菌策略的系统性挑战除上述药物局限外，当前抗菌治疗策略还面临更为严峻的整体性挑战。新类别抗生素的发现速度显著放缓，而耐药菌的进化与传播速度持续加快，二者形成明显失衡。现有抗生素多作用于经典靶点，如细胞壁、蛋白质或DNA合成，细菌可通过单一靶点突变、获得外排泵编码基因或产生药物修饰酶等方式，即可迅速产生耐药性，导致新药上市后不久即面临耐药性挑战。在生物膜相关感染或感染性心内膜炎中，即使体外药敏结果显示敏感，但在临床治疗中仍常失败，这主要与生物膜内细菌固有耐受性有关［40-41］。同时，广谱抗生素的长期或不合理使用可扰乱肠道等部位的共生微生物群落，增加艰难梭菌感染等继发风险，并促进耐药基因间的水平传播，加速耐药性扩散［42-43］。尽管现有抗菌药物在一定程度上能够有效治疗多数S. aureus感染，但其疗效受限于耐药性发展、药代动力学/药效学（pharmacokinetics/pharmacodynamics, PK/PD）缺陷、组织穿透性不足以及显著的毒副作用等多重因素的制约。因此，亟需开发作用机制新颖、可规避主流耐药途径、兼具良好安全性与组织分布特性的创新治疗策略。3S. aureus新型抗菌策略研究进展传统抗菌药物在应对耐药性、毒副作用及组织穿透性不足等方面的局限，促使新型抗菌策略的研究不断深化。开发具有新作用机制、能够规避主流耐药通路的创新疗法，已成为对抗耐药性S. aureus感染的关键方向。近年来的研究更加注重提高杀菌效率、减轻耐药压力及改善药物安全性，从而形成多种创新治疗方向，主要包括基于纳米技术的抗菌递送系统、天然或人工改造抗菌肽、噬菌体及其裂解酶、毒力因子抑制剂，以及调节宿主-病原体互作通路的免疫调节疗法等［11，44-46］。这些策略通过多靶点协同作用、增强局部杀菌活性或增强宿主免疫应答，为应对耐药性S. aureus感染提供新的希望。抗菌肽是哺乳动物先天免疫系统的关键效应分子，因其广谱抗菌活性、快速杀菌能力及较低的耐药诱导风险，被认为是应对耐药菌感染的潜在新型抗菌剂。抗菌肽通常带正电荷，可与细菌膜表面的负电结构结合，形成跨膜孔道导致细胞内容物泄漏；也可进入细菌胞内干扰DNA复制、蛋白质合成或关键酶活性等核心代谢过程，从而抑制细菌增殖。为克服天然肽易被蛋白酶降解、体内半衰期短及高浓度下潜在的溶血毒性等问题，研究重点已从直接利用天然抗菌肽转向设计和优化其合成类似物或模拟物。如brilacidin和Omiganan，在针对S. aureus感染的体外实验中均显示出良好的抗菌活性［54-55］。近年来，深度学习技术在抗菌肽设计中的应用显著加快了候选分子的发现进程。基于序列-功能关系建模的算法能够高效预测和优化新型肽序列。近期研究利用ProteoGPT生成了多个新型抗菌肽序列，其中部分候选肽在体外及小鼠大腿感染模型中对MRSA表现出显著抑制活性，且在血清中具有较好的稳定性，表明该方法在抗菌肽理性设计中具有应用潜力［56］。抗毒力疗法是另一类极具潜力的抗菌策略，其核心思路是靶向细菌毒力因子而非直接杀灭细菌。该策略通过削弱细菌的致病能力，增强其对宿主免疫清除的敏感性，并降低抗生素选择压力，有助于延缓耐药性的演化。针对S. aureus，多种靶向毒力因子的候选药物已进入研发阶段。其中，靶向Hla的单克隆抗体MEDI4893和Oroxylin A天然化合物，可分别阻断Hla寡聚化和抑制跨膜孔道形成［62-63］。靶向S. aureus辅助基因调节子群体感应系统的化合物，可抑制多种毒素和胞外酶的表达［64］。靶向宿主免疫系统的疗法通过调节免疫应答来促进病原体清除。例如，针对S. aureus关键毒力因子Hla和SpA为抗原的疫苗可诱导机体产生中和抗体，从而削弱S. aureus的致病能力［65-66］。免疫调节剂如IFN-γ，则被用于恢复或增强巨噬细胞和中性粒细胞等免疫细胞的抗菌功能［67-68］。单克隆抗体也可通过中和游离毒素或阻断其与宿主受体结合，实现特异性抗毒治疗［69］。表1不同抗S. aureus新型治疗策略的比较分析Table 1Comparative analysis of different novel anti-S. aureustreatment strategies4应对S. aureus感染的挑战与未来方向4.1新型抗S. aureus干预策略的临床转化障碍尽管抗 S. aureus 新型抗菌剂的研发已取得重要进展，其临床转化仍面临许多障碍。未来研究需突破传统单一靶点药物开发的局限，发展多机制协同作用和宿主-病原体共靶向为核心的治疗策略，以应对该菌的耐药演化、生物膜形成及免疫逃逸等复杂适应能力。S. aureus的耐药性与毒力在进化过程中持续变化，增加了临床治疗的复杂性。该菌具有高度遗传多样性，可通过基因突变和水平基因转移快速适应抗生素等环境压力。这种遗传可塑性不仅驱动了多重耐药和广泛耐药菌株的出现，还促使部分毒力基因通过噬菌体或SaPI等移动遗传元件在不同克隆复合体间发生水平转移，导致流行病学特征和临床表现不断变化。例如，社区获得性MRSA菌株常携带PVL基因，与侵袭性皮肤软组织感染和坏死性肺炎密切相关，而医院获得性MRSA则通常表现为多重耐药［98］。面对这种高度菌株异质性，未来治疗策略需具备高度的灵活性和精准性，以实现针对病原体特征的个体化治疗。现有新型抗菌剂的临床转化过程同样面临多重现实挑战。纳米抗菌剂与噬菌体/裂解酶疗法在体外和动物模型中展现出良好的抗菌活性，但在大规模生产、标准化制备流程、长期生物安全性评估以及复杂的监管审批要求等方面仍存在障碍，延缓了其进入临床应用的进程。噬菌体疗法的宿主特异性虽能减少对正常菌群的影响，但广泛噬菌体库的建立与进行精准配型工作增加了操作难度，难以满足紧急救治需求［99］。抗菌肽模拟物的结构优化虽可拓宽其抗菌谱，但其合成成本高、潜在的免疫原性以及在复杂生理环境中的稳定性问题，仍是产业化推进的主要瓶颈。抗毒力因子疗法和免疫疗法理论上可降低耐药选择压力，但其疗效与宿主免疫系统功能状态高度相关，在免疫功能低下患者中效果可能受限，且需要长期临床研究以明确其临床价值［100］。4.2构建多维度协同的未来防控体系针对 S. aureus 所引起的复杂感染，尤其是涉及生物膜形成或深部组织侵袭的感染类型，单药治疗往往难以奏效。多模式联合疗法通过整合不同作用机制的药物，有望突破耐药屏障并提升疗效。例如，将传统抗生素与新型抗菌剂联用，或联合抗毒力抑制剂、免疫调节剂等辅助手段，可产生协同抗菌效应。这种组合不仅可增强杀菌活性，还能通过降低单药剂量以减少毒性反应，并延缓耐药性的出现。如源自中药制剂痰热清的胆酸衍生物鹅去氧胆酸，在体外与阿米卡星联合使用时对S. aureus具有协同杀菌作用，且该协同效应对多种MRSA菌株均有效，包括小菌落变异株、生物膜形成菌株及持留细胞［101］。基础研究与临床研究的结合是抗S. aureus治疗取得突破的关键。当前需要阐明S. aureus在不同感染微环境中的代谢适应特征、持留细胞形成规律以及与宿主免疫系统的复杂互作。这些机制研究不仅揭示其致病本质，也为新靶点的发现和治疗策略的创新提供关键支撑。研究发现，S. aureus的丙酮酸脱氢酶复合物E2亚基是一种保守的兼职蛋白，可激活γδ T细胞介导的保护性免疫应答，为开发突破血清型限制、对耐药菌株有效的新型疫苗提供了新的路径［105］。同时，还需推动更多设计严谨的临床试验，尤其是针对新型抗菌剂的Ⅲ期研究，以获得可靠的疗效和安全性数据，支撑其临床转化。预防策略与疫苗研发是从源头控制S. aureus感染的关键。预防优于治疗是公共卫生的基本原则，在S. aureus感染防控中具有重要意义。除强化医院感染控制措施和社区健康教育外，开发安全有效的疫苗是从源头减少S. aureus感染发生的关键途径。虽然过去数十年S. aureus疫苗研发屡遭挫折，但近年来，以保守抗原或次显性抗原为靶点的策略在改善免疫应答质量方面取得了新的进展［105］。针对透析患者、外科手术患者等高危人群的主动筛查与去定植，以及开发针对特定毒力因子的单克隆抗体实施被动免疫，也是降低感染发生率的重要预防手段。应对S. aureus感染的复杂局面，需要推动基础科学、临床医学、药学、材料科学、微生物学以及公共卫生等多学科的紧密协作。未来应构建整合精准诊断、个体化治疗、多模式联合干预与主动预防的综合防控体系，实现对这一多重耐药病原体传播的有效控制，最终降低其全球疾病负担。5总结S. aureus，尤其是MRSA、VISA和VRSA的广泛传播，对全球抗感染治疗构成了严峻挑战。传统抗生素研发管线增长放缓，而耐药性的快速演化与扩散，使得新型S. aureus策略的研发需求尤为迫切。近年来，相关研究已突破传统抗生素的单一作用模式，探索了纳米抗菌材料、抗菌肽模拟物、噬菌体及其裂解酶、抗毒力抑制剂以及免疫调节疗法等多种创新方法。这些策略通过多靶点作用、生物膜穿透能力或特异性干扰致病过程，为克服现有耐药性提供了新的希望。然而，将这些实验室成果转化为有效的临床治疗仍面临诸多挑战，既涉及病原体自身的遗传可塑性、毒力演变及复杂感染中持留细胞与生物膜带来的治疗难题，也包含新型制剂在规模化生产、质量标准制定、长期体内生物安全性评估及临床转化成本控制等现实问题。应对耐药S. aureus病原体，需要采取整合与精准并重的策略。开发和应用联合用药方案是重要方向，有助于增强杀菌效果并延缓耐药性的出现。同时，快速诊断技术的进步对于实现个体化精准治疗至关重要，能指导临床及时选用最合适的药物。此外，基础研究与临床需求紧密结合，为新型抗感染疗法发现更多具有潜力的靶点。预防理念的强化同样关键，优化医院和社区的感染控制措施、加速有效疫苗的研发、以及加强高危人群的针对性管理，都是不可或缺的环节。最终，有效控制这类病原体的传播，依赖于深入的科学研究、严谨的临床验证，以及微生物学、临床医学、药学等多学科领域的紧密协作。返回搜狐，查看更多

1.Bayer/Vincerx: BAY-943 BAY-943 (VIP943) is the first ADC (Antibody-Drug Conjugate) developed by Vincerx using the company's platform, consisting of an anti-CD123 antibody, a unique linker cleaved by legumain within the cell, and a novel payload of a kinesin spindle protein inhibitor (KSPi). A Phase 1 dose-escalation trial is currently underway to assess the treatment of patients with relapsed/refractory CD123 positive Acute Myeloid Leukemia (AML), B-cell Acute Lymphoblastic Leukemia (B-ALL), or Myelodysplastic Syndromes (MDS) who are unresponsive to standard treatment regimens. The VNC-943-101 study is an open-label, multi-center, Phase 1 dose-escalation study using VIP943 as a monotherapy in patients with relapsed/refractory AML, B-ALL, and MDS. The primary objective of the trial is to determine the safe dosage of VIP943 for further clinical development. Three patients have been dosed in cohort 1 (0.2 mg/kg), and four patients in cohort 2 (0.4 mg/kg). All seven enrolled patients completed the 28-day DLT (Dose-Limiting Toxicity) assessment period. Pharmacokinetic (PK) data indicate that unbound free payload is minimal, consistent with the good safety profile observed preclinically and clinically. 2.AbbVie: Mirvetuximab Soravtansine Mirvetuximab soravtansine (also known as IMGN853, trade name: ELAHRET™) is the world's first antibody-drug conjugate (ADC) for folate receptor alpha (FRα)-positive ovarian cancer, developed by ImmunoGen, which was acquired by AbbVie. The drug was granted accelerated approval by the FDA in 2022; Huadong Medicine has the exclusive rights to it in Mainland China, Hong Kong, Macau, and Taiwan. The data disclosed herein pertain to a Phase II trial of mirvetuximab soravtansine (IMGN853) in combination with pembrolizumab for the treatment of patients with microsatellite-stable (MSS) recurrent or persistent endometrial cancer. Previously, the drug demonstrated good tolerability and single-agent activity in a Phase I dose-expansion study in patients with FRα-positive advanced/late-stage disease. The co-primary endpoints of the current study are objective response rate (ORR) measured according to RECIST 1.1 and the frequency of progression-free survival at 6 months (PFS6). Sixteen patients were enrolled in the first phase of the study; if ≥2 objective responses or ≥2 PFS6 responses were observed, an additional 19 patients would be recruited for the second phase. If a total of 4 objective responses or 8 PFS6 events were achieved, the combination would be considered worthy of further investigation. Results show that as of November 2023, a total of 16 patients had received study treatment, with a median follow-up of 4.7 months (IQR 2.9, 17.3). Among the 16 treated patients, 6 patients (37.5%, 95% CI: 15.2-64.6%) achieved an objective response, including 1 confirmed complete response (CR) and 5 partial responses (PR), with 3 confirmed PRs (18.8%) and 2 unconfirmed PRs (12.5%). Additionally, 31.3% (5/16) of patients had stable disease, with two patients surviving without progression at 6 months. In terms of safety, the most common treatment-related adverse events (TRAEs) included increased AST (50%), blurred vision (44%), fatigue (44%), and diarrhea (43%); two patients (12.5%) experienced a Grade 3 TRAE. Eye toxicity of any grade was reported in 56.3% of patients. 3.Novartis: JBH492 JBH492 is an ADC (Antibody-Drug Conjugate) that targets the CC-Chemokine Receptor 7 (CCR7). It is composed of a humanized anti-CCR7 IgG1 antibody conjugated to the maytansinoid microtubule inhibitor DM4 via a cleavable linker at a specific site. Preclinical studies have shown that this drug possesses effective target-dependent cytotoxic activity, demonstrating potent and durable efficacy in various clinically relevant lymphoma models. This disclosed study represents an ongoing first-in-human, open-label, phase I/Ib, multi-center trial being conducted in patients with relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), which has completed enrollment for the dose-escalation phase. The purpose of dose escalation is to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity, and preliminary efficacy of JBH492 and to determine the maximum tolerated dose (MTD) and the recommended dose. The study indicates that four NHL patients (two with T-cell NHL and two with B-cell NHL) experienced partial remission (PR), and two patients had stable disease, with PR observed at dosages ranging from 2.4 to 3.6 mg/kg every three weeks. Following the data cutoff, one patient with T-cell NHL achieved complete remission (CR) after four treatment cycles. No correlation between CCR7 expression and response could be established (CCR7 expression was observed in all samples from 14 patients). Regarding safety, 23 patients (92%) experienced at least one adverse event (AE) (Grade ≥ 3, n = 11). Fifteen patients (60%) reported treatment-related AEs (TRAEs) (Grade ≥ 3, n = 3). Of the six patients (24%) who had serious AEs (SAEs) (Grade ≥ 3, n = 3), two (8%) had TRSAEs. The most common AEs (≥ 20%) included anemia (32%), thrombocytopenia (28%), neutropenia, and dry eye syndrome (each 20%). There were two deaths due to underlying diseases. 4.ADC Therapeutics: Mipasetamab Uzoptirine Mipasetamab uzoptirine (ADCT-601) is a targeted Axl Antibody-Drug Conjugate (ADC) that consists of a humanized anti-AXL antibody conjugated to the pyrrolobenzodiazepine (PBD) dimer SG3199 via a cleavable linker. AXL is a cell surface receptor tyrosine kinase that is widely expressed in solid tumors (ST), including sarcomas. ADCT-601 has demonstrated antitumor activity in preclinical mouse models of sarcoma, adrenocortical carcinoma, and pancreatic cancer, and has shown clinical activity in ST patients during its first-in-human trials. In a Phase 1b, open-label, dose-escalation and dose-expansion study, patients were treated with ADCT-601 in a 3+3 dose-escalation design every three weeks at increasing dose levels. As of December 4, 2023, among 17 evaluable sarcoma patients according to RECISTv1.1, the best overall response was partial response (PR) (2 patients [11.8%]), including confirmed PR; stable disease (SD) (8 patients [47.1%]); and progressive disease (PD) (7 patients [41.2%]). Tumor reduction was observed at the doses of 7.5mg, 11mg, and 13mg. By week 12, 6/17 patients (35.3%) had not exhibited progression of disease (PD). In terms of safety, the most common treatment-emergent adverse events (TEAEs) of all grades and relationships (≥20%) were hand-foot syndrome (7 patients [38.9%]); anemia (6 patients [33.3%]); maculopapular rash (5 patients [27.8%]); cheilitis and constipation (4 patients each [22.2%]). TEAEs of grade ≥3 occurred in 9 patients (50%). The most common grade ≥3 TEAEs (≥10%) were increased GGT (2 patients [11.1%]). Two dose-limiting toxicities were observed: grade 2 and grade 3 cheilitis at doses of 15mg and 13mg, respectively. Skin reactions of all grades were more pronounced at higher doses. The maximum tolerated dose (MTD) has not yet been determined. 5.Roche: Trastuzumab Emtansine Trastuzumab emtansine is a HER2-targeted ADC that has been approved for the treatment of metastatic breast cancer with HER2 overexpression. HER2 point mutations are present in approximately 1.4% of solid tumors, but the prevalence varies among different tumor types. The TAPISTRY study disclosed here is a Phase II, global, open-label, multi-cohort trial designed to assess the efficacy and safety of several therapies in patients with advanced/metastatic solid tumors. The primary endpoint is the Objective Response Rate (ORR) as assessed by an Independent Review Committee (IRC), with key secondary endpoints including the ORR assessed by the researchers; duration of response; progression-free survival; overall survival rate; and drug safety. As of July 16, 2023, 35 patients with 10 different tumor types were evaluable for efficacy, with Non-Small Cell Lung Cancer (NSCLC) being the most common. After a median follow-up of 7 months, the ORR assessed by IRC for patients evaluable for efficacy was 14.3%; responses were observed in three tumor types: NSCLC (n/N=1/11), breast cancer (n/N=3/5), and endometrial carcinoma (n/N=1/1). The most common adverse events were decreased appetite, fatigue, and nausea (25.7% each). No new safety signals were found. 6.Heidelberg: HDP-101 HDP-101 is a BCMA-targeted ADC (antibody-drug conjugate) developed by Heidelberg, consisting of a BCMA antibody, VA-PABC linker, and an Amanitin derivative HDP 30.2115. Due to its high toxicity, the drug-to-antibody ratio (DAR) is set at 2, and a site-specific conjugation method is used to ensure homogeneity and reduce potential toxicity. As an immunoactivating agent, HDP-101 can induce immunogenic cell death (ICD) and shows synergistic effects with immune checkpoint inhibitors, offering possibilities for combination therapy in a clinical setting. The data disclosed here pertains to a first-in-human, open-label, non-randomized, multi-center, phase 1/2a trial aimed at determining the maximum tolerated dose and establishing a phase 2 trial recommended dose in patients with multiple myeloma. As of November 2023, 18 patients (7 females and 11 males) have been enrolled across 5 sequential dose cohorts with doses of 20, 30, 60, 80, and 100 µg/kg. Preliminary data indicates that the pharmacokinetics of HDP-101 are in line with expectations, and the exposure to HDP-101 is dose-proportional. Patients in cohort 3 exhibited stable disease (SD) after 15 cycles. In cohort 5, there are 4 ongoing patients who have shown promising results after 3-4 cycles: 2 patients achieved partial response (PR), and 2 patients reached SD. In terms of safety, the drug was well tolerated with no dose-limiting toxicities (DLT), including no signs of hepatorenal toxicity, infusion reactions, or ocular diseases. Of the 18 patients across the 5 treatment groups, 17 were evaluable for DLT assessment. 7.Daiichi Sankyo/AstraZeneca: Trastuzumab Deruxtecan Trastuzumab deruxtecan (T-DXd), also known as fam-trastuzumab deruxtecan-nxki, is an antibody-drug conjugate (ADC) that targets HER2, composed of a humanized anti-HER2 antibody, an enzymatically cleavable peptide linker, and a topoisomerase I inhibitor. The disclosed phase 2 DESTINY-Lung05 (DL-05) trial was conducted to evaluate its efficacy in Chinese patients with previously treated HER2-mutant non-small cell lung cancer (NSCLC). This open-label, single-arm, phase 2 trial primarily aimed to assess the objective response rate (ORR) confirmed by an Independent Central Review (ICR); secondary endpoints included ORR confirmed by investigator's assessment (INV), duration of response, disease control rate, progression-free survival, and safety evaluated by both ICR and INV. The results, as of September 23, 2023, demonstrated that the median exposure to T-DXd was 7.9 (0.7-13.5) months. A total of 71 patients experienced drug-related adverse events (AEs), with 51.4% being grade (G) ≥3. The most common G≥3 AEs by grouped terms included neutropenia (26.4%), thrombocytopenia (18.1%), and leukopenia (11.1%). Two patients (2.8%) experienced drug-related AEs leading to discontinuation of treatment. Seventeen patients (23.6%) experienced serious AEs with no G5 determined by INV. Central adjudication identified drug-related interstitial lung disease (ILD)/pneumonitis in 7 patients (9.7%; n=6 G2; n=1 G5). This suggests that the safety profile in the Chinese patient population is consistent with the known safety data.