Eblasakimab

作者：修梦晨 美工：何国红 罗真真 排版：马超 一、引言 特应性皮炎（Atopic Dermatitis, AD）是一种常见的慢性、复发性、炎症性皮肤病，以皮肤敏感干燥、剧烈瘙痒、出现局限性或泛发性湿疹样皮损为主要特征，常伴随过敏性鼻炎、哮喘等其他特应性疾病，严重影响患者生活质量。根据疾病严重程度可分为轻度、中度、重度三级。特应性皮炎在全球范围内影响广泛。流行病学数据显示，儿童患病率约为20%，青少年约为15%，成人约为10%。2019年，全球特应性皮炎患者人数约为6.49亿，预计到2030年，患者规模将扩大至7.55亿。 作为全球疾病负担第一的皮肤病，AD的药物市场需求持续旺盛。2023年已达112.3亿美元，并呈现持续增长趋势，预计将从2024年的118.1亿美元以5.12%的复合年增长率增长至2032年的176.1亿美元（图1）。虽增速略有放缓，但行业整体仍处于持续扩张阶段。 ▲ 图1 全球特应性皮炎市场规模（十亿美元） 二、AD的发病机制：从屏障缺陷到免疫紊乱的多环节调控 特应性皮炎的发病机制是一个由遗传、免疫和环境因素共同参与的复杂过程。遗传因素构成其重要基础，典型表现为皮肤屏障相关基因功能异常，例如FLG基因突变可导致丝聚蛋白的表达降低，进而破坏表皮屏障的完整性，增加经表皮水分流失并改变皮肤表面pH值，从而使皮肤更易受到外界刺激和过敏原侵袭。 在免疫层面（图2），皮肤屏障受损使外来过敏原更容易进入皮肤内部并激活免疫相关细胞，尤其是树突状细胞和角质形成细胞，角质形成细胞通过释放胸腺基质淋巴细胞生成素（TSLP）、IL-33、IL-25等炎症因子，激活树突状细胞，诱导其成熟并上调OX40L等共刺激分子，同时强化其Th2极化功能；成熟树突状细胞迁移至淋巴结，通过抗原呈递、OX40L-OX40结合以及分泌少量IL-4，驱动初始CD4⁺T细胞分化为Th2细胞。随后，Th2细胞迁移至皮肤皮损部位，通过分泌IL-4、IL-13、IL-5等细胞因子，介导IgE水平升高、瘙痒及炎症。此外，在疾病的不同阶段，Th1、Th17及Th22等T细胞亚群也参与调控，共同促进慢性炎症延续及皮肤增厚等病理改变。 ▲ 图2 特应性皮炎的病理生理学 环境因素则在遗传与免疫基础上进一步推动疾病的发展与加重，包括空气污染、低湿度气候、城市化生活方式以及心理压力等。其中，污染物和干燥环境会直接破坏皮肤屏障并诱导氧化应激，使皮肤更容易发生炎症。多种环境刺激的叠加作用既可触发疾病，也会加重原本已经受损的皮肤屏障和免疫反应，形成恶性循环。因此，特应性皮炎是一种由遗传基础、免疫失衡以及环境诱因共同作用而形成的复杂多因素疾病。 三、AD的治疗：从传统疗法到精准靶向治疗 随着对AD发病机制认识的不断深化，AD治疗已从早期的糖皮质激素、环孢素等非特异性药物，逐步发展为局部靶向药物（如克立硼罗）和系统性靶向药物（如度普利尤单抗等生物制剂、JAK抑制剂等小分子靶向药），覆盖人群也从成人逐步拓展至儿童乃至婴幼儿，治疗精准性与安全性均持续提升，实现了从“非特异性传统疗法”向“精准靶向疗法”的升级迭代（图3）。 ▲ 图3 特应性皮炎治疗药物的发展历程 01 传统治疗 ▶ 非药物治疗：非药物治疗是特应性皮炎的一线治疗策略。采用合理的皮肤清洁策略，并持续使用保湿剂、润肤剂，可减少经表皮失水量（TEWL）并增强皮肤屏障的锁水能力，防止过敏原及微生物入侵。 ▶ 外用药物治疗：对于非药物治疗无效的难治性患者，需升级至外用药物治疗。该治疗类别包括处方级保湿剂（按医疗器械监管）、外用糖皮质激素（TCS）、外用钙调神经磷酸酶抑制剂（TCIs）等。其中，TCS是目前AD传统治疗的一线药物，其通过与胞质内糖皮质激素受体（GR）结合发挥抗炎作用。目前，全球已有10款治疗AD的TCS药物获批上市，例如氢化可的松软膏，糠酸莫米松。TCIs则是通过特异性抑制钙调神经磷酸酶的活性，发挥阻断T淋巴细胞活化的作用，目前有2款治疗AD的TCIs获批上市，分别是他克莫司和吡美莫司。尽管外用药物是标准治疗手段，但由于其疗效有限，且可能引发皮肤变薄、给药部位疼痛、灼烧感及刺痛等问题，因此，仍有相当比例的中重度AD患者需要联合系统治疗。 ▶ 小分子免疫抑制剂治疗：对于局部外用药物疗效不佳的重度特应性皮炎患者，可采用环孢素 A（CsA）、甲氨蝶呤（MTX）、硫唑嘌呤（AZA）、吗替麦考酚酯（MMF）等小分子免疫抑制剂进行治疗。然而，免疫抑制剂类药物长期全身使用可能带来一系列不良反应，如胃肠道不适、肝肾功能损伤、骨髓抑制和血栓等。 ▶ 光疗：当一线局部治疗与传统全身性治疗效果不佳、存在禁忌症或患者耐受性较差时，光疗是特应性皮炎临床公认的二线干预方案。根据美国皮肤病学会（AAD）指南，窄谱中波紫外线（NB-UVB）光疗适用于中重度AD患者，它能诱导DNA光产物生成，干扰转录并抑制增生性表皮特有的快速细胞分裂；此外，光疗引发的氧化应激还能抑制抗原提呈及树突状细胞介导的T细胞活化。尽管光疗在AD治疗中具有确切疗效，但也存在诸多局限性，如轻则出现光化性损伤、红斑，重则可能诱发黑色素瘤、白内障等严重病变。 综上，由于传统治疗方式缺乏精准靶向性且易引发不良反应，因此难以满足临床对“低毒高效”的治疗需求。随着AD发病机制研究的不断深入，尤其是Th2炎症、细胞因子网络及关键信号通路在疾病发生发展中的核心作用逐渐明确，靶向关键分子和通路的精准治疗策略应运而生，为AD治疗开辟了更加针对性和高效的新途径。 02 系统性靶向治疗 ▶ 生物制剂：对于经局部治疗后病情仍难以控制的中重度特应性皮炎患者，需采用生物制剂（如单克隆抗体）进行系统性治疗干预。而这类抗体药物的临床应用，离不开从靶点发现到技术落地的持续演进：自1990s–2000s年间IL‑4、IL‑13等核心靶点被发现以来，AD的免疫发病机制逐渐明确。2017年，度普利尤单抗（Dupilumab）的上市标志着AD大分子药物时代的开启，实现了从“靶点探索”到“临床验证”的跨越。随后，AD抗体药物逐步进入“多靶点布局、全球及本土产品商业化”阶段。目前，IL‑4Rα/IL‑13靶点已形成成熟管线，而OX40等新靶点药物也进入临床后期研发阶段。本土药企的自研产品，如司普奇拜单抗，也在2024年后实现上市突破。整体管线正快速发展，朝着“覆盖更多炎症通路、适配不同患者群体”的方向推进（图4）。 ▲ 图4 特应性皮炎抗体药物的发展历程（Ⅲ期临床及以上阶段，2025年12月） 抗体药物通过特异性靶向AD致病相关的关键免疫细胞及细胞因子，阻断其介导的炎症反应通路与信号转导，从而有效抑制由此引发的皮肤屏障功能障碍及瘙痒反应，实现精准治疗。该类药物疗效显著且安全性较高，能精准调控病理免疫通路，为中重度患者提供了全新的治疗选择。经统计，目前有五款治疗AD的单克隆抗体药物获批上市（表1），分别是靶向IL13的来金珠单抗（Lebrikizumab）和曲罗芦单抗（Tralokinumab）、靶向IL31Rα奈莫利珠单抗（Nemolizumab）、靶向IL-4Rα的司普奇拜单抗（Spesolimab）和度普利尤单抗（Dupilumab）。度普利尤单抗作为首个靶向白细胞介素-4受体α亚基（IL-4Rα）的全人源化IgG4型单克隆抗体，2024年，该药全球销售额高达130.72亿欧元（约141亿美元），展现出强劲的市场增长势头，超越艾伯维的修美乐，跃升为自身免疫领域新一代的“药王”。 ▼ 表1 全球已上市特应性皮炎单抗药物总结 （2025年12月） 此外，我们对AD领域在研抗体药物所覆盖的49个靶点进行了系统梳理与统计（图5）。其中既包括IL-4Rα、IL-13、IL-31Rα等已有上市药物对应的成熟靶点，也涵盖了TSLP、OX40L、OX40等近年来逐步进入研发视野的新兴靶点。 ▲ 图5 特应性皮炎抗体药物靶点在研项目分布图 （2025年12月） (1) IL-4/IL13/IL4Rα/IL13α1 IL-4与IL-13作为特应性皮炎发病机制中核心的Th2型细胞因子，具有高度同源性且共享IL-4Rα受体亚基，其产生以活化的Th2细胞为主，2型固有淋巴细胞（ILC2s）、肥大细胞、嗜碱性粒细胞等固有免疫细胞也可少量分泌。二者通过结合靶细胞表面的IL-4Rα/IL-13Rα异二聚体受体，激活JAK/STAT等下游信号通路（图6），促进初始CD4+ T细胞向Th2细胞极化、抑制Th1/Th17细胞分化，刺激B细胞产生IgE抗体。基于其关键病理作用，靶向IL-4/IL-13通路的治疗已成为AD精准治疗的核心策略，度普利尤单抗、司普奇拜单抗等IL-4Rα靶向药物可同时阻断二者信号，曲罗芦单抗、来金珠单抗等IL-13特异性拮抗剂也展现出显著疗效，为中重度AD患者提供了重要治疗选择。 (2) IL31/IL31Rα IL-31主要由Th2细胞产生，是特应性皮炎中瘙痒-搔抓循环的关键驱动因子。其作用机制为：通过与免疫细胞(如活化的巨噬细胞、树突状细胞)、角质形成细胞和皮肤周围神经表面的IL-31受体（IL-31Rα/OSMRβ异二聚体组成）特异性结合，激活下游JAK/STAT、MAPK等信号通路（图6）。代表药物有奈莫利珠单抗（Nemolizumab），其通过特异性结合IL-31Rα，阻断IL-31介导的信号传导。 ▲ 图6 特应性皮炎Th2型免疫应答中的JAK-STAT信号通路 (3) TSLP 胸腺基质淋巴细胞生成素（TSLP）主要由角质形成细胞在受到外界刺激（如过敏原、病原体或物理损伤）后分泌释放，能够有效激活皮肤局部树突状细胞，增强其抗原呈递能力并诱导其表达共刺激分子，进而促进初始T淋巴细胞活化并向Th2表型极化，驱动以IL-4、IL-13等2型细胞因子为核心的炎症应答（图7）。在特应性皮炎患者中，血清及皮损局部组织内TSLP水平均显著升高，其表达强度与疾病活动度及严重程度呈正相关。代表药物有替泽普单抗（Tezepelumab），二期临床已经展现出了显著的疗效。 ▲ 图7 TSLP在特应性皮炎发病机制中的作用 (4) OX40/OX40L OX40受体及其配体OX40L均属于肿瘤坏死因子（TNF）超家族成员，OX40受体主要表达于T细胞表面，而OX40L的表达范围更为广泛，包括抗原呈递细胞、内皮细胞及气道平滑肌细胞等，二者的相互作用可介导T细胞活化、分化及存活（图8）。在AD皮损组织中，表达OX40的效应T细胞数量增加。抗OX40单克隆抗体通过阻断OX40与其配体OX40L的结合，抑制下游信号通路，从而减少T细胞的增殖、存活及记忆性T细胞的形成，并降低包括Th1、Th2、Th22和Th17在内的多个T细胞亚群功能，缓解疾病慢性化进程。目前国外有多款OX40/OX40L单抗正在研发，包括罗卡替珠单抗（Rocatinlimab）、替拉珠单抗（Telazorlimab）及阿莫利珠单抗（Amlitelimab）等，从已公布的临床研究数据来看，该类靶向药物在治疗终止后仍能维持持续的临床应答效应，为降低AD患者停药后的疾病复发风险提供了潜在的治疗策略。 ▲ 图8 OX40/OX40L在特应性皮炎发病机制中的作用 未来，AD生物制剂的治疗将围绕“多靶点协同抑制、分子形式迭代、个体化分段管理”形成核心趋势：一是开发双靶或三靶药物（如同时阻断IL-4Rα与IL-31Rα的双特异性抗体）以覆盖更复杂的炎症通路并提高整体疗效；二是持续挖掘新的治疗靶点（例如IL-22、IL-33等）以拓展治疗管线；三是聚焦长效化与给药优化，研发长效制剂（如半衰期延长型抗IL-13单克隆抗体APG777）及抗体融合蛋白、纳米抗体等新型分子，拓展皮下注射长效剂型与局部外用制剂，减少给药频次，提升特殊人群依从性；四是推动精准医学与个体化治疗，通过生物标志物或表型分型指导疗法选择，从而提高治疗匹配度和效果。 03 小分子靶向药物 抗体类生物制剂虽实现了精准靶向治疗，但仍存在给药不便（需注射）、靶点覆盖局限（多聚焦细胞外单一通路）及价格偏高的短板，无法满足部分患者（如对生物制剂应答不佳者）的治疗需求；而小分子靶向药物可穿透皮肤屏障或直接进入细胞内调控JAK-STAT等多通路，适配疾病复杂发病机制，且其化学合成工艺成熟、成本更低，口服或外用剂型大幅提升用药便捷性与可及性，因此成为特应性皮炎精准治疗体系的重要补充。 (1) Janus激酶抑制剂（JAKi） 是一类靶向JAK-STAT通路的新兴治疗药物，通过竞争性结合JAK的ATP结合位点，阻止JAK自身磷酸化与激活，从而中断JAK-STAT通路传导，减少促炎因子产生。目前，有六种JAKi已获批上市（表2），分别是三种口服JAKi：巴瑞替尼、阿布昔替尼及乌帕替尼，用于治疗中重度AD患者；以及三种外用JAKi：德戈替尼、艾玛昔替尼、芦可替尼，用于治疗轻度至中度AD患者。但需注意的是，口服JAKi作为具有全身生物利用度的小分子药物，其潜在不良反应风险是临床应用中需重点考量的问题。FDA目前要求所有JAK抑制剂的药品说明书中均须纳入黑框警告，明确提示该类药品可能伴随严重感染、恶性肿瘤、主要不良心血管事件、血栓形成等风险。 (2) 磷酸二酯酶4抑制剂（PDE4i） 能选择性抑制PDE4，升高cAMP水平，从而下调促炎细胞因子的产生。目前有3款治疗AD的PDE4i获批上市（表2），分别是克立硼罗、地法米司特、罗氟司特。其中，外用PDE4i的不良反应以局部表现为主，多为用药部位出现烧灼感、刺痛感、红斑、脱屑及皮肤干燥等症状。多发生在治疗初期，程度多为轻度至中度，随皮肤适应后逐渐缓解。 (3) 芳香烃受体（AHR）调节剂 通过激活AHR，调控角质形成细胞分化和屏障修复相关基因（如丝聚蛋白）表达，从而抑制Th2/Th22型炎症反应，改善皮肤屏障并减轻炎症，代表药物有本维莫德乳膏（表2）。但目前临床数据有限，潜在的长期风险仍需进一步验证。 ▼ 表2 全球已上市特应性小分子靶向药物总结 （2025年12月) 四、总结及展望 特应性皮炎作为一种与免疫失衡、遗传易感性及环境因素密切相关的慢性炎症性皮肤病，其临床管理与机制研究已取得阶段性突破，为后续研究奠定了坚实基础。当前AD治疗体系已形成“分层干预”的核心框架：轻中度患者以局部治疗为主，如外用糖皮质激素和钙调磷酸酶抑制剂，通过局部抗炎与免疫调节控制皮损；中重度或外用治疗不佳的难治性患者则可采用生物制剂、JAK抑制剂等靶向药物，实现全身性炎症的精准调控。基于生物制剂的靶向优势与特应性皮炎的异质性病理特征高度契合，以及单一药物应答不足时，不同靶向药物的联合/混合疗法，未来数年，生物制剂将在特应性皮炎治疗市场中占据主导地位。 尽管现有治疗已显著改善患者预后，但AD的复杂性仍决定了研究需向更深层次推进。未来研究应聚焦三大核心方向：其一，开展跨人群的长期结局追踪研究，明确现有及新型治疗手段在不同年龄、遗传背景患者中的疗效稳定性与安全性差异，为临床用药的个体化选择提供循证依据；其二，基于AD的遗传易感性特征，深化基因组学与转录组学研究，构建以个体分子图谱为核心的个性化治疗模型；其三，推动纳米技术在给药系统中的应用，依托纳米颗粒的靶向递送特性，解决传统药物皮肤渗透不足、全身不良反应显著等问题，通过提升药物生物利用度与剂量可控性，优化治疗效能。 综上，AD研究已从“机制阐释”迈入“精准干预”的新阶段。随着多学科交叉技术的融合应用与循证医学证据的不断积累，未来AD治疗将实现“机制精准解析、方案个性化定制、给药高效安全”的目标，为患者提供更优质的临床获益。 Sanyou 10th Anniversary: Atopic Dermatitis: From Immune Dysregulation to Precision Targeted Therapy Revolution 1. Introduction Atopic dermatitis (AD) is a common chronic, relapsing inflammatory skin disease characterized by dry and sensitive skin, intense pruritus, and localized or generalized eczematous lesions. It is frequently associated with other atopic disorders such as allergic rhinitis and asthma, severely impairing patients’ quality of life. According to disease severity, AD is generally classified into mild, moderate, and severe forms. AD represents a significant global health burden. Epidemiological studies indicate a prevalence of approximately 20% in children, 15% in adolescents, and 10% in adults worldwide. In 2019, the global number of patients with AD was estimated at approximately 649 million, and this figure is projected to rise to 755 million by 2030. As the leading skin disease in terms of global disease burden, AD continues to generate strong demand in the pharmaceutical market. In 2023, the global AD market reached USD 11.23 billion and is expected to grow from USD 11.81 billion in 2024 to USD 17.61 billion by 2032, at a compound annual growth rate (CAGR) of 5.12% (Figure 1). Although the growth rate has moderately slowed, the market remains in a sustained expansion phase. ▲ Figure 1. Global atopic dermatitis market size (USD billions) 2. Pathogenesis of AD: Multilevel Regulation from Barrier Dysfunction to Immune Dysregulation The pathogenesis of AD is a complex, multifactorial process involving genetic susceptibility, immune dysregulation, and environmental triggers. Genetic factors constitute a critical foundation of disease development, most notably abnormalities in genes related to skin barrier integrity. For example, mutations in the FLG gene lead to reduced filaggrin expression, compromising epidermal barrier function, increasing transepidermal water loss (TEWL), and altering skin surface pH. These changes render the skin more vulnerable to external irritants and allergens. At the immunological level (Figure 2), barrier disruption facilitates the penetration of exogenous allergens into the skin, activating immune cells such as dendritic cells and keratinocytes. Activated keratinocytes release epithelial-derived cytokines, including thymic stromal lymphopoietin (TSLP), IL-33, and IL-25, which promote dendritic cell activation, maturation, and upregulation of costimulatory molecules such as OX40L. These processes enhance Th2 polarization capacity. Mature dendritic cells migrate to draining lymph nodes, where they drive naïve CD4⁺ T-cell differentiation into Th2 cells through antigen presentation, OX40L–OX40 interaction, and low-level IL-4 secretion. Subsequently, Th2 cells migrate back to lesional skin and secrete IL-4, IL-13, and IL-5, leading to elevated IgE production, pruritus, and inflammation. In different disease stages, other T-cell subsets—including Th1, Th17, and Th22—also participate in disease modulation, collectively contributing to chronic inflammation and epidermal hyperplasia. ▲ Figure 2. Pathophysiology of atopic dermatitis Environmental factors further exacerbate disease development on this genetic and immunological background. Air pollution, low-humidity climates, urban lifestyles, and psychological stress can directly impair the skin barrier and induce oxidative stress, thereby amplifying inflammatory responses. The combined effects of multiple environmental insults can both initiate disease onset and aggravate pre-existing barrier and immune dysfunction, forming a self-perpetuating vicious cycle. Therefore, AD is best understood as a complex disease driven by the interplay of genetic predisposition, immune imbalance, and environmental triggers. 3. Treatment of AD: From Conventional Therapies to Precision Targeted Therapies With increasing insight into AD pathogenesis, therapeutic strategies have evolved from nonspecific immunosuppressive agents—such as topical corticosteroids and cyclosporine—to targeted topical agents (e.g., crisaborole) and systemic targeted therapies, including biologics (e.g., dupilumab) and small-molecule inhibitors (e.g., JAK inhibitors). Treatment indications have expanded from adults to children and even infants, with continuous improvements in precision and safety. This evolution marks a paradigm shift from “nonspecific conventional therapy” to “precision targeted therapy” (Figure 3). ▲ Figure 3. Evolution of therapeutic agents for atopic dermatitis 01 Conventional Therapies ▶ Non-pharmacological therapy: Non-pharmacological management represents the first-line strategy for AD. Appropriate skin cleansing combined with consistent use of moisturizers and emollients reduces TEWL, enhances skin hydration, and reinforces barrier function, thereby preventing allergen and microbial penetration. ▶ Topical pharmacotherapy: For patients with inadequate response to non-pharmacological measures, topical pharmacological treatments are required. These include prescription emollients (regulated as medical devices), topical corticosteroids (TCS), and topical calcineurin inhibitors (TCIs). TCS remain the cornerstone of traditional AD therapy and exert anti-inflammatory effects by binding to cytoplasmic glucocorticoid receptors. To date, ten TCS products have been approved globally for AD treatment, including hydrocortisone and mometasone furoate. TCIs, such as tacrolimus and pimecrolimus, inhibit calcineurin activity and prevent T-cell activation. Despite their standard use, topical agents are limited by suboptimal efficacy and potential adverse effects, including skin atrophy, burning, and stinging sensations. Consequently, a substantial proportion of patients with moderate-to-severe AD require systemic therapy. ▶ Small-molecule immunosuppressants: For severe AD refractory to topical therapy, systemic immunosuppressants such as cyclosporine A (CsA), methotrexate (MTX), azathioprine (AZA), and mycophenolate mofetil (MMF) may be employed. However, long-term systemic use is associated with significant adverse effects, including gastrointestinal intolerance, hepatotoxicity, nephrotoxicity, bone marrow suppression, and thrombotic events. ▶ Phototherapy: Phototherapy is considered a second-line intervention for patients who respond poorly to topical and conventional systemic treatments or who have contraindications or intolerance. According to American Academy of Dermatology (AAD) guidelines, narrowband ultraviolet B (NB-UVB) phototherapy is recommended for moderate-to-severe AD. NB-UVB induces DNA photoproducts that disrupt transcription and inhibit hyperproliferative epidermal cell division. In addition, phototherapy-induced oxidative stress suppresses antigen presentation and dendritic cell–mediated T-cell activation. Despite its efficacy, phototherapy carries limitations, including photodamage, erythema, and potential long-term risks such as melanoma and cataracts. Overall, the lack of precise targeting and the risk of adverse effects associated with conventional therapies limit their ability to meet clinical demands for “high efficacy with low toxicity.” As the central roles of Th2 inflammation, cytokine networks, and key signaling pathways in AD pathogenesis have become increasingly clear, precision targeted therapies have emerged, opening new avenues for more effective and disease-specific treatment. 02 Systemic Targeted Therapies ▶ Biologics: For patients with moderate-to-severe AD inadequately controlled by topical therapy, systemic biologic agents—primarily monoclonal antibodies—are required. The clinical success of biologics reflects decades of progress in target discovery and translational development. Since the identification of IL-4, IL-13, and other core targets in the 1990s–2000s, the immunopathology of AD has been progressively elucidated.The approval of dupilumab in 2017 marked the beginning of the biologics era in AD treatment, representing a major milestone from target discovery to clinical validation. Subsequently, antibody development has entered a phase characterized by multi-target strategies and global and domestic commercialization. While IL-4Rα and IL-13 remain mature and well-established targets, emerging targets such as OX40 have advanced into late-stage clinical development. Locally developed biologics, including spesolimab, have achieved regulatory approval after 2024. Overall, the pipeline is rapidly expanding toward broader pathway coverage and patient-specific treatment options (Figure 4). ▲ Figure 4. Development timeline of antibody therapeutics for atopic dermatitis (Phase III and beyond, December 2025) Monoclonal antibodies exert therapeutic effects by selectively targeting key immune cells and cytokines involved in AD pathogenesis, thereby blocking inflammatory signaling cascades, restoring barrier function, and alleviating pruritus. These agents demonstrate robust efficacy and favorable safety profiles, offering transformative treatment options for patients with moderate-to-severe disease. To date, five monoclonal antibodies have been approved globally for AD (Table 1): lebrikizumab and tralokinumab (anti–IL-13), nemolizumab (anti–IL-31Rα), spesolimab (anti–IL-4Rα), and dupilumab (anti–IL-4Rα). Dupilumab, the first fully human IgG4 monoclonal antibody targeting IL-4Rα, achieved global sales of EUR 13.07 billion (~USD 14.1 billion) in 2024, surpassing Humira and becoming a new benchmark therapy in the autoimmune disease field. ▼ Table 1. Approved monoclonal antibodies for atopic dermatitis worldwide (December 2025) A systematic analysis of 49 therapeutic targets currently under investigation in AD is shown in Figure 5. These include established targets such as IL-4Rα, IL-13, and IL-31Rα, as well as emerging targets including TSLP, OX40L, and OX40. ▲ Figure 5. Distribution of antibody drug targets under development for atopic dermatitis (December 2025) (1) IL-4/IL13/IL4Rα/IL13α1 IL-4 and IL-13 are central Th2 cytokines in AD pathogenesis. They share structural homology and the IL-4Rα receptor subunit and are primarily produced by activated Th2 cells, with additional contributions from type 2 innate lymphoid cells (ILC2s), mast cells, and basophils. Binding of IL-4 and IL-13 to IL-4Rα/IL-13Rα heterodimeric receptors activates downstream pathways such as JAK/STAT (Figure 6), promoting Th2 differentiation, suppressing Th1/Th17 responses, and inducing IgE production. Targeting this axis represents a cornerstone of precision therapy in AD. Agents such as dupilumab and spesolimab block IL-4Rα signaling, while IL-13–specific antibodies (tralokinumab and lebrikizumab) have also demonstrated significant clinical efficacy. (2) IL31/IL31Rα IL-31, predominantly produced by Th2 cells, is a key mediator of the itch–scratch cycle in AD. It exerts its effects by binding to IL-31Rα/OSMRβ heterodimeric receptors expressed on immune cells, keratinocytes, and peripheral sensory neurons, activating JAK/STAT and MAPK pathways (Figure 6). Nemolizumab, a monoclonal antibody targeting IL-31Rα, effectively interrupts IL-31–mediated signaling and alleviates pruritus. ▲ Figure 6. JAK–STAT signaling pathway in Th2-mediated immune responses in atopic dermatitis (3) TSLP Thymic stromal lymphopoietin (TSLP) is produced by keratinocytes in response to allergens, pathogens, or physical injury. TSLP activates dendritic cells, enhances antigen presentation, induces costimulatory molecule expression, and promotes Th2 polarization, driving type 2 inflammation dominated by IL-4 and IL-13 (Figure 7). Elevated TSLP levels in serum and lesional skin correlate positively with disease activity and severity in AD patients. Tezepelumab, an anti-TSLP monoclonal antibody, has demonstrated significant efficacy in phase II clinical trials. ▲ Figure 7. The role of TSLP in the pathogenesis of atopic dermatitis (4) OX40/OX40L OX40 and its ligand OX40L belong to the TNF superfamily. OX40 is primarily expressed on activated T cells, whereas OX40L is expressed on antigen-presenting cells, endothelial cells, and airway smooth muscle cells. Their interaction promotes T-cell activation, differentiation, and survival (Figure 8). Increased numbers of OX40-expressing effector T cells are observed in AD lesions. Anti-OX40 antibodies block OX40–OX40L signaling, reducing T-cell proliferation, survival, and memory formation, and suppressing multiple T-cell subsets, including Th1, Th2, Th17, and Th22. Several OX40/OX40L-targeting antibodies—such as rocatinlimab, telazorlimab, and amlitelimab—are under development and have demonstrated durable clinical responses even after treatment discontinuation. ▲ Figure 8. The role of OX40/OX40L in the pathogenesis of atopic dermatitis Future trends in biologic therapy for AD are expected to center on multi-target synergy, molecular innovation, and individualized, stage-based disease management. Key directions include: 1. Development of bispecific or trispecific antibodies (e.g., dual blockade of IL-4Rα and IL-31Rα) to address complex inflammatory pathways; 2. Exploration of novel targets such as IL-22 and IL-33; 3. Optimization of pharmacokinetics and delivery through long-acting formulations, antibody fusion proteins, nanobodies, and extended-interval subcutaneous or topical formulations to improve adherence; 4. Advancement of precision medicine using biomarkers or endotype-based stratification to guide therapy selection. 03 Small-Molecule Targeted Therapies Although biologics provide highly precise targeting, they are limited by injectable administration, restricted pathway coverage, and relatively high cost. Small-molecule targeted therapies, by contrast, can penetrate the skin barrier or act intracellularly to modulate multiple signaling pathways, such as JAK–STAT, and offer advantages in manufacturing cost, oral or topical administration, and patient accessibility. As such, they represent a critical complement to biologic therapies in AD. (1) Janus kinase inhibitors (JAKi) JAK inhibitors competitively bind to the ATP-binding site of JAKs, preventing phosphorylation and activation of the JAK–STAT pathway and reducing pro-inflammatory cytokine production. Currently, six JAK inhibitors have been approved for AD (Table 2): three oral agents (baricitinib, abrocitinib, and upadacitinib) for moderate-to-severe disease, and three topical agents (delgocitinib, ruxolitinib, and others) for mild-to-moderate AD. However, due to systemic bioavailability, oral JAK inhibitors carry potential safety concerns. The U.S. FDA mandates boxed warnings for all JAK inhibitors, highlighting risks of serious infections, malignancies, major adverse cardiovascular events, and thrombosis. (2) Phosphodiesterase-4 inhibitors (PDE4i) PDE4 inhibitors selectively inhibit PDE4, leading to increased intracellular cAMP levels and suppression of pro-inflammatory cytokine production. Three PDE4 inhibitors have been approved for AD (Table 2), including crisaborole, difamilast, and roflumilast. Adverse effects of topical PDE4 inhibitors are predominantly local and include burning, stinging, erythema, scaling, and dryness, which are generally mild to moderate and tend to resolve with continued use. (3) Aryl hydrocarbon receptor (AHR) modulators AHR modulators activate the AHR pathway to regulate keratinocyte differentiation and barrier repair–related gene expression, including filaggrin, thereby suppressing Th2/Th22 inflammation and improving barrier function. Tapinarof represents a key example (Table 2). However, long-term safety data remain limited and require further validation. ▼ Table 2. Approved small-molecule targeted therapies for atopic dermatitis worldwide (December 2025) 4. Summary and Outlook Atopic dermatitis is a chronic inflammatory skin disease closely linked to immune imbalance, genetic susceptibility, and environmental factors. Substantial progress in both mechanistic research and clinical management has laid a solid foundation for future advances. Current treatment strategies follow a stratified intervention framework: topical therapies dominate management of mild-to-moderate disease, while biologics and JAK inhibitors enable precise systemic control in moderate-to-severe or refractory cases. Given the strong alignment between biologic targeting strategies and the heterogeneous immunopathology of AD—as well as the potential for combination or sequential targeted therapies when single agents are insufficient—biologics are expected to dominate the AD therapeutic landscape in the coming years. Nevertheless, the complexity of AD necessitates deeper investigation. Future research should focus on three key areas: 1. Long-term, population-spanning outcome studies to assess efficacy and safety across age groups and genetic backgrounds;  2. Integrative genomic and transcriptomic analyses to construct individualized molecular profiles for personalized therapy;  3. Application of nanotechnology-based drug delivery systems to enhance skin penetration, reduce systemic toxicity, and improve bioavailability and dose control.  In conclusion, AD research has transitioned from mechanistic elucidation to precision intervention. With continued integration of multidisciplinary technologies and accumulation of evidence-based clinical data, future AD management will achieve more precise mechanistic understanding, individualized treatment strategies, and safer, more effective therapeutic outcomes—ultimately delivering greater clinical benefit to patients. ▶ Reference [1] Yosipovitch G, Kim BS, Ständer S, Elmariah SB, Prajapati VH, Kabashima K, Gallo G, Rueda MJ, Pierce E, Ding Y, Kwatra SG. Efficacy of Lebrikizumab on Pruritus: A Narrative Review. Adv Ther. 2025 Dec 3. [2] Chai H, Siu WS, Ma H, Li Y. 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Science. 2025 Jan 31;387(6733):eadn9390. 关于三优生物 三优生物是一家以“让天下没有难做的创新生物药”为使命，以超万亿分子库和智能科技驱动的生物医药高科技企业。 公司致力于打造全球顶尖的原创新药创新工场。公司以智能超万亿分子库（AI-STAL）为核心；以干湿结合、国际领先的创新生物药智能化及一体化研发平台为依托；以多样化的业务模式推动全球创新药物的研发及产业化。 公司总部位于中国上海，在亚洲、北美洲、欧洲等多地建立了业务中心，形成了全球化的业务网络，现有投产及布局的研发及GMP场地20000多平方米。 公司已与全球2000多家药企、生技公司等建立了良好的合作关系，已赋能1200多个新药研发项目；已完成50多个合作研发项目，其中10多个协同研发项目已推至IND及临床研发阶段。 公司已申请130多项发明专利，其中30多项发明专利已获得授权，并获得了国家级高新技术企业、上海市专精特新、ISO9001、ISO27001等10余项资质及体系认证。 推荐阅读 三优十周年｜抗衰老-从长生神药到系统与精准干预 战略跃迁｜打造全球顶尖的原创新药创新工场 三优十周年｜恶病质的代谢紊乱与靶向药物的研发态势 三优十周年｜中国药企撬动千亿美元赛道 三优十周年｜平台篇-创新抗体产生平台 三优十周年｜眼科治疗前沿：用抗体药物精准点亮未来 三优十周年｜磁阵列全人源小鼠抗体发现平台 三优十周年｜新“药王”加冕：减重增肌 三优十周年｜抗体药物如何实现精准“狙击”炎症？ 三优十周年｜血液肿瘤治疗革命-精准分层治疗新时代 三优十周年｜抗体药免疫原性全方位解析 三优十周年｜肿瘤免疫2025及2018双诺奖解析 三优十周年｜TCE药物-重塑免疫治疗版图的新力量 三优十周年｜神经系统疾病治疗进展 三优十周年｜AI-STAL 智能超万亿分子库发展历程 三优十周年｜打造全球顶尖的原创新药创新工场

2025年12月12日，《英国医疗保健》报道了一则振奋人心的病例：一名确诊为脑转移性小细胞肺癌的患者V女士，在接受CAR-T细胞疗法治疗满一年后，病情实现完全缓解——她胸部的肿瘤彻底消失，脑部的癌细胞也已坏死并逐步被清除。 值得一提的是，V女士，是 美国首批接受CAR-T细胞疗法治疗脑转移性小细胞肺癌的患者之一 。她的康复案例，直观印证了临床研究的重大价值：能让前沿创新疗法在大规模普及应用前数年，就为深陷困境的患者带去重生的生机。这不仅是CAR-T细胞疗法在实体瘤治疗领域的一次亮眼突破，更给无数晚期癌症患者和家属注入了强心针！ ▲截图源自“uknow” CAR-T治疗实体瘤的里程碑案例：助肺癌脑转移患者逆转命运，从2个月生存期到完全缓解 V女士是美国首批接受CAR-T疗法治疗脑转移性小细胞肺癌的患者之一，她的康复案例直观印证了临床研究的重要价值——能让前沿疗法在大规模普及前，就为绝境中的患者带去生机。而她的这场抗癌之战，并非一帆风顺。 2022年，52岁的V女士因持续声音嘶哑就医，检查结果令人震惊：胸腔内长有一个垒球大小的肿瘤，已压断她两根脊椎骨；进一步诊断确诊为小细胞肺癌伴脑转移。在化疗、放疗、免疫疗法等常规治疗手段相继失效后，医生告知她仅剩两个月的生存期。 然而天无绝人之路，彼时肿瘤内科专家郝忠林医学博士（ZhonglinHao，M.D，Ph.D）正主导一项创新性临床试验——将此前多用于血液癌症的CAR-T细胞疗法，拓展应用于小细胞肺癌治疗。该疗法的核心原理是：提取患者自身的T细胞进行基因改造，使其具备精准识别并攻击癌细胞的能力，再回输患者体内。这项试验，也是CAR-T疗法向肺癌领域探索的关键一步，毕竟该疗法当时尚未获批用于肺癌治疗。 ▼嵌合抗原受体（CAR）的结构 ▲截图源自“uknow” 但遗憾的是，V女士因服用背痛药物存在潜在副作用，不符合临床试验入组条件。为了帮她抓住这最后一线生机，郝医生向FDA申请紧急新药研究授权，让她得以在试验之外接受治疗——这类授权本就是为常规方案用尽、时间紧迫的危重患者量身定制。令人欣慰的是，申请最终获批，V女士于2024年9月9日顺利接受CAR-T治疗。整个输液过程仅90分钟，治疗后仅需住院一天监测潜在副作用。V女士回忆，以往每次放化疗后，她都需要很久才能恢复，而这次治疗后竟毫无不适感，久违地找回了身体正常的状态。 治疗满一年后，令人振奋的好消息传来： V女士的病情实现完全缓解（CR），胸腔内的肿瘤彻底消失，脑部的癌细胞也已坏死清除 。如今的她，已经能够如常开车、购物，尽情陪伴儿孙共享天伦。她也希望用自己的经历鼓舞更多病友：“别像我当初那样恐惧，遇到愿意为你全力争取的医生，一定要选择相信。我坚信，这份生机也能惠及更多人”。 据悉，V女士的主治医生郝忠林博士正在撰写该病例报告，准备公开发表。他认为，这一病例充分展现了CAR-T疗法攻克脑转移实体瘤的巨大潜力，更坚定了科研人员探索创新疗法的决心，为那些治疗选择极其有限的癌症患者开辟新的希望之路。 ▼V女士的主治医师获FDA紧急授权，为她实施 CAR-T 细胞疗法治疗 ▲图源“uknow”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除 CAR-T疗法精准狙击非小细胞肺癌，疾病控制率高达87% 其实，CAR-T疗法早已在肺癌治疗领域崭露头角。早在2025年ASCO大会上，就公布了一项关于CEA CAR-T细胞疗法治疗复发或难治性非小细胞肺癌的Ⅰ期临床试验振奋数据。 ▲截图源自“ASCO” 该研究纳入18例经≥2线治疗后复发的成年转移性非小细胞肺癌患者，患者中位年龄60岁，既往接受治疗线数中位数达4线（范围2-10线）。其中15例患者接受了CEA CAR-T细胞静脉输注治疗，分别采用三种剂量水平（0.75×10⁶、1.5×10⁶和3×10⁶ CEA CAR-T细胞/kg），中位随访时间为5.7个月。 结果显示： 7例患者达到部分缓解（PR），6例病情稳定（SD） ； 最佳疾病控制率（DCR）达87%，客观缓解率（ORR）为47% 。值得关注的是，肿瘤细胞中CEA染色强度≥30%且完整表达、无脑转移的患者，其 无进展生存期（72.7%vs.25.0%，p=0.03） 和 总生存期（90.9%vs.0%，p=0.003）均显著优于其他患者 。 综上，单次输注低氧反应性CEA CAR-T细胞，在复发/难治性非小细胞肺癌治疗中展现出良好疗效与可控安全性。这一发现也凸显了特定NK细胞状态及免疫相互作用，在CEA CAR-T疗法疗效发挥中的潜在价值。 ▼不同剂量下的临床反应 除此之外，既往还报道过一则CAR-T疗法治疗肺癌的振奋案例：一名68岁男性非小细胞肺癌患者，治疗前右侧胸膜存在高摄取转移灶；在接受包含CAR-T细胞疗法的全身治疗后，PET/CT检查显示转移灶高摄取信号明显缩小，直接印证治疗有效。 ▲图源“MDPI”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除 两款创新CAR-T改写胶母治疗格局：国产通用型斩获80%缓解率，双靶点疗法1-2天缩小肿瘤 复发性高级别胶质母细胞瘤患者的中位生存期仅为6-8个月，且治疗选择极其有限。近年来，研究团队通过CRISPR-Cas9技术编辑，破坏内源性T细胞受体以预防移植物抗宿主病，并敲除HLAI类分子减轻宿主抗移植物反应，成功构建出通用型同种异体IL-13Rα2特异性CAR-T细胞（MT026）。 2026年1月6日，《自然通讯》杂志报道了我国一项针对MT026的首次人体临床试验（ChiCTR2000028801）该研究纳入了既往治疗失败、预期寿命较短的高级别胶质瘤患者，采用腰椎穿刺鞘内注射方式给予MT026。 结果显示：在入组的5例患者中， 1例达到完全缓解（CR），3例达到部分缓解（PR），临床缓解率达80% 。这些初步数据，有力支持了局部应用通用型异基因CAR-T细胞疗法治疗复发性胶质母细胞瘤的潜在价值。 ▲截图源自“Nat Commun” 事实上，早在2024年，《自然医学杂志》就曾报道过另一款双靶点CAR-T细胞（CART-EGFR-IL13Rα2）Ⅰ期临床试验（NCT05168423）的振奋数据。该疗法创新性打破传统CAR-T单一靶点局限，同时靶向胶质母细胞瘤高表达的IL13Rα2（75%患者存在）与EGFR（60%患者存在）两种抗原，这项试验共纳入6例复发性胶质母细胞瘤患者。 治疗数据同样令人振奋：所有患者在接受鞘内注射后的1-2天内，复查MRI即显示 肿瘤体积缩小 （详见下图），且 部分患者的疗效更维持了数月之久 ；此外 治疗相关神经毒性处于可控范围 。 ▲图源“PennMedicineNews”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除 综上，两款创新CAR-T细胞疗法的初步临床数据，均为治疗手段匮乏的复发性胶质母细胞瘤患者，点亮了新的生命希望。 GPRC5D CAR-T成多线治疗失败骨髓瘤免疫治疗新利器，PR率71%，CR率35% 靶向B细胞成熟抗原（BCMA）的CAR-T细胞疗法，虽已在晚期多发性骨髓瘤治疗中展现疗效，却存在较高复发率。在此背景下，G蛋白偶联受体C类5组D成员（GPRC5D）被证实为多发性骨髓瘤的全新免疫治疗靶点。 《新英格兰医学杂志》刊载了一项针对GPRC5D靶向CAR-T细胞疗法（MCARH109）的Ⅰ期剂量递增研究（NCT04555551）。该研究共纳入17例经多线治疗的多发性骨髓瘤患者，其中不乏BCMA CAR-T疗法复发的患者，研究设置四种剂量水平开展试验。入组患者中位年龄60岁（范围：38-76岁），既往接受治疗方案的中位数达6线（范围4-14线）。 研究结果显示：全队列中 71%的患者达到部分缓解（PR）及以上疗效 （95%置信区间[CI]：44%-90%），其中 59%达到非常好的部分缓解（PR）及以上，35%实现完全缓解或严格意义上的完全缓解（CR） 。全队列 中位缓解持续时间为7.8个月 （95%CI：5.7个月~未达到），25×10⁶~150×10⁶个细胞剂量组的 中位缓解持续时间同样为7.8个月 （95%CI：4.6个月至未达到）。中位随访10.1个月（95%CI：8.5至未达到）时， 12例达到部分缓解及以上疗效的患者中，50%仍处于无进展状态 ，其中2例患者在接受MCARH109输注后， 随访时间已超过1年 （详见下图A）。 ▲图源“N Engl J Med”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除 值得一提的是，下图展示了接受25×10⁶个CAR-T细胞治疗的患者1，在基线和治疗后的正电子发射断层扫描（PET）图像（详见下图B）。 ▲图源“N Engl J Med”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除 综上，这项研究证实GPRC5D是多发性骨髓瘤治疗中极具潜力的有效免疫靶点，为经多线治疗甚至BCMA CAR-T复发的患者，开辟了全新的治疗方向。 · CAR-T疗法的在招靶点及癌种 · 好消息是，目前有多款CAR-T临床实验正在火热招募中，主要针对 Claudin18.2、GPC3、GUCY2C、PSMA、CEA、间皮素（mesothelin）、MUC-1、BCMA、CD1、CD20 等靶点。以及 胰腺癌、胃癌、肝癌、结直肠癌、神经胶质瘤、肺癌、多发性骨髓瘤、多发性骨髓瘤、弥漫大B细胞淋巴瘤 等癌种。 ▼CAR-T细胞疗法的潜在治疗靶点 小编寄语 时至今日，CAR-T细胞疗法在血液系统恶性肿瘤的治疗领域已取得突破性进展，众多患者从中受益。令人欣慰的是，近年来全球的研究人员从未停止探索的脚步，持续钻研各种新型策略，致力于降低肿瘤抗原异质性，打破免疫抑制的困境，并在胃癌、脑瘤、胰腺癌、肝癌、结直肠癌等实体瘤领域取得了突破性进展！全球肿瘤医学部小编也期望随着越来越多明星靶点的涌现、技术的不断革新，CAR-T疗法可以早日突破价格和癌症治疗的瓶颈，造福更多的癌症晚期患者，实现长期带瘤生存、提高生存质量、降低复发风险的美好愿景！ 参考资料 [1]Wei S,et al.Hypoxia-responsive CEA CAR-T cells therapy for relapsed or refractory non-small cell lung cancer: A single-arm, open-label, phase I trial[J]. 2025. https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.8517 [2]Ma H Y,et al.Advances in CAR T cell therapy for non-small cell lung cancer[J]. Current issues in molecular biology, 2023, 45(11): 9019-9038. https://www.mdpi.com/1467-3045/45/11/566 [3]Li, X,et al.Intrathecal CRISPR-edited allogeneic IL-13Rα2 CAR T Cells for recurrent high-grade Glioma: preclinical characterization and phase I trial.Nat Commun(2026). http://nature.com/articles/s41467-025-68112-6 [4]Bagley S J,et al.Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results[J]. Nature Medicine, 2024, 30(5): 1320-1329. https://www.nature.com/articles/s41591-024-02893-z?fromPaywallRec=false [5]Mailankody S,et al.GPRC5D-targeted CAR T cells for myeloma[J]. New England journal of medicine, 2022, 387(13): 1196-1206. https://www.nejm.org/doi/full/10.1056/NEJMoa2209900 [6]https://uknow.uky.edu/uk-healthcare/markey-patient-cancer-free-after-landmark-car-t-treatment 本文为全球肿瘤医生网原创，未经授权严禁转载